Evidence Synthesis__________________________________

Number 86

Screening for Cervical Cancer: A Systematic Evidence

Review for the U.S. Preventive Services Task Force

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov

Contract No. HHS-290-2007-10057-I, Task Order No. 3

Prepared by:
Oregon Evidence-based Practice Center
Portland, Oregon

Investigators:
Kimberly K. Vesco, MD, MPH
Evelyn P. Whitlock, MD, MPH
Michelle Eder, PhD
Jennifer Lin, MD, MCR
Brittany U. Burda, MPH
Caitlyn A. Senger, MPH
Rebecca S. Holmes, MD, MS
Rongwei Fu, PhD
Sarah Zuber, MSW

AHRQ Publication No. 11-05156-EF-1

May 2011
The literature search conducted for this systematic review was completed in September 2010. A
manuscript that was derived from this systematic review was published in Annals of Internal
Medicine on October 18, 2011. In preparing this manuscript, the review team conducted an
ancillary search in PubMed (September 1, 2010 to August 3, 2011) to identify any updated
information from trials included (or identified as pending) in this review We also queried three
selected experts to determine their knowledge about recent relevant publications on August 8,
2011.

Our search identified nine additional studies, none of which provided additional data on trials
included in this review. Instead, the studies represented four reports from previously identified
cohorts that were contextually relevant1,2 or unrelated3,4 to the focus of this review, one
performance study for a new human papillomavirus test,5 two unrelated reports from trial
authors,6,7 and two public health reports.8,9

None of these reports added any new data to our review. Several were added to the discussion
section in the Annals manuscript, which is available at www.annals.org.

Additional Identified Reports

1. Katki HA, et al. Cervical cancer risk for women undergoing concurrent testing for human
papillomavirus and cervical cytology: a population-based study in routine clinical practice.
Lancet Oncol. 2011;12(7):663-72.
2. Schiffman M, et al. A long-term prospective study of type-specific human papillomavirus
infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort
Study. Cancer Epidemiol Biomarkers Prev. 2011;20(7):1398-409.
3. Castle PE, et al. Variable risk of cervical precancer and cancer after a human papillomavirus-
positive test. Obstet Gyencol. 2011;117(3):650-6.
4. Littell RD, et al. Risk of cervical precancer and cancer in women aged 30 years and older
with an HPV-negative low-grade squamous intraepithelial lesion screening result. J Low
Genit Tract Dis. 2011;15(1):54-9.
5. Castle PE, et al. Evaluation of a new DNA test for detection of carcinogenic human
papillomavirus. J Clin Microbiol. 2011;49(8):3029-32.
6. Kotaniemi-Talonen L, et al. Intensified screening among high risk women within the
organised screening programme for cervical cancer in Finland. Acta Oncol. 2011;50(1):106-
11.
7. Anttila A, et al. Cervical cancer patterns with automation-assisted and conventional
cytological screening: a randomized study. Int J Cancer. 2011;128(5):1204-12.
8. Arbyn M, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011 Apr 6. [Epub
ahead of print]
9. Franceschi S, et al. Eurogin 2010 roadmap on cervical cancer prevention. Int J Cancer.
2011;128(12):2765-74.

Screening for Cervical Cancer ii Oregon Evidence-based Practice Center

This report is based on research conducted by the Oregon Evidence-based Practice Center (EPC)
under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD
(Contract No. HHS-290-2007-10057-I). The findings and conclusions in this document are those
of the author(s), who are responsible for its content, and do not necessarily represent the views of
AHRQ. No statement in this report should be construed as an official position of AHRQ or of the
U.S. Department of Health and Human Services.

The information in this report is intended to help clinicians, employers, policymakers, and others
make informed decisions about the provision of health care services. This report is intended as a
reference and not as a substitute for clinical judgment.
This report may be used, in whole or in part, as the basis for the development of clinical practice
guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage
policies. AHRQ or U.S. Department of Health and Human Services endorsement of such
derivative products may not be stated or implied.
This document is in the public domain and may be used and reprinted without special
permission. Citation of the source is appreciated.

None of the investigators has any affiliation or financial involvement that conflicts with the
material presented in this report.

Suggested Citation: Vesco KK, Whitlock EP, Eder M, Lin J, Burda BU, Senger CA, Holmes
RS, Fu R, Zuber S. Screening for Cervical Cancer: A Systematic Evidence Review for the U.S.
Preventive Services Task Force. Evidence Synthesis No. 86. AHRQ Publication No. 11-05156-
EF-1. Rockville, MD: Agency for Healthcare Research and Quality; May 2011.

Screening for Cervical Cancer iii Oregon Evidence-based Practice Center

Structured Abstract
Purpose: We conducted this targeted systematic evidence review of five key questions to assist
the U.S. Preventive Services Task Force (USPSTF) in updating its 2003 recommendation on
cervical cancer screening.

Data Sources: We conducted literature searches of the Database of Abstracts of Reviews of

Effects, the Cochrane Database of Systematic Reviews, PubMed, the Health Technology
Assessment database, MEDLINE, the Cochrane Collaboration Registry of Clinical Trials, and
PsycINFO from January 2000 through September 2010. We also wrote trial authors for
unpublished data and searched for updated publications from trials of human papillomavirus
(HPV) screening.

Study Selection: We reviewed a total of 4,262 abstracts and 641 complete articles. We included
35 studies reported in 66 articles (only one of which was published at the time of the previous
USPSTF review): five related to initiating cervical cancer screening, four comparing liquid-
based and conventional cytology, 12 evaluating HPV for primary cervical cancer screening, four
evaluating the use of HPV plus cytology screening, one evaluating cytology triage of primary
HPV testing, six evaluating HPV for triage of abnormal cytology to colposcopy, and four
evaluating the harms of HPV testing.

Data Extraction: Two investigators independently reviewed all abstracts against a set of a priori
inclusion criteria for all key questions. One investigator abstracted data from included studies
into evidence tables and a second reviewer checked these data. At least two investigators
critically appraised each study using design-specific quality criteria from the USPSTF,
supplemented by the National Institute of Health and Clinical Excellence criteria for randomized
controlled trials and systematic reviews and the QUADAS tool for quality assessment of
diagnostic accuracy studies. Per the USPSTF methods, studies rated as poor quality were
excluded.

Data Synthesis: Our results focus on trials and studies conducted in countries that have well-
developed approaches to cervical cancer screening and are summarized primarily using
qualitative synthesis due to incomplete reporting and clinical heterogeneity among included
studies.

Key Question 1: Initiation of cervical cancer screening. The incidence of invasive cervical
cancer (ICC) peaks among U.S. women aged 40 to 44 years, and few cases of cervical cancer are
detected in women younger than age 20 (age-adjusted incidence rate of squamous cell
carcinoma, 0.05 cases per 100,000 U.S. women). In contrast, HPV infection is most prevalent
among women younger than age 20 years, occurring in about 20 percent of women, and is
primarily transient in nature (median duration, 13.7 months), as are cytologic abnormalities
(median duration, 8.7 months). Women younger than age 25 years have a higher proportion of
false-positive Pap smears (age 15 to 19, 3.1%; age 20 to 24, 3.5%) than women aged 25 to 39
years (age 25 to 29, 2.1%; age 30 to 39, 2.6%). A large case-control study in the United
Kingdom including 4,012 women with invasive cancer and 7,889 controls found that cervical
cancer screening among women younger than age 25 was not associated with a decreased

Screening for Cervical Cancer iv Oregon Evidence-based Practice Center

incidence of cervical cancer diagnosis prior to the age of 30, although an impact on stage IB+
cervical cancer in women aged 25 to 27 years could not be ruled out. An overall protective effect
of screening was not demonstrated until age 32 years, at which time screening was associated
with a 45 percent reduction in the incidence of ICC diagnosis between the ages of 35 and 39
years (odds ratio, 0.55 [95% CI, 0.44 to 0.69]).

Key Questions 2 and 4: Liquid-based cytology compared to conventional cytology. Liquid-based

cytology (LBC) and conventional cytology (CC) did not differ significantly in measures of
relative sensitivity or absolute sensitivity or specificity for detection of cervical intraepithelial
neoplasia (CIN)2+ or CIN3+ at any cytologic threshold. In two large randomized trials
(n=134,162; age 25 to 64 years), LBC yielded a lower proportion of unsatisfactory slides than
conventional cytology (0.4% and 2.6% of LBC slides vs. 1.1% and 4.1% of CC slides).

Key Question 3: HPV primary screening alone or followed by cytology triage.

Women aged 35 years and older. In a large fair-quality Italian randomized controlled trial
(RCT) (NTCC Phase II) testing Hybrid Capture 2 (HC2) high-risk HPV screening against CC in
35,471 women aged 35 to 60 years, about twice as many CIN3+ or CIN2+ cases were detected in
the HPV arm relative to CC after a single round, with relatively decreased CIN3+ in the second
screening round (RR, 0.23 [95% CI, 0.07 to 0.82]). Cumulative relative CIN3+ detection was
increased after a second screening round (which included cytology only) and 3.5 median years of
followup (RR, 1.57 [95% CI, 1.03 to 2.40]), with about the same number of invasive cancer
cases detected in both arms. Since women with a positive HPV test or atypical squamous cells of
undetermined significance (ASC-US) cytology were immediately referred for colposcopy,
baseline colposcopies were much higher in the HPV arm (5.8%), compared with cytology
(2.5%). Trial investigators pooled invasive cancer from these primary HC2 results (NTCC Phase
II) with HC2-CC co-testing results (NTCC Phase I) due to insignificant statistical heterogeneity
between trials. Pooled results suggested decreased invasive cancer in women aged 35 years and
older who were screened with HPV (6 total ICC cases in the HPV screening arms compared to
15 in the CC only arms; p=0.052). However, cancer outcomes would ideally come from
comparable screening strategies and reflect clearly similar opportunities for diagnosis through
comparable delivery of colposcopies and/or long enough followup with registry linkages to allow
disease ascertainment outside the screening program. Reported data on cumulative burden or
relative harms were lacking, since neither cumulative colposcopies nor cumulative relative
positive predictive value (PPV) over the screening rounds were reported, nor compared between
HPV and cytology screening. In absolute test performance studies, HC2 was much more
sensitive (about 40% or higher relative sensitivity), but less specific (3 to 5% relatively less
specific) than CC for CIN2+ or CIN3+ at a threshold of ASC-US or low-grade squamous
intraepithelial lesion (LSIL) in women aged 30 years and older.
A very large fair-quality trial in 59,757 Finnish women aged 35 to 65 years compared
primary HC2 screening (followed by CC triage for positive HPV tests) to CC screening alone at
a colposcopy referral threshold of LSIL+. HPV with cytology triage tended to identify about
one-third more CIN2+ or CIN3+ cases than CC alone after a single screening round (and at least
2 years of followup). However, extended followup (mean, 3.3 years) after this first screening
round with linkage to registry data was required to demonstrate a significant increase in CIN3+
(RR, 1.77 [95% CI, 1.16 to 2.74], including 11 ICC/adenocarcinoma in situ (ACIS) cases in

Screening for Cervical Cancer v Oregon Evidence-based Practice Center

HPV arm and 6 ICC/ACIS cases in CC only arm). In terms of colposcopy, cytology-triaged HPV
screening and cytology screening alone resulted in about the same number of immediate referrals
(about 1%), with slightly more women identified for retesting (and possible colposcopy referral
in the future) in the HPV-cytology triage arm (7.2%), compared with CC (6.6%). Data for total
colposcopies and compliance with colposcopy and retesting referrals for the entire first screening
round are not yet reported, but will be important, since about half of CIN3+ cases found during
extended followup came from those recommended for retesting. A second screening round at 3
years is planned. As more data from this trial are reported, differences with U.S. practice,
including cytology referral and CIN treatment thresholds, will also need to be considered.

Women younger than age 35 years. In the fair-quality Italian NTCC Phase II trial in 13,725
women aged 25 to 34 years, HC2 screening detected about four times the amount of CIN2+ and
CIN3+ cases as CC after a single round, with relatively decreased CIN3+ in the second screening
round (0.20 [95% CI, 0.05 to 0.93]). Cumulative detection of both CIN2+ and CIN3 was at least
doubled in the HPV arm relative to CC (after a second round of CC screening only in both arms),
with almost no invasive cancer cases in either arm. Pooled results for invasive cancer across the
NTCC Phase I and II trials in younger women were not considered due to significant
heterogeneity in age-specific protocols and statistical tests of between-trial results in younger
women. Only baseline colposcopy referrals were reported, and these were markedly increased in
the HPV primary screening arm (13.1%), compared with CC (3.6%). In the single study
reporting absolute test performance for HPV alone in women younger than 30, sensitivity was
relatively increased for CIN2+ or CIN3+ (23 to 27% higher than cytology at ASC-US+
threshold), while specificity was decreased to a much greater degree (11% relatively lower than
cytology) than in older women.
Among 11,580 women aged 25 to 34 years old in the Finnish trial, HC2 with CC triage
was little different from cytology in either CIN3+ detection or immediate colposcopy (2.8 vs.
2.7%), despite a higher percentage (16.7%) of HPV positive results initially. Complete
colposcopy referrals for the entire first screening round will likely be greater in the HPV-
cytology triage arm, since 15.8 percent of younger women—about twice the percentage in the
cytology arm—were targeted for repeat testing. A second screening round at 3 years is planned.

Key Question 3: Combination HPV and cytology screening (co-testing).

Women aged 30 or 35 years and older. Four large fair-quality RCTs (NTCC Phase I,
POBASCAM, Swedescreen, ARTISTIC) compared combined HPV-cytology (co-testing) to
cytology screening alone in 82,390 European women aged 30 to 64 years. Cumulative relative
CIN3+ detection was the same between HPV-cytology co-testing and cytology alone after two
screening rounds in all the RCTs, and most co-testing trials report differences in round-specific
relative CIN detection (e.g., more CIN2+ with co-testing after Round 1, and less CIN3+ with co-
testing after Round 2). Cumulative invasive cancer detection was similar or slightly higher in
cytology alone compared with co-testing, with findings limited due to incomplete reporting of
full followup for all participants, particularly after the second round of screening. Three of four
co-testing trials (POBASCAM, Swedescreen, ARTISTIC) had a high threshold for colposcopy
referral, generally referring women for high-grade squamous intraepithelial lesion (HSIL+)
cytology, with colposcopy referral for HPV positive results (with normal cytology, ASC-US, or
LSIL) only after repeat testing for persistent HPV positivity and/or abnormal cytology. Also,

Screening for Cervical Cancer vi Oregon Evidence-based Practice Center

none of these three trials has complete reporting for Round 2 (and therefore cumulatively) for a
substantial proportion of trial participants (POBASCAM), for the complete followup period
(Swedescreen), or for both (ARTISTIC). Data from a third screening round reported in 2011
from ARTISTIC do not correct these deficiencies, but address 6-year cumulative rates of CIN2+
and CIN3+ development by baseline screening test results.
In the only co-testing trial that found a cumulative increase in relative CIN detection for
any CIN measure (NTCC Phase I), women were referred to colposcopy immediately at a lower
cytology threshold (ASC-US+) or if HPV positive. Relative to cytology alone, this strategy
increased both CIN2+ and CIN3+ after one screening round and cumulative CIN2+ overall;
however, it did not significantly reduce CIN3+ in Round 2 or affect cumulative CIN3+. Invasive
cancers were higher in the cytology arm in both rounds, and therefore cumulatively, but small
numbers complicate interpretation. Cumulative CIN2+ was increased (RR, 1.50 [95% CI, 1.13 to
1.98]), perhaps reflecting overdiagnosis of regressive disease. Indirect comparisons between
NTCC Phase I and II in older women suggest no additional benefit from co-testing above HPV
primary screening alone, but possible increases in false positives. In NTCC Phase I, immediate
colposcopies were much higher (10.6%) with co-testing than with cytology alone (3.0%), and
neither phase of NTCC has reported cumulative colposcopies beyond those from immediate
referral after initial screening in Round 1. Cumulative colposcopies are reported for only two
trials (POBASCAM, ARTISTIC). Cumulative colposcopies were slightly higher in the co-testing
arm (3.4%) of POBASCAM, compared with cytology (2.8%), although both arms received HPV
testing with polymerase chain reaction (PCR) in Round 2, which might minimize differences.
For women aged 30 to 64 years, cumulative colposcopy referrals after two screening rounds
were 6.0 percent in the co-testing (HC2-LBC) arm in ARTISTIC, compared with 4.9 percent in
the LBC only arm. Results from a third screening round are expected from at least one trial
(ARTISTIC), which could be important, since ARTISTIC varied somewhat from other trials in
several round-specific findings. Age-specific ARTISTIC data are not completely reported by
rounds, thus some of these data include the 21 percent of women younger than age 30 years.
Two fair- or good-quality studies reported absolute sensitivity and specificity for HC2-
CC co-testing among 17,885 women aged 30 to 60 years in countries with established cervical
cancer screening programs. Studies used a positive definition from either co-test, so that all HPV
positives met the threshold. For the detection of CIN3+ or CIN2+, HC2 plus cytology was 44 to
56 percent more sensitive than ASC-US+ cytology alone, but was 4.2 to 4.8 percent less specific.
In these studies, the combination of HC2 plus cytology did not differ significantly from the use
of HC2 alone in sensitivity (100% vs. 97 to 98%) or specificity (93 to 94% vs. 94 to 95%) for the
detection of CIN2+ or CIN3+ lesions.
Indirect comparisons in trials and absolute test performance studies suggest that adding
cytology to primary HPV screening (HPV-CC co-testing) does not significantly improve
sensitivity but may decrease specificity compared to HPV alone. More rounds of screening could
help determine if there may be other values for co-testing, such as identification of a cohort
negative on both tests, that are appropriate for prolonged intervals before rescreening.

Women younger than age 30 or 35 years. Two co-testing trials included women younger than
age 30 or 35 years (NTCC Phase I and ARTISTIC). Because complete age-specific results are
not available from ARTISTIC, it is discussed with results for women older than 30, who

Screening for Cervical Cancer vii Oregon Evidence-based Practice Center

represent almost 80 percent of the total sample. Among 11,810 women aged 25 to 34 in NTCC
Phase I, women were referred for ASC-US+ cytology but retested for HPV positive-cytology
normal results. In contrast to other co-testing trials, no impact on CIN3+ in any round or
cumulatively was seen in younger women. CIN2+ detection was relatively greater after Round 1
and cumulatively with co-testing, perhaps reflecting overdiagnosis of regressive disease. No
cancer was found in the co-testing arm, although three cases were found in the cytology only
arm. Although cumulative colposcopies are not yet reported, much higher initial colposcopies
after co-testing compared with cytology (11.9 vs. 4.1%) are consistent with likely increased false
positives and related harms in a co-testing strategy, compared with cytology alone, in younger
women. Very limited absolute test performance data in younger women suggest a single co-test
(with positive defined as LSIL+ or both ASC-US+/HPV+) decreased sensitivity relative to HPV
testing alone, but remained similar to cytology alone, while specificity improved relative to
either HPV testing alone or cytology alone. This strategy mimics triage if either test is positive
(HPV+ or ASC-US+) using the other, and requires both to be positive for colposcopy referral.

KQ3: HPV for triage of ASC-US or LSIL cytology. Three cross-sectional (two of fair quality and
one of good quality) and one prospective cohort study (of fair quality) compared HC2 with
repeat cytology for the triage of women aged 15 to 78 years with ASC-US cytology results to
colposcopy, two of which also compared HC2 with repeat cytology for triage of LSIL. Pooled
estimates for the detection of CIN2+ among women with ASC-US cytology results demonstrated
a 12 percent higher relative sensitivity for HC2 compared to repeat cytology (95% CI, 0 to 24) at
a threshold of ASC-US, but no difference in specificity. One study evaluated HPV triage of
ASC-US for the detection of CIN3+ and found no difference between HPV and repeat cytology.
HPV testing strategies showed very poor absolute specificity for triaging LSIL (29.9 to 44.0%
for CIN2+, 27.1% for CIN3+). In one small study (n=749) of ASC-US only, age-specific
sensitivity for CIN2+ did not differ by age among women older and younger than age 35 years.
However, in women aged 35 years and older, specificity for HC2 was better than for repeat
cytology (84.8 vs. 74.7%), while specificity for HC2 in women younger than age 35 years tended
to be lower than repeat cytology (60.4 vs. 65.5%).
Two good-quality RCTs evaluated HPV testing and repeat cytology versus repeat
cytology alone for triage of ASC-US and LSIL Pap smears. Women were referred for HPV+ in
either trial, for cytology of HSIL+ in the ALTS trial, or for ASC-US+ in the Swedish trial.
Among women aged 18 to 35+ years (78% younger than age 35 years) in the ALTS trial, those
triaged with HPV and repeat cytology for ASC-US screening results showed a nonsignificant
increase in CIN3+ detection (RR, 1.24 [95% CI, 0.88 to 1.73]), compared to repeat cytology
alone every 6 months for 2 years. Due to high prevalence of HPV in women with LSIL, 85
percent of women in the HPV-enhanced triage arm were referred to colposcopy, which was
therefore discontinued as an unsuccessful triage strategy. The smaller Swedish trial mixed
outcomes for women referred for either LSIL or ASC-US, but showed a similar impact on
CIN3+ detection (RR, 1.20 [95% CI, 0.88 to 1.63]). Relative CIN3+ detection may be better in
women aged 30 years or older compared to women younger than age 30 years. Both trials
increased relative colposcopies. Neither trial exactly mimics current U.S. practice or guidelines.

Key Question 5: Harms of HPV testing. Four studies that examined the psychological impact of
HPV testing found increased levels of immediate anxiety and distress in women testing positive
for HPV compared to HPV negative women. These differences, however, were resolved at 6-
month followup.

Screening for Cervical Cancer viii Oregon Evidence-based Practice Center

Conclusions: The evidence we reviewed indicates that a reasonable age at which to initiate
cervical cancer screening in women is age 21. Screening before this age is complicated by
relatively high rates of transient HPV and regressive cervical abnormalities, with very few actual
cancer cases. Current data cannot assure that beginning screening after this age is clearly safe,
particularly in the United States, which has no centralized national cervical cancer screening
program.
For cytology-based screening, LBC does not differ from CC in sensitivity, specificity, or
relative CIN detection, but may yield a lower proportion of unsatisfactory slides. Cost, overall
screening strategy, and other considerations may also pertain to local decisions on which
approach to use for collecting cytology samples.
In women older than age 30 years, a single HC2 test is clearly more sensitive for CIN2+
and CIN3+ (about 40% greater) than cytology alone. However, a single HC2 test is also 3 to 5
percent less specific than cytology. Thus, while HPV-enhanced screening strategies offer a
potential disease detection benefit compared with cytology alone, the potential burden due to
increased false-positives is critical to understand, particularly given the relatively low incidence
of cervical cancer and the established practice of repeated cervical screening.
Based on large trials, primary screening using a clinically validated HPV test, such as
HC2, appears very promising in women aged 35 years and older, particularly when coupled with
reflex cytology to triage positive HPV results before colposcopy. HPV testing enhances the
detection of CIN3+, but also increases CIN2+ detection and immediate colposcopy referrals,
compared with cytology alone. Cytology triage of positive HPV results identifies women with
milder abnormalities for further followup and retesting, thus reducing the proportion
immediately referred for diagnostic colposcopy. Eventually, after repeated screening rounds are
reported, this strategy may be shown to reduce overall colposcopies and false-positive related
harms—including some of the overdiagnosis and treatment of regressive disease—which both
absolute test performance and existing trial data suggest are likely with primary HPV screening
alone. While not yet reported, cumulative colposcopy requirements, treatments, and related
harms are essential to determine net benefit from any enhanced CIN detection/cancer prevention
with primary HPV screening. Thus, the net impact of primary HPV screening (with or without
cytology triage) remains to be determined through completion of ongoing trials and more
detailed reporting of potential harms, as well as benefits from completed trials.
Screening with combined HPV/cytology (co-testing) in women 30 years and older is
much more sensitive than cytology alone, but may represent a strategy that adds little to HPV
screening. Based on indirect comparisons between trials and on test performance data, one-time
HPV/cytology co-testing appears to be very similar to HPV testing alone for the detection of
CIN2+ or CIN3+, with similar (or slightly reduced) specificity. Compared with cytology alone,
co-testing trials of repeated screening did not clearly report a consistent disease detection pattern
indicating benefit, although most reported reduced relative CIN3+ detection in the second
screening round, which may suggest benefit. Determination of net program impact is not
possible, since most trials have not yet reported complete cumulative outcomes ascertainment for
the entire study population, nor cumulative colposcopy requirements and related harms. Once
trial data are more completely reported, judgment as to their applicability will be required, since
co-testing trials to date used screening and retesting protocols that are not entirely relevant to
U.S. practice.

Screening for Cervical Cancer ix Oregon Evidence-based Practice Center

 In women younger than 30 years, there are much less data on primary HPV screening
(with or without cytology triage) or co-testing with HPV-cytology. Where available, these
indicate using HPV in any primary screening strategy is associated with a substantially inferior
specificity (about 10 to 11% less specific) compared with cytology. Thus, HPV screening in
younger women is likely to result in substantially more colposcopy referrals, greater regressive
CIN2+ detection and treatment, and increased treatment-related harms, particularly compared
with older women. Current data are inadequate to determine whether, and how much, cytology
triage might mitigate specificity concerns with primary HPV screening performance in younger
women, but caution is warranted.
For all HPV-enhanced primary screening approaches, results to date raise questions about
possible overdiagnosis of regressive (or non-progressive) lesions and/or a high burden for a
small net benefit in the context of frequently repeated screening as is typically done for cervical
cancer in the United States. No available trials report adequate cumulative data on the proportion
of women undergoing repeat testing, resulting colposcopy referrals, rates of treatment and
diagnosis, or treatment-related harms, all of which are critical to addressing the issues of relative
burden and harms of newer strategies relative to cytology. Thus, the net impact of HPV-
enhanced primary screening remains elusive, but may become clearer after more in-depth
reporting from trials reviewed here and reports from ongoing trials and studies, as well as
international efforts to pool results of HPV-enhanced cervical cancer screening trials. Modeling
exercises may also be useful.
A major benefit of HPV-enhanced primary screening could be identification of a low-risk
cohort in whom a prolonged screening interval would be appropriate. Risk-stratifying approaches
have not been directly incorporated into trials to date, and safety data for prolonged screening
intervals in low-risk women based on baseline HPV testing (with or without cytology) are still
accruing from trials and cohort studies. However, ensuring the acceptability of overall program
requirements and feasibility would be important considerations in cervical cancer screening
policy, even after it is shown that a large proportion of women could be safely risk-stratified to
longer screening intervals. Ongoing research in HPV subtypes, as well as HPV-related
biomarkers, could further advance efforts in risk stratification for appropriately targeted
screening.
For the triage of women with ASC-US cytology to colposcopy, a single HC2 test has a
higher sensitivity and similar specificity compared to single repeat cytology at a threshold of
ASC-US for the detection of CIN2+. No additional benefit occurs when HC2 triage is combined
with cytology, but this strategy increases false positives. HC2 does not appear useful for the
triage of women with LSIL cytology because such a high proportion of women will test positive.
HPV testing has few unique harms compared with cytology screening, but a positive HPV test
may increase anxiety and distress, in the short-term only. Further research could be useful.
The most thoroughly studied HPV test for use in cervical cancer screening or triage is
HC2. Data reported in this review primarily reflect results using HC2 at a positive threshold of 1
pg/ml and, to a lesser extent, PCR GP5+/6+. Careful consideration of all aspects of other tests’
performance characteristics (sensitivity, specificity, PPV, negative predictive value) in screening
settings is warranted before substituting tests, particularly in a population-based screening
program.

Screening for Cervical Cancer x Oregon Evidence-based Practice Center

Table of Contents
Chapter 1. Introduction ............................................................................................................... 1
Scope and Purpose ...................................................................................................................... 1
Background ................................................................................................................................. 1
Condition Definition ............................................................................................................... 1
Prevalence and Burden of Disease/Illness .............................................................................. 2
Risk Factors ............................................................................................................................ 3
Etiology and Natural History .................................................................................................. 4
Current Screening Uptake in U.S. Women ............................................................................. 5
Rationale for and Types of Screening/Screening Strategies ................................................... 6
Management of Abnormal Cervical Cytology ........................................................................ 7
Interventions/Treatment of Cervical Intraepithelial Neoplasia............................................... 8
Potential Harms Related to Diagnosis and Treatment of CIN ................................................ 8
Efforts to Prevent HPV Infection .......................................................................................... 10
Current Clinical Practice ....................................................................................................... 10
Previous USPSTF Recommendation ........................................................................................ 11
Chapter 2. Methods .................................................................................................................... 12
Key Questions and Analytic Framework .................................................................................. 12
Literature Search Strategy......................................................................................................... 13
Study Selection ......................................................................................................................... 13
Data Extraction and Quality Assessment .................................................................................. 14
Data Synthesis and Analysis ..................................................................................................... 14
USPSTF Involvement ............................................................................................................... 15
Chapter 3. Results ....................................................................................................................... 16
Key Question 1. When Should Cervical Cancer Screening Begin, and Does This Vary By
Screening Technology or By Age, Sexual History, or Other Patient Characteristics? ............. 16
Key Question 2. To What Extent Does Liquid-Based Cytology Improve Sensitivity,
Specificity, and Diagnostic Yield and Reduce Indeterminate Results and Inadequate Samples
Compared to Conventional Cervical Cytology? ....................................................................... 19
Unsatisfactory Slides ............................................................................................................ 21
Key Question 3. What Are the Benefits of Using HPV Testing as a Screening Test, Either
Alone or in Combination With Cytology, Compared With Not Testing for HPV? ................. 21
1) Primary Screening With HPV Test Alone........................................................................ 22
2) HPV Testing With Cytology Triage of Positive HPV (Reflex Cytology) ....................... 25
3) Combination HPV and Cytology Testing (Co-Testing) ................................................... 26
4) Cytology Testing With HPV Triage of Positive Cytology (Reflex HPV) ....................... 29
Key Question 4. What Are the Harms of Liquid-Based Cytology? ......................................... 31
Key Question 5. What Are the Harms of Using HPV Testing as a Screening Test, Either Alone
or in Combination With Cytology?........................................................................................... 32
Chapter 4. Discussion ................................................................................................................. 35
Summary of Review Findings .................................................................................................. 35
Initiation of Cervical Cancer Screening .................................................................................... 35
Liquid-Based Cytology Compared to Conventional Cytology for Primary Cervical Cancer
Screening................................................................................................................................... 36
HPV-Enhanced Primary Cervical Cancer Screening ................................................................ 37
The Rationale and Potential Pitfalls of HPV-Enhanced Screening ...................................... 38

Screening for Cervical Cancer xi Oregon Evidence-based Practice Center

 Interim Conclusions about HPV-Enhanced Screening From Available Data ...................... 39
Potential Subgroup Considerations With HPV-Enhanced Cervical Cancer Screening ........ 42
Cytology Screening With HPV Triage (Reflex HPV) for ASC-US or LSIL Cytology ....... 44
Harms of HPV Testing.......................................................................................................... 45
Are All HPV Tests the Same? .............................................................................................. 46
Age at Which to Stop Cervical Cancer Screening .................................................................... 46
Limitations ................................................................................................................................ 49
Emerging Issues/Next Steps ..................................................................................................... 51
Future Research ........................................................................................................................ 52
Conclusions ............................................................................................................................... 53
References .................................................................................................................................... 55

Figures and Tables

Figure 1. U.S. Age-Adjusted Cervical Cancer Incidence Rates By Age and Race/Ethnicity .......70
Figure 2. U.S. Age-Adjusted Incidence and Death Rates of Invasive Cervical Cancer By Age ...71
Figure 3. U.S. Age-Adjusted Cervical Cancer Mortality Rates By Age and Race/Ethnicity ........72
Figure 4. Prevalence of High-Risk HPV By Age ......................................................................... 73
Figure 5. Analytic Framework and Key Questions ...................................................................... 74
Figure 6. High-Risk HPV Prevalence and CIN3+ Incidence ....................................................... 75
Figure 7. Comparison of HC2 and Repeat Cytology Sensitivity for the Detection of CIN2+
Among Women Referred With ASC-US Cytology ................................................................ 76
Figure 8. Comparison of HC2 and Repeat Cytology Specificity for the Detection of CIN2+
Among Women Referred With ASC-US Cytology ................................................................ 77

Table 1. Cervical Pathology: Comparison of Cytologic and Histologic Test Results and
Current U.S. Guidelines for Management of Cytologic Abnormalities ................................. 78
Table 2. U.S. Age-Specific Crude Cervical Cancer Incidence Rates By Race ............................ 79
Table 3. Characteristics of Liquid-Based Cytology RCTs and Observational
Studies (KQ2) ........................................................................................................................ 80
Table 4. Characteristics of Liquid-Based Cytology Test Performance for RCTs and
Observational Studies (KQ2) .................................................................................................. 81
Table 5a. Population and Screening Program of RCTs of HPV Screening Strategies for
Cervical Cancer Screening (KQ3) .......................................................................................... 82
Table 5b. Colposcopy Referral, Retesting, and Treatment Protocols of RCTs of HPV
Screening Strategies for Cervical Cancer Screening (KQ3) ................................................... 83
Table 5c. Quality Rating and Limitations of RCTs of HPV Screening Strategies for
Cervical Cancer Screening (KQ3) .......................................................................................... 84
Table 6. Characteristics of RCTs of Cytology Testing With HPV Triage of Positive
Cytology (KQ3). ..................................................................................................................... 86
Table 7. Characteristics of Studies Examining Absolute Test Performance of Primary
Screening With HPV Test Alone and Combination HPV and Cytology Testing (KQ3) ....... 87
Table 8a. Results for RCTs of HPV Screening Strategies in Cervical Cancer Screening,
Women ≥30 or 35 Years of Age (KQ3).................................................................................. 89
Table 8b. Results for RCTs of HPV Screening Strategies in Cervical Cancer Screening,
Women <30 or 35 Years of Age (KQ3) ................................................................................. 91
Table 9a. Absolute Test Performance By Age of Primary Screening With HPV Test

Screening for Cervical Cancer xii Oregon Evidence-based Practice Center

 Alone and Combination HPV and Cytology Testing Among Developed Countries
Only, Women ≥30 Years of Age (KQ3) ................................................................................. 93
Table 9b. Absolute Test Performance By Age of Primary Screening With HPV Test
Alone and Combination HPV and Cytology Testing Among Developed Countries
Only, Women <30 Years of Age (KQ3) ................................................................................. 94
Table 10. Characteristics of Studies Examining Absolute Test Performance of Cytology
Testing With HPV Triage of Positive Cytology (KQ3) ......................................................... 95
Table 11. Results of RCTs for Cytology Testing With HPV Triage of Positive Cytology .......... 98
Table 12. Absolute Test Performance of Cytology Testing With HPV Triage of Positive
Cytology (KQ3) .................................................................................................................... 100
Table 13. Characteristics of HPV Harms Studies (KQ5) ........................................................... 102
Table 14. Outcomes of HPV Harms Studies (KQ5) ................................................................... 104
Table 15. Summary of Evidence By Key Question .................................................................... 105
Table 16a. Relative Detection Ratio By Screening Round for RCTs of HPV Screening
Strategies in Cervical Cancer Screening (Women ≥30 or 35 Years).................................... 111
Table 16b. Relative Detection Ratio By Screening Round for RCTs of HPV Screening
Strategies in Cervical Cancer Screening (Women <30 Years). ............................................ 113
Table 17. European Perspective in Interpreting Comparative HPV Screening Trials ................ 114
Table 18. What Data Are Reported in RCTs of HPV Screening Strategies in Cervical
Cancer Screening .................................................................................................................. 115
Table 19. Cumulative Incidence of CIN3+ By Baseline Testing Status of RCTs and
Cohort Studies With Long-Term Followup Data ................................................................. 117

Appendixes
Appendix A. Terminology and Abbreviations
Appendix B. Detailed Methods
Figure 1. Search Results and Article Flow
Table 1. Search Strategies
Table 2. Exclusion Criteria for Key Questions
Table 3. Quality Rating Criteria
Appendix C.
Table 1. Evidence Table for Age at Which to Begin Screening (KQ1)
Table 2. Evidence Table for Liquid-Based Cytology (KQ2)
Table 3. Evidence Table for Benefits of HPV Testing (KQ3)
Table 4. Evidence Table for Harms of HPV Testing (KQ5)
Appendix D.
Table 1. Studies Excluded From the Review for KQ1
Table 2. Studies Excluded From the Review for KQ2
Table 3. Studies Excluded From the Review for KQ3
Table 4. Studies Excluded From the Review for KQ4
Table 5. Studies Excluded From the Review for KQ5
Appendix E. Screening Benefit Considerations Illustrated by NTCC Phase II Trial
Appendix F. Ongoing and Pending Trials
Appendix G. Recommendations of Other Groups
Appendix H. Cervical Cancer and HPV: Prevalence, Incidence, and Mortality Rates

Screening for Cervical Cancer xiii Oregon Evidence-based Practice Center

Chapter 1. Introduction

Scope and Purpose

We undertook this systematic review to assist the U.S. Preventive Services Task Force
(USPSTF) in updating its 2003 recommendation on cervical cancer screening. During the
planning phase of this evidence review on cervical cancer screening, the Agency for Healthcare
Research and Quality (AHRQ) decided to fund a separate modeling study to be conducted
simultaneously. The USPSTF determined that the scope for both the systematic review and the
modeling study would focus on important clinical questions that could inform effective use of
screening in practice. This systematic review focuses on when to begin screening and on
updating test accuracy and harms data on liquid-based cytology (LBC) and human
papillomavirus (HPV) testing, either alone or in combination with cytology. The modeling study
focuses on the effectiveness of strategies that use different ages at which to begin screening and
different screening intervals.1 These two reports are intended to provide the USPSTF with
complementary information to update its recommendation on cervical cancer screening.

Background
Condition Definition
Two primary histologic abnormalities account for the majority of cancer of the uterine
cervix—squamous cell carcinoma (SCC) and adenocarcinoma. The majority of cervical cancer
cases (70% or more) are SCC, which is thought to arise from the transformation zone of the
cervix.2,3 The transformation zone is the region between the original and subsequent locations of
the junction between the squamous and columnar cells of the cervix (squamocolumnar junction),
which migrates from the exocervix to the distal endocervical canal with advancing age.4
Adenocarcinoma, which develops from the mucus-producing cells of the endocervix, accounts
for approximately 18 percent of cervical carcinomas. The remainder of cervical carcinomas are
adenosquamous (4%) and other carcinomas (5%) or malignancies (1.5%).4
Cervical cancer does not develop suddenly2 and is preceded by precancerous changes of
the cervix. Precancerous changes of the cervix are histologically defined as cervical
intraepithelial neoplasia (CIN) and are identified at varying levels of severity: CIN1, CIN2, and
CIN3. The latter includes CIS (carcinoma in situ, a preinvasive carcinomatous change of the
cervix).5,6 Progression of neoplasia to invasive cervical cancer (ICC) is slow. The rate of
progression of CIN3 to cancer has recently been estimated as 31.3 percent in 30 years. This rate
was determined using retrospective data from an unethical clinical study in New Zealand
between 1965 and 1974 that left a number of women with CIN3 disease incompletely treated or
untreated.6 Other rough estimates from early studies of precancer suggest a 20 to 30 percent risk
of invasion over a 5- to 10-year timeframe.7,8
Screening for cancerous or precancerous changes of the cervix has traditionally been
performed by scraping cells from the cervix and fixing them to a glass slide in a method
developed by Papanicolaou called the Pap smear. The Pap smear is a cytologic screening test
used to detect CIN and early cervical cancer so that these conditions can be managed or treated
to prevent disease progression due to invasive cancer. Cervical cytology results are not

Screening for Cervical Cancer 1 Oregon Evidence-based Practice Center

diagnostic of CIN or cancer, as biopsy and histologic confirmation are required for diagnosis.
While the incidence of SCC of the cervix has declined significantly since the introduction of the
Pap smear,9 the incidence of adenocarcinoma has risen, leaving the optimal method of screening
to detect adenocarcinoma of the cervix uncertain.9
The terminology for reporting the spectrum of cervical cytologic abnormalities is derived
from the Bethesda System and is displayed in Table 1.10 The 2001 Bethesda Workshop was
convened to update terminology initially established in 1988 and revised in 1991.11 Atypical
squamous cells of undetermined significance, or ASC-US, is the least reproducible of all the
cytologic categories and emphasizes that a specific diagnosis cannot be made. Atypical glandular
cell (AGC) abnormalities (previously called AGUS) may be reported as endocervical,
endometrial, or not otherwise specified. The percentage of AGC Pap smears associated with
underlying high-grade disease (CIN2 or worse) is higher than for ASC-US.10 High-grade
squamous or glandular lesions can be seen in 10 to 39 percent of cases of AGC.10 The term
LSIL, or low-grade squamous intraepithelial lesion, includes cellular HPV changes and CIN1.
The term HSIL, or high-grade squamous intraepithelial lesion, includes CIN2 and CIN3. While
LSIL and HSIL are terms generally used to describe cytology, they have also been used to
describe histology. The term CIN2+ is used to indicate CIN2 or worse (CIN2, CIN3, or cancer),
and CIN3+ is used to indicate CIN3 or worse (CIN3 or cancer). Similarly, the term ASC-US+ is
used to indicate ASC-US or worse cytology, LSIL+ to indicate LSIL or worse, and HSIL+ to
indicate HSIL or worse.

Prevalence and Burden of Disease/Illness

The incidence and associated mortality of cervical cancer have continued to decrease in
the United States since the introduction of cervical cytology screening programs in the 1950s and
60s. In 1950, the Centers for Disease Control (CDC) ― Vital Statistics of the United States‖
reported an unadjusted death rate of 10.2 per 100,000 for white women and 18.0 for nonwhite
women (age-adjusted mortality not reported).12 In 2007, age-adjusted mortality had dropped to
2.2 for white women, 4.3 for black women, and 2.4 overall.13 Although these results are based on
ecologic data, these changes have been seen in the United States and other countries with long-
standing population screening and attributed to that screening.14
However, cervical cancer still remains a significant public health issue. Incidence figures
for 2000 to 2008 from the National Cancer Institute’s Surveillance Epidemiology and End
Results (SEER) database suggest that incidence varies significantly by age and race/ethnicity
(Table 2 and Figure 1). The overall age-adjusted incidence rate of cervical cancer is 8.4 per
100,000 women per year. The incidence is highest among Hispanics (12.1 per 100,000 women)
and blacks (10.7) and lowest among nonHispanic whites (7.5), American Indians and Alaska
Natives (7.5), and Asian and Pacific Islanders (7.7) (Figure 1).15 Based on 2004 to 2008 SEER
data, the median age at diagnosis for cervical cancer in all women was 48 years.16 Half of all
incident cervical cancer cases between 2004 and 2008 occurred in women between the ages of
35 and 55 years. The age-adjusted death rate for cervical cancer was 2.5 per 100,000 women in
200717 and the median age for mortality was 57 years.16 Mortality rates increase with age (Figure
2) and also vary by race and ethnicity (Figure 3).17 The national target established in Healthy
People 2010 was a mortality reduction to 2.0 deaths per 100,000 women. For 2010, SEER data
estimate 12,200 new cases of cervical cancer and 4,210 deaths.15

Screening for Cervical Cancer 2 Oregon Evidence-based Practice Center

 Studies of screening history of women diagnosed with ICC repeatedly show that at least
half have been inadequately screened. Studies of women diagnosed with ICC in the 1980s and
1990s in Connecticut18 and California19,20 showed that 50 to 60 percent had not been screened
within 3 years of diagnosis. For comparison, the CDC’s 2008 Behavioral Risk Factor
Surveillance System found that just 17 percent of all adult women in the United States had not
had a Pap test within the past 3 years.21 In the Connecticut study, about half of women diagnosed
with ICC had no screening within 5 years, and about 30 percent had never been screened.18 A
recent study of a high-risk urban population in London diagnosed with ICC between 1999 and
2007 showed very similar results, with 47 percent of women having no screening within 5 years
and 31 percent with no prior screening.22 Inadequate screening might be less of a contributing
factor to cancer diagnosis for younger women. Sasieni and colleagues, for example, found that
just 7 percent of women aged 20 to 24 years diagnosed with cervical cancer had never been
screened or had had a lapse in screening.23 These data also indirectly suggest that relatively rare
rapid-onset cancer in younger women may be less amenable to earlier screening.24

Risk Factors
It is well recognized that infection with oncogenic HPV types is a necessary, although not
sufficient, cause of virtually all cervical cancer.25 The 12 HPV types most strongly associated
with cervical cancer are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Other potentially
carcinogenic HPV types include 26, 53, 66, 67, 68, 70, 73, and 82.26-28 Eight HPV types (16, 18,
45, 31, 33, 35, 52, and 58) account for 95 percent of SCCs positive for HPV deoxyribonucleic
acid (DNA).26 HPV types 16 and 18 alone are responsible for approximately 70 percent of
cervical cancer cases.29,30 Results from a large international collection of cervical tumor
specimens also revealed the presence of HPV DNA in 99.7 percent of cases.31
The prevalence of HPV infection declines with increasing age.32-34 A cross-sectional
study of 9,657 women screened for 13 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52,
56, 58, 59, and 68 ) in 26 sexually transmitted infection, family planning, and primary care
clinics in six U.S. cities demonstrated that the prevalence of high-risk HPV was highest among
women aged 14 to 19 years (35% [95% confidence interval (CI), 32 to 38]), and lowest among
women aged 50 to 65 years (6% [95% CI, 4 to 8]) (Figure 4).34
Although we have not identified a published systematic review of other cervical cancer
risk factors, pooled analyses of data from observational studies worldwide have been conducted
by the International Collaboration of Epidemiological Studies of Cervical Cancer35-37 and the
International Agency for Research on Cancer.38-41 Based on these and other reviews, cervical
cancer risk factors may affect the risk of HPV acquisition, its persistence, or the likelihood of
progression to neoplasia and cancer; however, the specific mechanisms underlying measured
associations with risk are poorly understood.
The risk of acquiring HPV dramatically increases with the number of lifetime sexual
partners.35,42 Coinfection with other sexually transmitted agents such as chlamydia trachomatis
and herpes simplex virus may also be associated with risk of HPV infection.25,38,43,44 Other risk
factors for cervical cancer include high parity (five or more pregnancies) and long-term oral
contraceptive use, each associated with a two- to three-fold higher overall risk of precancer or
cancer,35,36,38,40,41,45 along with younger age at first intercourse and at first pregnancy.35,36
Smoking is clearly associated with increased risk of SCC, but shows no association with the risk
of cervical adenocarcinoma.35,37-39 For SCC, the larger pooled studies show risk increases of 50

Screening for Cervical Cancer 3 Oregon Evidence-based Practice Center

to 60 percent for current smokers.35,37 In a pooled analysis restricted to HPV positive women,
smoking was associated with a larger risk increase (relative risk [RR], 1.95 [95% CI, 1.43 to
2.65]), suggesting that smoking affects HPV persistence or disease progression more than HPV
acquisition.37 Reduced risk of both types of cervical cancer is seen with a history of cervical
screening, although the reduction is larger for SCC than for adenocarcinoma.35

Etiology and Natural History

The progression from HPV infection to cervical cancer occurs over a series of four steps:
1) HPV transmission, 2) acute HPV infection, 3) persistent HPV infection leading to
precancerous changes, and 4) ICC.45 Transmission of HPV to the anogenital region occurs
primarily as a result of skin-to-skin or mucosa-to-mucosa contact.45 Malignant transformation of
HPV-infected cells is believed to be mediated by the integration of the viral DNA into the host
genome. The virus reproduces separately in most low-grade lesions, but the HPV genome may
be integrated into the host’s DNA in many advanced precancerous lesions and most cancer
cases.46
A high proportion of sexually active women become infected with HPV, but only a small
proportion of HPV infections become persistent. Among 4,504 women aged 18 years and older
with a cytologic diagnosis of ASC-US or LSIL, 91 percent of prevalent HPV infections detected
at enrollment cleared within 24 months.47 The probability of persistent infection increased with
duration of infection, such that about two-thirds of infections that had persisted to 18 months
were still present at 24 months. Also, odds of persistent infection were highest in the 50 years
and older age group, compared with those aged 20 years and younger (odds ratio [OR], 1.47
[95% CI, 1.11 to 1.94]).
HPV-associated risks are type-specific, with types 16 and 18 conferring the highest risk
for HPV persistence and progression to high-grade lesions. In an HPV 16 vaccine trial, women
aged 16 to 23 years had HPV DNA testing at 6-month intervals for up to 4 years. Among
unvaccinated women in the placebo arm, the mean duration of incident HPV infections was 17.1
months (95% CI, 15.0 to 19.2) for HPV 16 and 16.6 months (95% CI, 13.4 to 19.7) for HPV
18.48 The proportion cleared at 36 months was 85.3 percent (95% CI, 75.0 to 91.5) for HPV 16
and 91.1 percent (95% CI, 84.6 to 94.9) for HPV 18.48 These studies illustrate that even high-risk
HPV types are quite likely to clear in younger women.
In the same HPV 16 vaccination trial, the rate of progression to CIN2+ at 36 months was
16.5 percent for HPV 16 and 8.2 percent for HPV 18.48 In a U.S. cohort of 20,514 women aged
16 years and older (median age, 34 years) tested at baseline for 13 oncogenic HPV types, the 10-
year cumulative incidence rates of CIN3+ were 17.2 percent (95% CI, 11.5 to 22.9) among HPV
16 positive women and 13.6 percent (95% CI, 3.6 to 23.7) among HPV 18 positive women, but
only 3 percent (95% CI, 1.9 to 4.2) among women who were positive for an HPV type other than
16 or 18.49 Repeated HPV testing is required to identify type-specific incident infection and
clearance.
These data illustrate that HPV infections are very likely to regress, and persistence of
HPV infection is more likely to occur in older women. While HPV 16 and 18 are most likely to
persist and be associated with CIN3 or cancer, a high proportion of HPV 16 and 18 infections
also regress. Regression of HPV infection is presumably due to a successfully mounted immune
response,50,51 and increased incidence and persistence of HPV infections are observed in
immunocompromised populations.42,52 It is unknown whether viral infections resolve as a result

Screening for Cervical Cancer 4 Oregon Evidence-based Practice Center

of complete clearance of the virus or by maintenance of the virus in a latent state.45 While cohort
studies have demonstrated that a viral type can reappear even after it has been thought to have
cleared,53 incident HPV infections may not confer a great deal of risk given the high probability
of clearance and the long time period between HPV infection and cancer development,
particularly among older women.24
Numerous analyses, including large cohort studies, have demonstrated that CIN not only
progresses, but may also regress. In an historical cohort of about 20,000 Toronto women during a
period when lesions were managed conservatively, CIN2 progression to ICC was 0.3 percent
within 2 years, 0.7 percent within 5 years, and 1.2 percent within 10 years.54 Rates of CIN3
progression to ICC were considerably higher (1.6% within 2 years, 2.6% within 5 years, and
9.9% within 10 years). Regression from CIN2 to a second normal smear occurred in 6.9 percent
within 2 years, 29.0 percent within 5 years, and 53.7 percent within 10 years.
Using composite data from cytology, histology, or both to define CIN lesions, a review
summarized studies published between 1950 and 1990 on persistence, regression, and
progression of CIN.55 Over followup from 1 to 25 years, regression or persistence was most
common for CIN1 (57% regressed, 32% persisted, and 1% progressed). For CIN2, 43 percent
regressed, 35 percent persisted, and 5 percent progressed to cancer. For CIN3, regression rates
were 32 percent, persistence rates were 56 percent, and progression rates were greater than 12
percent. Neither the Holowaty54 nor Ostor55 reports discuss treatment for CIN3 specifically, or its
effect on the results reported. The results from an unethical New Zealand study,6 in which
women with CIN3 were untreated or inadequately treated, estimated that 31.3 percent of these
women progressed to cancer within 30 years, compared to 0.7 percent in those with adequate
treatment.
Newer data suggest that CIN1 does not predict any meaningful risk of CIN3.45,56 In
addition, CIN1 diagnoses in the United States are poorly reproduced,45,56 which has also been
established recently for CIN2 diagnoses in the United States and other countries.57,58 Despite
poor reproducibility, data from the ASCUS-LSIL Triage Study (ALTS) trial have been used to
estimate that up to 40 percent of CIN2 detected through colposcopy referral after positive
primary screening tests (cytology and HPV) in younger women may regress, particularly in the
presence of less severe cytology such as ASC-US+, LSIL+, or HPV positive tests that are not
HPV 16 positive.59

Current Screening Uptake in U.S. Women

While it is estimated that around 80 percent of U.S. women have had cervical cytology
screening within the past 3 years,60 screening history varies by educational attainment,
race/ethnicity, and age.61 In 2008, women with low educational attainment (a high-school
diploma, general equivalency diploma, or less) were less likely to report a Pap test within 3 years
than those with some college or more; fewer Asian and American Indian/Alaskan Native women
reported recent Pap smears than other racial/ethnic groups. While 80 to 85 percent of women
aged 18 to 64 years reported at least one Pap test within 3 years in 2008, the proportion of
women aged 65 years and older reporting a similarly recent Pap history was about 50 percent
(down from about 65 percent in 2000). Given the 2003 USPSTF recommendation against
ongoing cervical cancer screening in women aged 65 years and older with a previously adequate
history, it is unclear how to interpret this age difference. Updated information on the screening

Screening for Cervical Cancer 5 Oregon Evidence-based Practice Center

history of women with ICC in all age groups will continue to be important in monitoring the
overall success of cervical cancer screening in the United States.

Rationale for and Types of Screening/Screening Strategies

While the great majority of U.S. women have had recent cytology screening, the majority
of cervical cancer cases occur in those without such a history. Access to health care may be one
concern.62 Even among women with no health care access barriers to screening, however, the
reasons for screening failures are similar. Among 833 women in a health maintenance
organization diagnosed with ICC from 1995 to 2000, most (56%) had no Pap smear within the
previous 36 months, while about one-third represented Pap test failures, and the remainder
failure to followup.63 Race/ethnicity was not a predictor of any type of failure, although high-
poverty area of residence, lower education, and age older than 40 at diagnosis were associated
with lack of recent screening. Data on false-negative results of one-time Pap smears suggest a
failure rate of about 28 to 41 percent in developed countries.20,64 Imperfect sensitivity as well as
errors in sample collection and interpretation across settings underpin the need for frequent
repeated screening and underscore interest in developing more accurate, reliable screening
tests.65 To address these issues, researchers have begun to look for technological advances, such
as using LBC and high-risk HPV tests.65
LBC differs from CC in how the cervical specimen is sent to the cytology laboratory for
evaluation. For CC, the cervical specimen is smeared onto a glass slide immediately after
collection and the slide is either sprayed with or placed in fixative. For LBC, the sample
collected from the cervix is suspended in fixative either by swirling the collection device in the
fixative (ThinPrep, Hologic, Inc., Bedford, MA)66 or by placing the collection device in the
fixative (SurePath, TriPath Imaging, Burlington, NC).67 In the laboratory, the cells in the fixative
are dispersed and suspended, collected by filtration on a membrane, and then transferred onto a
microscope slide in a monolayer.
In recent years, high-risk HPV testing has been incorporated into screening and screening
triage algorithms by the American Society for Colposcopy and Cervical Pathology (ASCCP), as
well as in post-colposcopy and post-treatment surveillance.68,69 High-risk HPV testing is
specified for use as a combined test (co-test) in women aged 30 years and older to determine
rescreening interval in women who are cytology negative and as one possible triage strategy to
determine colposcopy in women with ASC-US+ cytology (discussed more below). Additionally,
HPV genotyping for types 16 and 18 is specified for use as a triage to colposcopy in women aged
30 years or older who have cytology negative, high-risk HPV positive screening results.
There are many methods available for detecting HPV, including in situ hybridization,
polymerase chain reaction (PCR), and Hybrid Capture technology. Hybrid Capture technology
uses specific ribonucleic acid (RNA) probes, hybridization, antibody capture, and signal
amplification to allow rapid, standardized testing of genetic material. The Digene Hybrid
Capture 2 (HC2) high-risk HPV DNA test (Qiagen Inc., Germantown , MD) is the most
commonly used in the United States. In 2000, the Food and Drug Administration (FDA)
approved HC2 for testing patients with ASC-US Pap smear results to determine the need for
referral to colposcopy. In addition, the HC2 high-risk HPV DNA test was approved in 2003 for
use in women aged 30 years or older in conjunction with the Pap smear to assess the absence or
presence of high-risk HPV types.70,71 The high-risk HPV types identified by HC2 include 16, 18,
31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. In 2009, the FDA approved Cervista HR HPV

Screening for Cervical Cancer 6 Oregon Evidence-based Practice Center

(Hologic, Inc., Bedford, MA) for HPV testing for the same indications as HC2.72 Cervista HR
HPV tests for 14 high-risk HPV types, including type 66 as well as those identified by HC2.
There is also an FDA-approved Cervista HPV 16/18 test that individually identifies these two
high-risk HPV types.73 Other HPV test systems are also under development. For example, Roche
Diagnostics manufactures Amplicor HPV, a PCR-based test for 13 high-risk HPV types
approved for use in Europe, Canada, and Japan. There are also two tests in use in Europe that
identify specific HPV types—the Cobas 4800 HPV and Linear Array HPV genotyping tests.
Roche has announced FDA reviews of all three of its tests, and received FDA approval in April
2011 for the Cobas 4800 HPV test (which reports results for HPV 16 and 18 and pooled results
for 12 other high-risk HPV types [31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68]).74
Gen-Probe’s APTIMA HPV assay detects 14 high-risk HPV types and also messenger
RNA (mRNA) from viral oncogenes E6 and E7. The assay is approved for use in Europe, and
Gen-Probe applied for FDA approval in late 2010.

Management of Abnormal Cervical Cytology

According to the American Congress of Obstetricians and Gynecologists (ACOG),
colposcopy with directed biopsy has been the criterion for disease diagnosis and remains the
technique of choice for treatment decisions.75
The process of triaging women with abnormal cytology to colposcopy is now being
influenced by HPV testing.76 Consensus guidelines developed by ASCCP in 2006 state that
either HPV testing or repeat cytology at 6 and 12 months (or immediate colposcopy) are
acceptable for managing ASC-US cytology in women older than age 20 years, although HPV
testing is preferred if LBC or co-collection is available.68 This is because HPV testing may be
performed ― reflexively‖ if the cytologic specimen collected was liquid-based and a residual
sample is still available for HPV testing, or if a separate specimen was collected at the time CC
was performed.
According to the ASCCP algorithm, women with their first ASC-US cytology result and
a negative high-risk HPV DNA test should undergo repeat cytology at 12 months. Women with a
positive high-risk HPV DNA test or a second cytology result of ASC-US or worse within 6 or 12
months should undergo colposcopy. In 2009, ACOG generally supported a similar algorithm
(i.e., immediate colposcopy, high-risk HPV DNA testing with colposcopy if positive, or repeat
cytology in 6 and 12 months).77 Neither ASCCP nor ACOG support HPV DNA testing in
adolescents, and both recommend that adolescents with ASC-US or LSIL cytology have repeat
cytology in 12 months and should only undergo colposcopy if followup cytology is HSIL or
greater at 12 months or ASC-US or greater at 24 months.
According to ASCCP and ACOG, women with ASC-H (atypical squamous cells-cannot
exclude HSIL), LSIL, HSIL, or AGC should undergo colposcopy.68 There are two categories of
women for which alternative strategies for management of LSIL cytology exist—adolescents and
postmenopausal women. ASCCP now makes the same recommendations for LSIL in adolescents
as they do for ASC-US. Postmenopausal women with LSIL may undergo reflex high-risk HPV
DNA testing, repeat cytology at 6 and 12 months, or immediate colposcopy.

Screening for Cervical Cancer 7 Oregon Evidence-based Practice Center

Interventions/Treatment of Cervical Intraepithelial Neoplasia
Once identified, CIN may be treated by ablative (cryotherapy or laser ablation) or
excisional modalities (loop electrosurgical excision [LEEP], laser conization, or cold knife
conization [CKC] of the cervix).76 Current guidelines recommend observation of CIN1, as it is
highly likely to regress spontaneously without treatment.68 Treatment of CIN2 and CIN3 is
advised, and both ablative and excisional modalities are acceptable. If CIN2 or CIN3 recurs,
however, excision is preferred.68 In adolescents, CIN2 may be observed and treated only if it
persists for 24 months or progresses to CIN3.68
A randomized controlled trial (RCT) of cryotherapy, laser, and LEEP reported similar
success rates (less than 5% rate of persistence of CIN, less than 20% rate of recurrence of CIN
over approximately 3 years) and no significant difference in complication rates among the three
treatment modalities.78 Risk of persistent disease was higher among women with large lesions
(risk ratio, 18.9 [95% CI, 3.2 to 110.6]). Recurrence risk was higher among women aged 30
years and older (risk ratio, 2.1 [95% CI, 1.2 to 4.3]), those with HPV type 16 or 18 (risk ratio, 2.1
[95% CI, 1.1 to 4.0]), and those who had had prior treatment for CIN (risk ratio, 2.1 [95% CI, 1.1
to 3.9]).
A systematic review published in 2000 of controlled and randomized studies of cone
biopsy, cryotherapy, laser, and LEEP of the cervix found no substantive differences in the
persistence or resolution of CIN among these modalities.79 The pooled rates of resolution for
low- and high-grade lesions or mixed histology ranged from 85 to 95 percent. The median
duration of followup for these studies ranged from 2 to 45 months. A more recent Cochrane
Collaboration review published in 2010 found no difference in residual disease between 1)
LEEP, laser, or CKC or 2) laser ablation and laser, cold knife, or LEEP conization procedures.80
There was no difference in residual disease between cryotherapy and laser ablation or between
cryotherapy and LEEP at 6 months. However, there was a significantly lower risk of residual
disease at 12 months among women who underwent LEEP compared to cryotherapy (risk ratio,
0.32 [95% CI, 0.13 to 0.78]).
A recently published retrospective cohort study used data from the British Columbia
Cancer Agency cytology database to determine long-term risk of CIN recurrence among women
with CIN1 to CIN3 treated by various modalities (cryotherapy, LEEP, CKC, and laser
vaporization or excision).81 The authors compared 37,142 women who underwent treatment for
CIN1 to CIN3 between 1986 and 2000 with 71,213 women with normal cytology and no
previous CIN using followup data through the end of 2004. The overall incidence of invasive
cancer (per 100,000 woman-years) was higher among women with a history of CIN (37 cases
[95% CI, 30.6 to 42.5]) than in the comparison cohort (6 cases [95% CI, 4.3 to 7.7]). Among all
methods evaluated, cryotherapy was associated with the highest rate of subsequent disease
(adjusted odds rate for invasive cancer, 2.98 [95% CI, 2.09 to 4.60]).
As the risk of ICC persists after treatment of CIN,81-83 post-treatment followup is
advised.68,82 There is no specific treatment for HPV in the absence of CIN. Since current
treatment only targets CIN after it has developed, the prevention of HPV infection and,
consequently, the development of CIN is important.

Potential Harms Related to Diagnosis and Treatment of CIN

Risks of colposcopy and cervical biopsy include pain, bleeding, infection, failure to
diagnose (inadequate sampling), and cost to the patient (e.g., time off work and psychological

Screening for Cervical Cancer 8 Oregon Evidence-based Practice Center

impact). One large, multicenter trial of 4,439 women aged 20 to 59 years with low-grade cervical
abnormalities who were randomized to cytologic surveillance versus immediate referral (Trial of
Management of Borderline and Other Low-Grade Abnormal Smears [TOMBOLA]) attempted to
quantify the potential harms (i.e., clinically significant anxiety and depression and self-reported
after effects such as pain, bleeding, and vaginal discharge) associated with colposcopic
evaluation versus surveillance.84 Results from the TOMBOLA group indicated similar
proportions of women with depression in the surveillance and immediate colposcopy groups at 6
weeks after the procedure, although women in the surveillance group were more likely to be
anxious (13.4 vs. 7.9%; p<0.001). Significantly lower proportions of women in the surveillance
group reported any pain (15.0 vs. 38.9%; p<0.001), bleeding (17.2 vs. 46.9%; p<0.001), or
discharge (8.6 vs. 34.2%; p<0.001), compared with women in the immediate colposcopy arm.
Within the TOMBOLA cohort, an observational study (n=929) compared the physical after
effects (pain, bleeding, and discharge) of colposcopic examination only, cervical punch biopsies,
and LEEP.85 Among women aged 20 to 59 years with colposcopy and no biopsy, 14 to 18
percent reported pain, bleeding, or discharge at 6 weeks. In those with colposcopic biopsy, 53
percent reported pain, 79 percent reported bleeding, and 46 percent reported discharge. For
women who had LEEP, these numbers were 67, 87, and 63 percent, respectively. The duration of
bleeding and discharge was longer for women treated by LEEP than women in the other groups
reporting these symptoms.
Potential harms of treatment of CIN include immediate, short-term, and long-term risks.
These risks may include pain, injury to adjacent organs such as the bowel or bladder, infection,
bleeding, adverse reactions to medications used during the treatment procedure, incomplete
treatment (i.e., residual disease after treatment) requiring additional testing or treatment, cervical
stenosis resulting in difficulties with future attempts at endocervical (or endometrial) assessment,
and cervical shortening with possible subsequent increased risk for preterm birth. Other potential
issues to consider are the cost to the patient for time off of work, treatment of lesions that might
regress on their own, and the psychological impact of the diagnosis or procedure.
One review of obstetrical outcomes published in 2006 evaluated cold knife and laser
conization, laser ablation, and LEEP. CKC was significantly associated with preterm delivery
(less than 37 weeks: 8 studies; RR, 2.59 [95% CI, 1.80 to 3.72]), low birthweight (less than 2,500
grams: 4 studies; RR, 2.53 [95% CI, 1.19 to 5.36]), and cesarean delivery (4 studies; RR, 3.17
[95% CI, 1.07 to 9.40]), but no increase in perinatal mortality.86 LEEP was also significantly
associated with preterm delivery (8 studies; RR, 1.7 [95% CI, 1.24 to 2.35]), low birthweight (6
studies; RR, 1.82 [95% CI, 1.09 to 3.06]), and premature rupture of membranes (3 studies; RR,
2.69 [95% CI, 1.62 to 4.46]), but not cesarean delivery or perinatal mortality. Similar effects on
preterm delivery were noted for laser conization, but these were not statistically significant. No
increased risk for adverse obstetric outcomes was detected among women who underwent laser
ablation.
A 2008 review of excisional or ablative therapies found that CKC was associated with an
increased risk of preterm birth prior to 30 weeks (4 studies; RR, 5.33 [95% CI, 1.63 to 17.40])
and prior to 34 weeks (5 studies; RR, 2.78 [95% CI, 1.72 to 4.51]), birthweight less than 2,000
grams (1 study; RR, 2.86 [95% CI, 1.37 to 5.97]), and perinatal mortality (7 studies; RR, 2.87
[95% CI, 1.42 to 5.81]).87 LEEP was not associated with an increased risk of perinatal mortality,
preterm birth prior to 32 to 34 weeks, or preterm labor prior to 28 to 30 weeks. One included
study evaluated the impact of LEEP on low birthweight and found no significant increased risk
of low birthweight less than 2,000 or 1,500 grams. Ablative procedures (2 studies of cryotherapy

Screening for Cervical Cancer 9 Oregon Evidence-based Practice Center

and 4 of laser ablation) were not associated with an increased risk of preterm birth, perinatal
mortality, or low birthweight.
Neither of the two reviews addressed the relationship between the depth of the tissue
specimen excised and preterm birth, or addressed important confounders such as socioeconomic
status and previous preterm birth. One recent large retrospective U.S. cohort study, published
after these two reviews, found no increased risk of preterm birth associated with LEEP.88

Efforts to Prevent HPV Infection

HPV vaccination may allow disease prevention early in the progression to cervical
cancer, before persistent HPV infection is established. In 2006, the FDA approved the Merck
vaccine GARDASIL for multiple indications, including use in females aged 9 to 26 years for
prevention of diseases including CIN and cervical cancer. GARDASIL is a quadrivalent vaccine
against HPV types 6, 11, 16, and 18 and is given in a three-dose schedule.89 More recently
(2009), CERVARIX by GlaxoSmithKline, a bivalent vaccine against HPV types 16 and 18, has
also been approved for the prevention of CIN and cervical cancer in females aged 10 to 25
years.90
Clinical trials of GARDASIL,91 CERVARIX,92 and their precursors showed vaccine
efficacy of close to 100 percent for prevention of CIN2+ related to HPV 16 or 18 among women
who were HPV negative at enrollment. Among all women enrolled, regardless of baseline HPV
status, efficacy was much lower: 44 percent for GARDASIL and 53 percent for CERVARIX.
Thus, HPV vaccination93 is expected to be most effective before HPV exposure. Sexually active
women, however, can also receive and benefit from vaccination. Since the two approved
vaccines protect against just two of the 15 common oncogenic HPV types, efficacy against
cervical lesions irrespective of HPV type is also lower, about 20 to 30 percent among all women
enrolled.

Current Clinical Practice

A 2004 survey of 2,980 nonfederal, nonmilitary U.S. clinicians performing cervical
cancer screening indicates that LBC is the primary screening modality used by the majority of
clinicians surveyed. In addition, the majority reported that they had ordered an HPV test in
response to abnormal cytology. According to the survey, 22 percent (range, 8 to 42% by
specialty) of clinicians used CC only, and 65 percent (range, 45 to 78%) used LBC only.94 Of the
various clinical specialties surveyed, 78 percent of obstetricians reported use of LBC only,
versus 45 percent of adolescent medicine specialists. Overall, 21 percent of clinicians (range, 11
to 37%) ever ordered or collected an HPV DNA test as an adjunct to cytology to be run
regardless of the cytology result, and 63 percent (range, 44 to 91%) ever ordered or collected an
HPV DNA test to be run in response to abnormal or borderline cervical cytology results. Of the
21 percent of clinicians who reported ever using HPV tests as an adjunct to cytology, more
reported testing women younger than age 30 years (35% [range, 27 to 46%]) than women aged
30 years or older (29% [range, 9 to 36%]). Currently, the FDA has only approved the HPV DNA
test (HC2) for 1) screening patients with ASC-US cytology to determine the need for referral to
colposcopy, and 2) use in women aged 30 years or older as an adjunct to cytology to assess the
absence or presence of high-risk HPV types.70,71 Clearly, current use is beyond FDA approval.

Screening for Cervical Cancer 10 Oregon Evidence-based Practice Center

 Previous USPSTF Recommendation

In 2003, the USPSTF found good evidence that screening with cervical cytology reduces
incidence of, and mortality from, cervical cancer.94 It strongly recommended screening for
cervical cancer in women who have been sexually active and have a cervix (A recommendation).
The USPSTF found limited evidence to determine the benefits of continued screening in women
older than age 65 years and fair evidence that screening in this age group is associated with an
increased risk for potential harms; thus, it recommended against routinely screening women
older than age 65 years for cervical cancer if they have had adequate recent screening with
normal Pap smears and are not otherwise at high risk for cervical cancer (D recommendation).
The USPSTF found fair evidence that the yield of cytologic screening in women after
hysterectomy is very low. It found poor evidence that screening to detect vaginal cancer
improves health outcomes, and recommended against routine screening in women who have had
a total hysterectomy for benign disease (D recommendation). The USPSTF concluded that the
evidence was insufficient to recommend for or against the routine use of new technologies (such
as LBC or automated screening) to screen for cervical cancer (I statement). Finally, the USPSTF
concluded that the evidence was insufficient to recommend for or against the routine use of HPV
testing as a primary screening test for cervical cancer (I statement).

Screening for Cervical Cancer 11 Oregon Evidence-based Practice Center

Chapter 2. Methods

Key Questions and Analytic Framework

Using the USPSTF’s methods (detailed in Appendix B),95 we developed an analytic

framework (Figure 5) and five key questions (KQs) to guide our literature search. These KQs
include:
KQ1: When should cervical cancer screening begin, and does this vary by screening technology
or by age, sexual history, or other patient characteristics?
KQ2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional
cervical cytology?
KQ3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
KQ4: What are the harms of liquid-based cytology?
KQ5: What are the harms of using HPV testing as a screening test, either alone or in
combination with cytology?
The scope of the review was set in early 2007 and was conducted in the intervening years
without a change in scope. This report’s scope differs from the 2002 USPSTF evidence report in
several ways. KQ1, which was not included in the 2002 evidence report, addresses when cervical
cancer screening should begin. Both LBC and automated screening technologies were evaluated
in the prior review, and the evidence was determined to be insufficient to recommend for or
against the use of these technologies in cervical cancer screening programs. For this review, we
updated the evidence regarding LBC (KQ2) and focused on studies that evaluated either
ThinPrep or SurePath, which are both FDA approved. However, we did not update the direct
evidence for automated screening technologies because they are less relevant to primary care
clinicians. These technologies are implemented by laboratories and not performed by the
clinician at the time of cervical cytology collection. The previous review evaluated the sensitivity
and specificity of the HPV test for detection of histologically proven HSIL and LSIL. The
authors also evaluated the use of the HPV test as a tool to facilitate triage of women with
abnormal cytology. The current review expanded the scope of KQ3 to evaluate the evidence
regarding the use of HPV testing in the following scenarios:
1. Primary screening with HPV test alone.
2. HPV testing with cytology triage of positive HPV (reflex cytology).
3. Combination HPV and cytology testing (co-testing).
4. Cytology testing with HPV triage of positive cytology (reflex HPV).
We restricted the scope of KQ3 to include only HC2 or PCR methods for HPV testing.
We did not evaluate the use of HPV testing for followup after treatment for CIN. KQs 4 and 5,
neither of which was framed as a separate KQ in the prior review, address the harms of LBC and
HPV testing.
We addressed one contextual question that evaluated the efficacy of screening in women
older than age 65 years according to the USPSTF’s specified nonsystematic approach.96 The
previous review addressed this question systematically, and the USPSTF recommended against
routinely screening women older than age 65 years, based on limited evidence regarding the
benefits of continued screening in these women. We did not update the direct evidence for

Screening for Cervical Cancer 12 Oregon Evidence-based Practice Center

screening in women after a hysterectomy because the prior USPSTF recommendation to
discontinue screening after hysterectomy for benign disease is clearly supported. Because the
HPV vaccine is so new, data to determine the long-term efficacy of the vaccine or how the HPV
vaccine will affect screening is limited. Therefore, the USPSTF did not include a KQ addressing
the impact of the HPV vaccine on cervical cancer screening. This will be an important topic for
future evidence reviews, when more data regarding this issue become available. The USPSTF
judged that a thorough review of cost effectiveness analyses was beyond the scope of our review.
We did not review evidence on appropriate screening intervals, as this issue is rarely studied
directly and the concurrent modeling study addresses this topic. We did not systematically
review the harms of treatment procedures such as LEEP, cryotherapy, and laser cone biopsy.

Literature Search Strategy

For all KQs, we searched for systematic reviews, meta-analyses, and evidence-based
guidelines on cervical cancer screening in the Database of Abstracts of Reviews of Effects, the
Cochrane Database of Systematic Reviews, PubMed, and the Health Technology Assessment
database from 2000 through January 2007. We also conducted a series of searches for each KQ
and reviewed the search results for applicability to all KQs. For KQs 1, 3, 4, and 5, we conducted
searches to identify studies published since the previous USPSTF review (2000 through
September 2010). We searched in MEDLINE and the Cochrane Collaboration Registry of
Clinical Trials (CCRCT) without restrictions on study designs. For KQ5, we also searched
PsycINFO to capture adverse psychological effects of HPV testing. The search period for LBC
(KQ2) began in 2003 because two systematic reviews provided a complete and thorough search
of the relevant literature through July 2003.97,98 We used these reviews as source documents to
locate relevant studies from before 2003 and bridged their searches for LBC using MEDLINE
and CCRCT, without restrictions on study designs, from the beginning of 2003 through
September 2010. We evaluated the studies included in the previous review by Hartmann and
colleagues99 against the inclusion and exclusion criteria for the current review, and found only
one study was eligible for inclusion.100 We also obtained articles from outside experts and
bibliographies of other relevant articles and systematic reviews. In addition to these searches for
published trials, we searched federal agency trial registries for unpublished trials of cervical
cancer screening. All searches were limited to articles published in the English language.

Study Selection
While differences in inclusion, exclusion, and quality criteria precluded us from
incorporating any of the existing systematic reviews or meta-analyses that were identified, the
high-quality reviews and meta-analyses were used to check the completeness of our searches for
primary studies.
For KQ1, in the absence of RCTs addressing when to begin screening, we included
cohort studies that evaluated the incidence and prevalence of cervical cancer in young screened
populations, natural history studies of CIN and HPV infection in young women, and studies
reporting outcomes of population-based screening programs targeting young women.
For KQs 2 and 3, evaluating LBC and HPV testing, we included studies that provided
evidence regarding absolute and relative test performance. Our specific criteria were as follows:

Screening for Cervical Cancer 13 Oregon Evidence-based Practice Center

 1. To determine absolute test performance, we required that the reference standard of
colposcopy and/or biopsy was systematically applied to all those screening positive and
at least a random sample of screen negatives, with valid adjustment for verification bias
when necessary. The reference standard must have been independent of the screening test
(i.e., the screening test results were not used to establish the final diagnosis).
2. If a study did not test negatives appropriately with the gold standard, we could not use
their absolute test performance estimates. However, if the study was an RCT, compared
test performance within the randomization scheme, and was of appropriate quality, then
we included relative test performance measures.
3. To evaluate screening demands and potential harms, we abstracted the following data
where available as absolute or relative measures: test positivity, colposcopy referrals,
colposcopy compliance, positive predictive value (PPV), false-positive proportion, and
appropriately calculated specificity. For trials with multiple screening rounds, we looked
for round-specific and cumulative data. For all studies, we looked for age-specific data.
4. Many studies reported theoretical test performance by estimating results for different
screening and management programs, rather than by what was actually done in the trials.
We determined these calculations could not be included if the assumptions required to
estimate performance introduced potential threats to validity. We usually could not
determine how to fairly assess whether these assumptions affected the validity of the
calculated test performance, and if they did, what direction or degree of bias was
introduced.
Studies of LBC and HPV primary screening must have been conducted in routine
screening populations. Other inclusion and exclusion criteria specific to each question are
detailed in Appendix B.

Data Extraction and Quality Assessment

Two investigators independently reviewed all abstracts for all KQs. Two investigators
evaluated articles against a set of inclusion/exclusion criteria. Each investigator independently
reviewed articles for quality using design-specific quality criteria based on the USPSTF
methods, supplemented by the National Institute of Health and Clinical Excellence criteria for
quality of systematic reviews and the QUADAS tool for quality assessment of diagnostic
accuracy studies (Appendix B, Table 3).95,101,102 Two investigators critically appraised all studies
and agreed when articles were excluded for quality reasons. One reviewer abstracted data from
included studies into evidence tables, and a second reviewer checked the data.

Data Synthesis and Analysis

Except for cytology testing with HPV triage of positive cytology (KQ3), data synthesis
for all questions was qualitative because heterogeneity in the samples, settings, study designs,
and instruments did not allow for quantitative synthesis. In the results section, studies are
summarized qualitatively within the KQs. For KQ3 addressing HPV testing, studies are
categorized by four different uses of HPV testing in cervical cancer screening. For each question,
we first describe RCTs comparing cytology with HPV-enhanced screening strategies within
existing screening programs that report absolute and relative CIN2+/CIN3+ detection for one or
two screening rounds, followed by cross-sectional studies reporting absolute test performance

Screening for Cervical Cancer 14 Oregon Evidence-based Practice Center

data. Studies from countries with less developed cervical cancer screening programs are
discussed separately due to their lower applicability to the U.S. population.
For evidence on the benefits of using HPV testing to triage women with ASC-US
cytology, we estimated the combined difference in sensitivity and specificity between HPV and
repeat CC. A random effects model was used to incorporate variation among studies. For the
difference in sensitivity and specificity between HC2 and cytology, we used risk difference as
the effect measure. Statistical heterogeneity was assessed by Cochran’s Q test and the I2
statistic.103 All analyses were performed using Stata 10.0 (StataCorp, College Station, TX).
Many of the results reported in the evidence and summary tables are calculated from data
provided in the articles using methods cited in Appendix B. Such calculations are indicated in the
evidence tables by ― (calc).‖ In the RCTs, results were generally reported using women screened
(instead of women randomized, as in an ― intention-to-screen‖ analysis, which also includes
opportunistic screening results) within each arm and each round. To be consistent, we abstracted
from the articles or calculated results using the number of women screened within each
randomized arm as the denominator unless noted as otherwise in the tables. Consideration of
program results among women screened only may be less appropriate to determine overall
population impact, but acceptable when primarily evaluating the relative merits (including false
positives and other adverse effects) of efficacious screening alternatives.
Evidence tables for all KQs are in Appendix C. Detailed methods can be found in
Appendix B.

USPSTF Involvement

This research was funded by AHRQ under a contract to support the work of the USPSTF.
The authors worked with eight USPSTF liaisons at key points throughout the review process to
develop and refine the scope, analytic framework, and KQs; to resolve issues around the review
process; and to finalize the evidence synthesis. AHRQ had no role in study selection, quality
assessment, or synthesis, although AHRQ staff provided project oversight, reviewed the draft
evidence synthesis, and distributed the initial evidence report for external review of content by
outside experts, including representatives of professional societies and federal agencies. The
final published systematic evidence review was revised based on comments from these external
reviewers.

Screening for Cervical Cancer 15 Oregon Evidence-based Practice Center

Chapter 3. Results

Key Question 1. When Should Cervical Cancer Screening

Begin, and Does This Vary By Screening Technology or By
Age, Sexual History, or Other Patient Characteristics?
Various factors should be considered when determining the age of onset for cervical
cancer screening and type of screening test to be used. These factors include the prevalence and
incidence of CIN2, CIN3, and cervical cancer among women in their teens and early 20s, as well
as the rate of progression of CIN2 and CIN3 to cervical cancer. Screening for cervical cancer or
CIN2 and CIN3 may be of little net benefit if these conditions are rare or progress slowly in
younger age groups. This is particularly true if screening for and treatment of preinvasive disease
causes excess harm. For screening to be beneficial, it should lead to earlier detection of disease
that, when treated, results in decreased morbidity and mortality from cervical cancer. Given
HPV’s significant association with preinvasive and invasive disease of the cervix, the natural
history of HPV infections in young women is also important, including persistence and
progression from HPV infection to cervical cancer. All of this evidence informs whether women
in their teens and early 20s should be screened for cervical cancer and, if so, how they should be
screened.
The ideal study for determining when cervical cancer screening should begin would be an
RCT in which women are randomized to begin screening at different ages and then followed for
the development of CIN3 and cancer, including morbidity and mortality. We did not identify any
RCTs evaluating the age at which screening should begin. We considered cohort studies that
evaluated the incidence and prevalence of cervical cancer in young, screened populations by age
and other risk factors, the natural history of CIN and HPV infection in young women, and the
effects of population-based screening programs targeting young women. We identified one large,
fair-quality, population-based, case-control study evaluating the association between cervical
cancer screening at ages 20 to 69 and future cervical cancer detection among 11,901 women in
the United Kingdom;23 two fair-quality cohort studies (from the United States104 and United
Kingdom32) examining age-specific screening outcomes in 199,707 women aged 15 years and
older; one fair-quality population-based correlational study evaluating screening in all 20- to 34-
year-olds attending routine screening in Iceland;105 and one good-quality prospective cohort
study (from the United Kingdom) describing the natural history of incident HPV and CIN
infection in 1,075 15- to 19-year-olds106 (Appendix C Table 1). The best evidence comes from
the case-control study and is supported by the cohort studies.
Although evidence is based on a limited number of studies, these studies show that high-
risk HPV infections and cytologic abnormalities among women younger than age 20 years are
common and transient, whereas CIN3+ is much less common in this group than in women aged
25 years and older. They also show that screening in younger women (younger than age 25) has
lower detection rates and higher false positives than in older women. Screening these women
also does not result in decreased incidence of cervical cancer among women younger than age 30
years.
A population-based, case-control study conducted within the United Kingdom’s National
Health Service (NHS) used prospectively recorded data on cervical cancer screening to estimate
the association between having an adequate smear test taken in a particular 3-year age group

Screening for Cervical Cancer 16 Oregon Evidence-based Practice Center

(such as ages 22 to 24) and the incidence of cervical cancer in a subsequent 5-year age group
(such as ages 25 to 29).23 The study cohort included 4,012 women with invasive cancer and
7,889 controls (two controls per case). The authors found that cervical cancer screening among
women younger than age 25 years was not associated with a decreased incidence of cervical
cancer diagnosis prior to age 30 years. However, the authors could not rule out the possibility
that screening women in the age group of 20 to 24 years would be effective in reducing stage
IB+ cervical cancer in women aged 25 to 27 years, because the group was small (65 women) and
thus confidence intervals were wide (OR, 0.52 [95% CI, 0.23 to 1.2]). A statistically significant
protective effect of screening was not demonstrated until age 32 years, when screening was
associated with a 45 percent reduction (OR, 0.55 [95% CI, 0.44 to 0.69]) in the incidence of ICC
diagnosis between ages 35 and 39 years.23
This study’s major strength was that it was designed specifically to answer the question
of when cervical screening should begin, measuring the association between age at screening and
the outcome of greatest interest—cervical cancer incidence. Additional strengths of this study
include a study population comparable to that of the United States and the extensive electronic
database from which the data were abstracted. The authors’ use of random control selection
minimized selection bias, and their use of prospectively recorded data on screening history
reduced the recall bias that would otherwise be a weakness of the study’s retrospective design.
However, confounding is another limitation of observational studies, and the authors did not
report or adjust for many potential risk factors for cervical cancer.
A population-based study in Iceland evaluated the value of cervical cancer screening in
the 20- to 34-year-old age group by analyzing trends in CIN2, CIN3, and cervical cancer.105
Iceland’s national cervical cancer screening program commenced in 1969 for women aged 25 to
69 years at 2- to 3-year intervals. After 1987, women aged 20 years or older were also invited to
screening at 2-year intervals. In the years following the introduction of cervical cancer screening
for women aged 20 to 24 years, the rate of ICC did not change among this age group. This rate
did decrease significantly among women aged 35 to 39 years, however, with a stage shift toward
earlier disease detection. In contrast, the detection rate of CIN2 and CIN3 increased among
women aged 20 to 29 years, whereas detection of CIN2 increased among women aged 30 to 34
years but detection of CIN3 decreased.105 In Iceland, the usual practice is to observe smears with
low-grade cytologic abnormalities (≤LSIL) and refer women with high-grade smears for
colposcopy with biopsy and endocervical curettage. However, screening and treatment practices
may change over time or vary across institutions or providers. So, at an ecologic level, it is
difficult to establish causality or to attribute changes in CIN2, CIN3, and cervical cancer
detection rates solely to the initiation of screening younger women. This study’s strength was the
large timeframe over which the data were reviewed, which allowed for evaluation of shifts in
trends of disease detection. This study and the UK study were rated fair quality. One advantage
of the UK study’s design is the use of prospectively collected individual-level data rather than
population data. The Icelandic study supports initiation of screening in women in their early 20s,
whereas the UK study was limited in power to determine whether screening among this group of
women is beneficial. Neither study provided sufficient detail to allow determination of a specific
age at which screening should be initiated.
A large cohort study conducted among 150,052 women aged 15 years or older enrolled in
a Kaiser Permanente health plan between 1997 and 2002 examined age-specific cervical cancer
screening outcomes.104 In this population, the 25- to 29-year-old age group was the most
frequently screened of all age groups—650 screened per 1,000 females enrolled compared to 217

Screening for Cervical Cancer 17 Oregon Evidence-based Practice Center

per 1,000 for women aged 15 to 19 years.104 The likelihood of detecting CIN3 was lower in
women younger than age 25 years, compared to women aged 25 to 29 years, but the risk of
having a false-positive smear was higher. The proportion of smears yielding CIN3 was 0.2
percent for women aged 15 to 19 years and 0.2 percent for women aged 20 to 24 years,
compared to 0.6 percent for women aged 25 to 29 years and 0.4 percent for women aged 30 to 39
years. False-positive smears occurred in 3.1 percent of women aged 15 to 19 years, 3.5 percent
of women aged 20 to 24 years, 2.1 percent of women aged 25 to 29 years, and 2.6 percent of
women aged 30 to 39 years. One limitation of these data is that they were drawn from a screened
population of women with relatively stable health insurance, and therefore may not be
generalizable to the U.S. population. The remaining included studies also evaluated populations
of women with health insurance.
A second large cohort study, which provides important evidence on the prevalence of
high-risk HPV by age in a population of women similar to those in the United States, evaluated
49,655 British women of any age presenting for routine screening between 1988 and 1993.32
This study’s goal was to describe the relationship between HPV detection at entry and cytologic
and histologic followup. The 78,062 cervical samples obtained during the study were stratified
according to the 12-month period in which they were taken and into 5-year age groups. HPV
testing (PCR) was performed on an age- and period-stratified random sample to limit cost
(n=6,462). The authors found that the prevalence of high-risk HPV was greatest in women aged
15 to 19 years (20%) and decreased with increasing age to 2.6 percent among women aged 50 to
54 years (Figure 6).32 Across all age groups, the prevalence of high-risk HPV positivity was
much lower for women with normal smears than those with abnormal smears (17.2% vs. 73.7%
among women aged 15 to 19 years; 1.6% vs. 40.7% for women aged 50 to 57 years). Although
the prevalence of high-risk HPV peaked among adolescents, prevalent cases of CIN3+ peaked
among women aged 35 to 39 years, and incident cases of CIN3+ peaked among women aged 25
to 29 years (Figure 6). Among women with no previous smear, the prevalence of CIN3+ was 0.2
percent among women aged 15 to 19 years compared to 1.7 percent among women aged 35 to 39
years. No prevalent cancer cases were identified among women younger than age 20 years. The
annual incidence of new cases of CIN3+ for women with a screening interval of less than 5 years
following a normal smear was 1.56/1,000 per year among women aged 15 to 19 years, peaked at
4.07/1,000 for women aged 25 to 29 years, and decreased with increasing age to the lowest
incidence rate, which was 0.19/1,000 among women aged 60 to 64 years.
In a prospective cohort study of 1,075 British women aged 15 to 19 years with normal
cytology and negative high-risk HPV tests, each woman was followed with serial smears and
HPV testing at 6-month intervals.106 The study’s goal was to describe the natural history of
incident HPV infection and its temporal relation to the occurrence of cytologic and histologic
abnormality; it provides valuable information on the acquisition and remission of high-risk HPV
among adolescents, and the risk of development of CIN2+ in relation to HPV status. All women
with cytologic abnormalities underwent colposcopy and biopsy of abnormal areas. Treatment
was postponed until there was histologic evidence of CIN2 or greater. The median number of
visits was four, and median duration of followup was 29 months. This study demonstrated the
frequent occurrence of new high-risk HPV infections and their transient nature as well as the
transient nature of cytologic abnormalities among young women. The authors also identified a
small percentage of young women who developed CIN2+ despite continuing to test negative for
high-risk HPV.

Screening for Cervical Cancer 18 Oregon Evidence-based Practice Center

 During study followup, 38 percent of women became positive for any HPV type, and 26
percent of women became positive for high-risk HPV types (16, 18, 31, 33, 52, or 58). The
cumulative risk at 3 years of any HPV type was 44 percent, and at 5 years the risk was 60
percent. The median duration of the first HPV positive episode was 13.7 months (interquartile
range [IQR], 8.0 to 25.4) for any HPV type, 10.3 months (IQR, 6.8 to 17.3) for HPV 16, and 7.8
months (IQR, 6.0 to 12.6) for HPV 18. The cumulative risk at 3 years of any cytologic
abnormality was 28 percent (95% CI, 25 to 32). The median duration of the first episode of
cytologic abnormality was 8.7 months (IQR, 5.8 to 13.8). In this cohort, 28 women (2.6%)
developed CIN2 (1.3%) or CIN3 (1.3%) during a median of 36 months of followup. Five of
these women consistently tested HPV negative. The risk of being diagnosed with CIN2+ was 8
times greater for women who became HPV positive during followup than for those who
remained negative (RR, 7.8 [95% CI, 2.7 to 22.0]).

Key Question 2. To What Extent Does Liquid-Based Cytology

Improve Sensitivity, Specificity, and Diagnostic Yield and
Reduce Indeterminate Results and Inadequate Samples
Compared to Conventional Cervical Cytology?
We identified two RCTs,107,108 one cohort,109 and one cross-sectional study110 that
provide data comparing LBC (ThinPrep) and CC. Only one RCT, a cluster-randomized trial
rated as good quality (Netherlands ThinPrep versus Conventional Cytology [NETHCON]), set
out with the primary purpose of comparing LBC and CC.108 The other RCT, the New
Technologies for Cervical Cancer Study (NTCC) Phase I, rated as fair quality, was designed to
compare CC with LBC in combination with HPV testing.107 Both provide relative test
performance data only. The two remaining observational studies, both rated as fair quality,
provide absolute test performance data, since colposcopy and/or biopsy was systematically
applied to all women.109,110 The NTCC and NETHCON trials included a total of 134,162 eligible
women, and the nonrandomized trials included a total of 7,404 women. All of the studies were
conducted in primary care settings in nonU.S. populations (periurban South Africa, France, the
Netherlands, and Italy) (Table 3).
The NTCC and NETHCON trials showed no difference between LBC and CC in relative
detection ratio of CIN2+ or CIN3+ (Table 4).107,108 The NETHCON trial demonstrated no
difference between LBC and CC in relative PPV for detection of CIN2+ and a higher PPV of
borderline statistical significance (p=0.036) favoring LBC for the detection of CIN3+,108 while
the NTCC trial demonstrated a lower PPV for LBC for the detection of both CIN2+ and CIN3+,
compared to CC.107 The NTCC trial found a higher relative proportion of false-positive test
results for LBC compared to CC (1.97 for detection of CIN2+ and 1.93 for detection of
CIN3+),107 whereas the NETHCON trial found a slightly lower proportion of false-positive test
results with LBC (0.90 for detection of CIN2+ and 0.89 for detection of CIN3+).108
The cluster-randomized NETHCON trial was designed to compare LBC to CC among
women aged 30 to 60 years participating in the Dutch cervical screening program.108 Overall,
this is a well-designed study with good applicability to the United States, and it provides the best
available evidence to address KQ2 in terms of the use of LBC in a large cervical cancer
screening program. Randomization was by clinical site, with 88,988 women at 246 family
practices included in the analysis. Exclusion criteria were not reported. Followup for screen-

Screening for Cervical Cancer 19 Oregon Evidence-based Practice Center

positive women followed Dutch clinical guidelines, with colposcopy referral and directed biopsy
for high-grade or persistent low-grade abnormalities.
Among 40,047 women with cytology results of ASC-US or worse, 280 cases of CIN2+
and 190 cases of CIN3+ were detected in the CC arm, of whom 420 underwent colposcopy only
(n=2) or colposcopy and biopsy (n=418). In the LBC arm, 346 cases of CIN2+ and 253 cases of
CIN3+ were detected among 48,941 women screened, of whom 484 underwent colposcopy only
(n=4) or colposcopy and biopsy (n=480).108
The NETHCON trial found no significant difference between LBC and CC in the
adjusted relative detection ratio (adjusted for age, site, urbanization, and study period) of either
CIN2+ (1.00 [95% CI, 0.84 to 1.20]) or CIN3+ (1.05 [95% CI, 86 to 1.29]). The unadjusted
relative PPV (adjusted results not provided by the authors) for CIN2+ was similar between the
two screening tests (PPV for ASC-US+, 1.09 [95% CI, 0.95 to 1.25]; PPV for LSIL+, 1.04 [95%
CI, 0.93 to 1.15]). For detection of CIN3+, the relative PPV for LBC bordered on statistical
significance, compared to CC (PPV for ASC-US+, 1.17 [95% CI, 0.99 to 1.39]; PPV for LSIL+,
1.17 [95% CI, 1.01 to 1.36]). The relative false-positive proportion (RFPP) for LBC was 0.90
(95% CI, 0.82 to 0.99) for detection of CIN2+ and 0.89 (95% CI, 0.82 to 0.98) for detection of
CIN3+, compared to CC.108
The NTCC study was not a randomized trial of LBC versus CC. Rather, this study was a
randomized screening program of LBC plus the HC2 HPV test (experimental group) versus CC
(control group).107 The referral threshold for colposcopy was ASC-US for the experimental arm,
and either ASC-US (72%) or LSIL (28%) for the control arm. Since the referral criterion differed
for the two study groups, we present results for the centers that used the same referral criterion
for both tests. In their comparison of LBC versus CC, the authors included CIN2 lesions or
worse that were detected during the recruitment phase of the trial, within 1 year of referral to
colposcopy.
Among women with cytology results of LSIL or worse, 70 cases of CIN2+ and 44 cases
of CIN3+ were detected in the CC arm among 22,466 women, of whom 317 underwent
colposcopy. In the LBC arm, 73 cases of CIN2+ were detected (relative detection ratio, 1.03
[95% CI, 0.74 to 1.43]; relative PPV, 0.58 [95% CI, 0.43 to 0.78]) and 32 cases of CIN3+ were
detected (relative detection ratio, 0.72 [95% CI, 0.46 to 1.13]; relative PPV, 0.40 [95% CI, 0.26
to 0.62]) among 22,708 women screened, of whom 1,337 underwent colposcopy. Overall, more
colposcopies were required in the LBC group (15/1,000 for CC vs. 27/1,000 for LBC). The
relative detection ratio and PPV values noted for cytology results of ASC-US or worse
(confidence intervals provided per correspondence with primary author, Dr. Ronco, on March
11, 2008) were also not significantly different.111 The RFPP for LBC compared to CC was 1.97
(95% CI, 1.75 to 2.21) for detection of CIN2+ and 1.93 (95% CI, 1.72 to 2.21) for detection of
CIN3+ for cytology results of ASC-US or worse, and 1.80 (95% CI, 1.48 to 2.19) for detection
of CIN2+ and 1.72 (95% CI, 1.42 to 2.07) for detection of CIN3+ for cytology results of LSIL or
worse.107
One substantial limitation of this study is that the colposcopists were not blinded to study
arm. Therefore, they would have known the women’s HPV test results.107 Furthermore, no data
were provided to determine that randomization provided comparable groups for this secondary
analysis in which some women were excluded from the LBC arm because of positive HPV test
results, but not from the control arm (since this group was not tested for HPV).
Two studies, one conducted in South Africa109 and one in France,110 provided absolute
test performance results for comparison of LBC and CC for the detection of CIN2+ (Table 4).

Screening for Cervical Cancer 20 Oregon Evidence-based Practice Center

Only the South African study provides data on detection of CIN3+.109 For the detection of
CIN2+ and CIN3+, the sensitivity of both LBC and CC decreased with increasing cytologic
threshold, whereas specificity increased. LBC and CC did not significantly differ in sensitivity,
specificity, false positive rates, or PPV for detection of CIN2+ and CIN3+, although wide,
overlapping confidence intervals suggest limited power to detect a difference in sensitivity.
The French study was limited by a split-sample study design, which could bias the results
because the smear prepared first may have the best sample of cells.110 If that is so, then it might
be expected that in this study, where the conventional smear was prepared first, the sensitivity of
CC would be higher than LBC, but that was not the case. Both tests performed similarly.
The South African study has limited applicability, as the women in this study had never
been screened prior to enrollment, which would be unusual for most U.S. women in the same age
group.109 Second, a high proportion of women in the study were infected with HIV. Finally, 14.5
percent had recently been treated for CIN. The proportion of women with HIV infection and/or
recent CIN treatment was similar in both arms, so this is unlikely to bias the results in the
direction of either cytology method; however, it is unclear how the absolute test performance of
either method was impacted. The method of cervical sampling was not randomized or blinded, so
there is some potential for introduction of bias through unequal allocation. The strength of this
study lies in the fact that the gold standard was systematically applied to all study participants
after collection of the screening test, therefore limiting differential application of the gold
standard and verification bias.

Unsatisfactory Slides
Both the NETHCON and NTCC trials demonstrated a lower proportion of unsatisfactory
cytology samples for LBC than CC, with 0.37 and 2.6 percent of LBC slides considered
unsatisfactory, compared to 1.09 and 4.1 percent of CC slides, respectively (Table 4).107,108 These
findings are different than what had previously been demonstrated in the cohort and cross-
sectional studies, in which LBC had more unsatisfactory samples. However, study design might
explain these earlier results in at least one of the nonrandomized studies, in which the collected
sample was first used to prepare the CC slide and the residual material was used to perform the
LBC test.110

Key Question 3. What Are the Benefits of Using HPV Testing

as a Screening Test, Either Alone or in Combination With
Cytology, Compared With Not Testing for HPV?
We identified 22 unique studies in 48 publications that assessed the benefits of using
HPV testing, either alone or in combination with cytology, as an initial screening or to triage
abnormal initial screening cytology. These strategies were compared with cytology screening
strategies that did not involve HPV testing. Results from these studies are summarized here, with
more individual study details provided in Appendix C.
These studies address four different cervical cancer screening strategies using HPV: 1)
primary screening with HPV test alone; 2) HPV testing with cytology triage of positive HPV
(reflex cytology); 3) combination HPV and cytology testing (co-testing); and 4) cytology testing
with HPV triage of positive cytology (reflex HPV). Within each HPV screening strategy, we
found at least one fair- or good-quality RCT specifically testing that strategy compared with

Screening for Cervical Cancer 21 Oregon Evidence-based Practice Center

cytology (Tables 5 and 6). Although most trials evaluated only one type of HPV screening
strategy, the Italian NTCC trial addressed two different HPV screening strategies through
separate recruitment phases—combined HPV and cytology testing (Phase I)112 and HPV testing
alone (Phase II).113 The HPV test used in most trials was HC2, to detect 13 high-risk types of
HPV (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) at a positive test cut-off of >1
pg/ml, except for two trials that tested PCR using general primers GP5+ and GP6+ to detect 14
high-risk HPV types (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).114,115
Similarly, most trials compared various HPV screening strategies to cytology performed using
CC, except for two that used LBC.116,117 Colposcopy referral threshold varied between studies,
and in three studies, different cytology thresholds were used by different study sites.112,113,115
All RCTs except one118 (which enrolled previously unscreened women in rural India to
evaluate one-time HPV testing versus cytology) were conducted in developed countries (i.e.,
United States, Italy, Sweden, England, the Netherlands, Finland) where cervical cancer screening
is well established. The Sankaranarayanan trial is important in that it establishes a mortality
benefit in reduced cervical cancer deaths (adjusted hazard ratio [HR], 0.52 [95% CI, 0.33 to
0.83]) with one-time HPV screening in never-screened Indian women aged 30 to 59 years
compared to no screening. Trials addressed HPV screening strategies appropriate to
unvaccinated women. Three trials limited recruitment to middle-aged women (excluding those
younger than age 30 years or older than ages 56 to 64 years),114,115,118 while six included women
younger than age 30 years.112,113,116,117,119,120 Only one study included women older than age 60
years.116 We provide data stratified by age where possible for two primary reasons: 1) the FDA
has approved the use of HC2 in women aged 30 years and older as an adjunct to cytology to
assess the absence or presence of high-risk HPV types;70,71 and 2) the prevalence of high-risk
HPV is much lower in women aged 30 years and older than in women younger than age 30
years, dropping sharply from a prevalence of 35 percent for women aged 15 to 19 years to less
than 15 percent for women aged 30 to 39 years (Figure 4).34
Five RCTs112-115,117 reported program results after two rounds of screening, while the
other four reported results after a single round of screening.116,118-120 Treatment was generally
offered for patients with CIN2+ histology, although in several studies this information was not
clearly reported114,115,118 or a different threshold was used.119,120 Most RCTs reported relative
results (estimating HPV screening strategy performance relative to cytology) by providing
relative test performance characteristics and detection of CIN2+/CIN3+ for a single screening
round and/or comparing cumulative disease detection after multiple screening rounds. The
NTCC Phase I and II trials reported invasive cancer separately from CIN2 and CIN3,112,113 but
the author provided recalculated results for CIN2+ and CIN3+ by age to allow cross-study
comparability. One trial was designed to allow randomized comparison of a differing order in
which cytology and HPV specimens were collected.121 This trial reported cross-sectional data
most comparable with other observational studies, and is reported with these.

Primary Screening With HPV Test Alone

Countries with developed cervical cancer screening programs. One fair-quality RCT
within the national screening program in Italy (NTCC Phase II) compared HC2 to cervical
cytology for primary cervical cancer screening in 49,196 women aged 25 to 60 years (13,725
younger than age 35 years).113 In the second screening round 3 years later, both groups were
screened with cytology alone (Table 5a). Immediate colposcopy referral occurred for positive
HC2 tests or for ASC-US+ cytology (Table 5b). The author provided data reported here for

Screening for Cervical Cancer 22 Oregon Evidence-based Practice Center

CIN3+ and CIN2+, since published data separated out invasive cancer cases. Published outcome
data reporting CIN3 and adenocarcinoma in situ (AIS) (with or without CIN2) are provided in
Appendix C, along with authors’ analyses combining ICC results across two protocols in NTCC
(HPV screening and HPV-LBC co-testing). Trial data are supplemented by one good-quality122
and five fair-quality cohort studies in community settings in the United States, Canada,
Switzerland, Germany, and France (Table 7).110,121,123-125 These studies compared the sensitivity
and specificity of one-time HC2 screening to cervical cytology (primarily ASC-US+) in 40,732
women aged 17 to 93 years, with less than 10 percent (n=3,301) younger than age 30 years.
Women aged 30 or 35 years and older. After two rounds of screening in NTCC Phase
II (one round of HPV screening) and a median of 3.5 years of followup, cumulative detection of
CIN3+ (CIN3, AIS, or ICC) was increased in 17,724 women screened with HC2 relative to
17,747 women screened with cytology alone (55 vs. 35 CIN3+ lesions; RR, 1.57 [95% CI, 1.03
to 2.40]), with about the same number of invasive cancer cases detected in both arms (HC2 arm:
4 ICC/AIS cases; cytology alone: 5 ICC/AIS cases) (Table 8a).113 Trial investigators pooled
invasive cancer cases from these primary HC2 results (NTCC Phase II) with HC2-CC co-testing
results (NTCC Phase I) due to insignificant statistical heterogeneity between trials.113 Pooled
results suggested decreased invasive cancer in women aged 35 years and older who were
screened with HPV (6 total ICC cases in the HPV screening arms compared to 15 in the CC only
arms; p=0.052). However, cancer outcomes would ideally come from comparable screening
strategies and reflect clearly similar opportunities for diagnosis through comparable delivery of
colposcopies and/or long enough followup with registry linkages to allow disease ascertainment
outside the screening program. Because cumulative results are not reported for PPV, false-
positive results, or colposcopy, it is difficult to assess the relative harms of HC2 versus cytology
alone, or the net benefit of the two screening approaches.
Reported baseline colposcopy referrals were higher in HC2 screened women (5.8%),
compared with cytology screened women (2.5%). Colposcopy referral data are not reported for
the second screening round and are incomplete for the entire first round of screening. However,
baseline colposcopy referrals in this trial may be a close approximation for the entire Round 1
screening, since women in both arms had a low threshold for immediate colposcopy referral, so
few would undergo repeat testing strategies. Thus, there were about 3.3 percent more
colposcopies after a single HPV test in Round 1, compared with cytology (ASC-US+ referral
threshold) in women aged 35 years and older. In addition to incomplete reporting of harms and
the use of different screening tests in Rounds 1 and 2 (with cytology alone in both arms in Round
2), another limitation of NTCC Phase II is that referral criteria differed by site in the control arm;
two sites referred patients to colposcopy for LSIL+, and seven sites referred patients for ASC-
US+.
Six community-based studies in both urban and rural settings in Europe, North America,
and Asia reported absolute test performance of HPV alone compared with cytology. In a large
study among women aged 30 years and older (n=7,908), one-time HC2 testing was much more
sensitive than cytology (threshold of ASC-US+) for CIN3+ (HC2: 97.3% [95% CI, 83.2 to 99.6];
cytology: 46.0% [95% CI, 30.8 to 61.9]) and slightly less specific (HC2: 95.2% [95% CI, 93.4 to
96.5]; cytology: 98.0% [95% CI, 96.7 to 98.8]) (Table 9a).123 A second, much smaller, study
(n=774) provided similar estimates of greatly improved sensitivity with slightly reduced
specificity, but with very wide confidence intervals.122 This study’s applicability to women older
than age 30 years is limited, since more than 80 percent of women enrolled were younger than 30
years of age. More studies reported sensitivity and specificity for CIN2+, which generally

Screening for Cervical Cancer 23 Oregon Evidence-based Practice Center

showed the same pattern of markedly higher sensitivity for HC2, with slightly decreased
specificity (Table 9a and Appendix C).110,121,123-128 One study with notably different sensitivity
and specificity estimates for HC2 than the rest may have been affected by misclassification of
women; this study attempted to report results for primary screening separately using an
― enriched‖ screening sample (i.e., 26% of women were already referred for abnormalities
detected in previous screening, while 74% were presenting for primary screening).
Women younger than age 30 or 35 years. The pattern of results in 13,725 younger
women was similar to older women, but with a much higher rate of colposcopy referrals after
HC2 screening (Table 8b). After two rounds of screening in NTCC Phase II, cumulative
detection of CIN3+ also increased in younger women screened with HC2 relative to cytology
alone (47 vs. 21 CIN3+ lesions; RR, 2.19 [95% CI, 1.31 to 3.66]), with few ICC cases detected
in either arm (HC2 arm: 1 case; cytology arm: 0 cases). Relative CIN3+/CIN2+ detection was
increased after HC2 screening in Round 1 to a much greater degree than in older women, with a
possibly greater decrease in Round 2. Colposcopy referrals (reported for Round 1 only) were
much higher in HC2 screened younger women (13.1%), compared to those screened with
cytology (3.6%). One study (n=3,301) provided absolute test performance of HC2 compared
with cytology in women younger than age 30 years.122 HC2 sensitivity (for CIN3+ or CIN2+)
was much higher (23 to 27%) than cytology, similar to markedly increased HC2 sensitivity in
older women. Specificity of HC2, however, was relatively reduced compared to cytology to a
much greater degree in younger women (about 11%) (Table 9b).
Countries without developed cervical cancer screening programs. A fair-quality cluster-
randomized RCT of 131,806 never-screened women aged 30 to 59 years in rural India compared
cervical cancer deaths and incidence up to 8 years after one-time HPV, CC, or visual inspection
with acetic acid (VIA) screening to a never-screened control group.118 One-time HPV testing
significantly reduced the incidence of cervical cancer deaths (adjusted HR, 0.52 [95% CI, 0.33 to
0.83]) and Stage II or higher cervical cancer (adjusted HR, 0.47 [95% CI, 0.32 to 0.69]),
compared to not screening. Neither VIA nor CC significantly reduced either cervical cancer
deaths or incidence of Stage II or higher cervical cancer. Per 100,000 person-years of followup,
there were 19.6 fewer Stage II or higher cervical cancer cases and 13.1 fewer cervical cancer
deaths in the HPV screening group, compared with the unscreened controls. Since 25 percent of
the cervical cancer deaths in the HPV screening group were in women who were not screened
(about 20% of those randomized to the HPV arm), there is potential for even greater benefit if a
larger proportion of never-screened women received a single HPV screening. This study’s intent
was to improve cervical cancer screening in a country developing its population-based screening,
so applicability to the U.S. population or other developed countries is very limited (poor).
Differences in treatment protocols and clinical care between rural India and the United States
also suggest that cancer mortality data should be interpreted with caution. Another important
limitation is that about 20 percent of eligible women randomized to one of the three screening
interventions were neither screened nor included in the analysis.
We found four fair- or good-quality observational studies of primary HPV screening
compared with cytology among 37,245 women aged 25 to 65 years in countries in the process of
developing more robust cervical cancer screening.129-132 All except one of these studies130 show a
pattern consistent with the observational studies conducted in developed countries (i.e., HPV
testing is more sensitive but less specific than cytology). These studies were all judged to have
poor129-131 or fair-to-poor132 applicability to the U.S. population, so they are not discussed
further, but are included in Appendix C Table 3.

Screening for Cervical Cancer 24 Oregon Evidence-based Practice Center

HPV Testing With Cytology Triage of Positive HPV (Reflex Cytology)
We identified one fair-quality RCT120 of 71,337 women aged 25 to 65 years
(approximately 16% younger than age 35 years) within the Finnish national screening program
comparing HC2 testing (with CC testing to triage positive HPV results) to cytology alone.133
HPV+ women with LSIL+ results on cytology triage were referred for immediate colposcopy,
with retesting for ASC-US or HPV+/normal cytology results (Table 5b). Unlike most other
studies, CIN1+ results were treated in all but the latter years of the trial, during which CIN1 in
women younger than age 30 years was surveyed. A second round of screening (5 years after the
initial round) is planned, but results from this second round have not yet been reported.
Additional limitations of the Finnish trial include a high proportion of post-randomization loss
(approximately one-third of women randomized to each study arm did not attend screening);
unequal cross-over between study arms (more women in HPV arm screened with cytology [8%]
than the converse [<0.1%]); and incomplete reporting of colposcopy referral rates (reported for
baseline only) and false positives, particularly important for women aged 35 years and younger.
Women aged 35 years and older. After a single screening round (minimum 2 years of
followup), HC2 testing with CC triage using an LSIL+ threshold nonsignificantly increased
detection of CIN3+ after at least 2 years of followup, compared to cytology, in women older than
35 years (32 vs. 23 CIN3+ cases; RR, 1.38 [95% CI, 0.81 to 2.36]) and significantly increased
CIN2+ detection (RR, 1.36 [95% CI, 0.98 to1.89]) (Table 8a). Six cases of invasive cancer were
detected with HPV screening and four with conventional screening. Colposcopy referrals were
modest in women older than age 35 years and similar between HPV screening (0.9%) and
cytology alone (1.0%). Based on test positivity, these data appear to reflect immediate referrals
for LSIL+ and appear not to include colposcopy due to retesting during initial or extended
followup.
Extended followup (mean, 3.3 years; maximum, 5.0 years) of this first screening round
with linkage to registry data in 38,670 screened women aged 30 to 64 years found significantly
increased CIN3+ (and cancer) after cytology triage of HC2 testing, compared with cytology
alone (HC2: 59 CIN3+ cases, including 11 ICC/ACIS; CC: 33 CIN3+ cases, including 6
ICC/ACIS; RR, 1.77 [95% CI, 1.16 to 2.74]).134 Extended followup included just over half of the
original cohort, with women from eight of the original nine municipalities and only women older
than age 30 years. Additional cases were detected in those who were invited but did not attend
program-based screening. However, relative detection of CIN3+ was also increased using an
intention-to-screen analysis among all women invited (1.44 [95% CI, 1.01 to 2.05]). The
majority of women who tested positive in both arms (1244/1354 in HPV with triage arm and
1053/1125 in cytology arm) were not referred for immediate colposcopy, but had retesting
recommended (data not shown). Almost half of CIN3+ cases detected in both arms came from
the groups recommended for retesting. It also took longer for a relative CIN3+ detection
advantage to emerge between women immediately referred for colposcopy and those who
underwent repeat testing. Within 1 year of initial screening, cases of CIN3+ from women with
LSIL+ cytology were detected, while it took 3 to 3.5 years for all CIN3+ cases to accrue among
women undergoing repeat testing for less abnormal results (HPV+ with or without ASC-US+
cytology). Thus, adequate length and completeness of followup appears important in determining
the comparative detection impact of screening strategies. Women who screened HPV negative
tended toward a relatively lower risk of CIN3+ compared with cytology negative women (0.28
[95% CI, 0.04 to 1.17]) (data not shown).

Screening for Cervical Cancer 25 Oregon Evidence-based Practice Center

 Women younger than age 35 years. Round 1 results (without extended followup) in
11,580 women younger than age 35 years found no enhanced CIN3+ or CIN2+ detection and
little difference between HC2 screening with cytology triage and cytology alone in immediate
colposcopy referrals (2.8 vs. 2.7%) (Table 8b). Complete Round 1 colposcopy referrals are likely
higher in the HC2-cytology triage arm, since 15.8 percent of younger women in this arm were
targeted for repeat testing, about twice as many as in the colposcopy arm alone (data not shown).

Combination HPV and Cytology Testing (Co-Testing)

We found four fair-quality RCTs within national screening programs in Italy, the United
Kingdom, Sweden, and the Netherlands comparing cytology screening alone to combination
testing (co-testing) in a total of 127,149 women aged 20 to 64 years (16,976 younger than age 30
or 35 years).112,114,115,117 Trials tested HC2 plus LBC against CC (NTCC Phase I); HC2 plus LBC
against LBC (A Randomised Trial in Screening to Improve Cytology [ARTISTIC]); or PCR
using GP5+/6+ plus CC against CC (Population Based Screening Study Amsterdam Program
[POBASCAM], Swedescreen). Colposcopy referral thresholds for cytology results varied
considerably between trials (HSIL+ for ARTISTIC and POBASCAM, HSIL+ or ASC-US+ for
different sites within Swedescreen, ASC-US+ or LSIL+ for different sites within NTCC Phase I).
A cytology referral threshold of ASC-US+ or LSIL+ is probably most applicable to U.S.
screening practice. Three trials (POBASCAM, Swedescreen, ARTISTIC) based immediate
colposcopy referral on cytology results alone in both arms, using HPV positive results (alone or
in combination with milder cytology abnormalities) to determine enhanced followup testing
protocols (Table 5b).114,117,115 NTCC Phase I followed a similar approach in women younger than
age 35 years (retesting for HPV+ in persons with normal cytology), but referred older women
with either HPV positive or ASC-US+ cytology results for immediate colposcopy.112 No trials
represented screening and retesting protocols identical to U.S. practice (as represented by
ASCCP guidelines) for ASC-US or LSIL in combination with HPV results. Two trials changed
screening strategies in the second round: POBASCAM screened both arms with PCR plus
cytology after 5 years, while NTCC Phase I screened both arms after 3 years with cytology only
(Table 5b).112,114
Duration of overall followup and completeness of followup for the whole sample varied
between studies, which potentially affected complete ascertainment of outcomes. Followup
interval from baseline was reported as 4.1 years (mean) in Swedescreen, up to 7 years in
ARTISTIC, at least 6.5 years (median, 7.2) in POBASCAM, and up to 3.5 years after Round 2
invitation in NTCC Phase I. Based on incomplete followup, program impact could not be
reported for a substantial portion of the sample in POBASCAM (not reported for the two-thirds
without full 6.5 years of followup), while 29 percent of the sample in ARTISTIC had less than
the minimal (2.5 years) followup after Round 2. Reporting of results after a third screening round
in ARTISTIC did not remedy this.135 Followup after a second screening round at 3 years in
Swedescreen averaged less than 1 year, and did not include retesting of low-grade abnormalities.
Another limitation of the co-testing trials was adherence to trial protocols. Just 50 to 60 percent
of POBASCAM participants complied with repeat testing recommendations in each screening
round. Twenty percent of POBASCAM participants in each arm had opportunistic screening
outside the study, and 10 percent of ARTISTIC participants had no HPV test in Round 2; these
deviations from protocol would be expected to attenuate measured differences between screening
strategies. Given the variability in HPV-cytology co-testing strategies between trials and the lack

Screening for Cervical Cancer 26 Oregon Evidence-based Practice Center

of complete implementation and reporting for all trials at this time, we did not try to
quantitatively combine results.
We supplemented trial data with test performance data from four cohort studies (three of
fair quality and one of good quality) in community settings in the United States, Canada,
Germany, and France (Table 7).110,121-123 These studies compared the sensitivity and specificity
of one-time HC2 plus cervical cytology (defining a positive result using various combinations of
test results) to cytology alone (ASC-US+) or HC2 alone in 25,040 women aged 18 to 69 years
(3,301 younger than age 30 years) (Table 9).
Women older than age 30 or 35 years. In contrast with HPV screening alone, HPV plus
cytology co-testing (using any of the variable screening, retest, and referral protocols) did not
detect more CIN3+ after two rounds of screening than cytology alone in any of the trials (Table
8a). This finding may reflect the more stringent colposcopy referral protocols employed in most
co-testing trials, compared with the one primary HPV screening trial (NTCC Phase II) (Table
5b). Round-specific screening results were somewhat mixed between trials, but generally
detected relatively more CIN2+ with co-testing compared with cytology alone after Round 1, and
less CIN3+ after Round 2. In all but one trial,117 51 to 78 percent more women with CIN2+ were
detected in Round 1. ARTISTIC reported a 21 percent increase in CIN2+ detection that was not
statistically significant, but also included all ages when reporting round-specific data (21% of
women younger than age 30 years). All trials found 47 to 54 percent less CIN3+ detected in
Round 2, although not all differences were statistically significant. Most trials detected the same
or slightly fewer cancer cases overall in the HPV-tested arm, with few reporting impact on
cancer incidence (i.e., second round relative cancer detection). Cumulative CIN2+ detection was
relatively increased in the co-testing arm of a single trial (NTCC Phase I) that referred women
with a positive HPV test or ASC-US+ cytology for immediate colposcopy.112
Given the many between-trial differences, it is difficult to interpret the mixed pattern of
results. Findings to date do not reflect full followup of the second round of screening for any trial
except NTCC Phase I (Table 5c). Reported results for colposcopy referral/attendance were also
incomplete (NTCC Phase I, Swedescreen),112,115 or round-specific colposcopy by age was not
reported (ARTISTIC).117 Colposcopy compliance was rarely reported. Cumulative colposcopies
in ARTISTIC were higher in women randomized to co-testing (8.3%) than in those in the LBC
only arm (6.4%), with a much higher colposcopy burden carried by women younger than age 30
years receiving co-testing (17.1%), compared with co-tested older women (6.0%) or with
similarly young women receiving cytology only (12.0%) (Table 8).117 Cumulative colposcopies
reported in POBASCAM were low (3.4% for co-testing, 2.8% for cytology alone) and
inadequate for estimating the burden associated with co-testing (compared with cytology alone),
since both arms received HPV testing in Round 2.114 Also, as with ARTISTIC, POBASCAM’s
immediate colposcopy referral threshold (HSIL+, with retesting protocols for ASC-US or LSIL
results with or without HPV positivity) does not replicate recommended U.S. practice, so
complete results will need to be judged for applicability. Nonetheless, most co-testing studies
report reduced CIN3+ in the second round of screening compared with cytology screening.
Reduced CIN3+ after a second screening round was used as the primary outcome for power
calculations in several co-testing trials (ARTISTIC, POBASCAM) and an HPV with cytology
triage trial (Finnish trial), indicating its perceived value.

Screening for Cervical Cancer 27 Oregon Evidence-based Practice Center

 Findings from trials are complemented by fair- or good-quality studies of one-time
combined HC2 plus cytology (co-testing) test performance (Table 7). In these cross-sectional
studies of 17,885 women aged 30 to 60 years, a one-time co-test was generally more sensitive
than cytology (for detection of CIN2+ or CIN3+), but also less specific. Reported sensitivity and
specificity are not completely comparable across studies since most used different thresholds for
test positivity (Table 9a). Two studies, in which co-testing was positive if either HPV or
cytology were abnormal, reported very high sensitivity for HC2 plus cytology co-testing that was
clearly superior to cytology alone (44 to 56% more sensitive) at an ASC-US+ threshold, but not
clearly more sensitive than HC2 alone.121,123 This co-testing strategy (either test positive) was
also 4 to 5 percent less specific than cytology alone, and appeared similar to HC2 testing
alone.121,123 Other co-testing strategies required both HPV and cytology tests to be positive,
unless cytology met a threshold. One co-testing study based a positive result on HSIL+ cytology
or a co-test result of HPV positive with ASC-US+ cytology,110 while the other based a positive
result on LSIL+ cytology or HPV+/ASC-US+ cytology results.122 With these strategies,
sensitivity of co-testing for CIN2+ or CIN3 was the same or somewhat better than cytology
alone, but worse than HC2 alone (although confidence intervals were very wide). As expected,
specificity for this more stringent definition of a positive co-test was better than HC2 alone, and
similar or better than cytology alone. These co-test strategies are more similar to testing with
either test alone, followed by triage if HPV+ or ASC-US cytology results using the other test,
than to administering and acting on both tests.
Women younger than age 30 or 35 years. Only two co-testing trials (NTCC Phase I,
ARTISTIC) included women younger than age 30 or 35 years (Table 8b).112,117 Complete age-
specific data were reported in NTCC Phase I only, and ARTISTIC is discussed with the results
for women aged 30 or 35 years and older, since it largely reflects older women. NTCC Phase I
compared one round of co-testing followed by cytology with two rounds of cytology. In contrast
with the general pattern in older women (in NTCC Phase I and other co-testing trials), NTCC
Phase I found no impact on CIN3+ in Round 1, Round 2, or cumulatively in 11,810 women aged
25 to 34 years. CIN2+ detection in younger women, however, was significantly increased in
Round 1 and cumulatively. We had particular quality concerns for younger women in NTCC
Phase I. Per protocol, the trial did not refer HPV positive/cytology negative younger women for
immediate colposcopy, as it did with older women. Instead, younger women were retested at 1
year (Table 5b), a strategy reflecting the higher prevalence of HPV infection and likelihood of
regression in young women. However, this difference in testing protocols led to differential loss
to followup between the intervention and control arms, as many participants did not comply with
repeat testing protocols. No cumulative data on colposcopy referrals in NTCC Phase I are
available, and the higher baseline rate of colposcopy in younger women after co-testing
compared with cytology alone (11.9 vs. 4.1%) is likely an underestimate, since these data reflect
only immediate referrals.
In the only co-testing test performance study conducted primarily in younger women,122
co-test positives were defined as both ASC-US+ and HPV+ (Table 9b). Co-testing was
significantly less sensitive for CIN3+ (64.0% [95% CI, 51.1 to 77.6]) than HC2 alone (92.5%
[95% CI, 83.5 to 97.3]), but not different than cytology alone (65.4% [95% CI, 51.9 to 79.1]).
Specificity (87.6% [95% CI, 86.7 to 88.4]) was significantly higher than cytology alone (81.5%
[95% CI, 80.7 to 82.3]) and HC2 alone (70.1% [95% CI, 66.5 to 73.1]). This strategy is
dissimilar to that used in NTCC Phase I, and primarily mimics testing with either test alone,

Screening for Cervical Cancer 28 Oregon Evidence-based Practice Center

followed by triage if HPV+ or ASC-US+ cytology results using the other test. Positive results on
both tests would be considered necessary for immediate colposcopy referral.

Cytology Testing With HPV Triage of Positive Cytology (Reflex HPV)

We identified two good-quality RCTs in the United States116 and Sweden119 (Table 6)
that addressed HPV triage of positive cytology. Neither study, however, compared HPV testing
alone to repeat cytology in women referred with ASC-US or LSIL cytology. We also located
four prospective cohort studies in countries with developed cervical cancer screening programs
(United States, Sweden, France, Italy), three of fair quality136-138 and one of good quality,100 that
evaluated the use of HPV testing using HC2 for triaging 2,261 women aged 15 to 78 years with
ASC-US and LSIL cytology to colposcopy (Table 10). Three of the cohort studies compared
one-time HPV screening to repeat cytology for triage of women referred with ASC-US or LSIL
cytology.100,136,137 In the fourth cohort study, women with ASC-US received repeat cytology and
HPV testing at enrollment.138 Women who tested positive on either test were invited for repeat
HPV and cytology testing 6 months later. All women received HPV and cytology testing at 12-
month followup. All studies compared HC2 to repeat CC, except ALTS, which compared HC2
and LBC to LBC alone (ThinPrep).
ALTS was a three-armed RCT that compared immediate colposcopy referral to HPV
testing (HC2) plus repeat LBC or cytology (LBC) retesting alone (conservative management) to
determine colposcopy referral in 5,060 U.S. women aged 18 to 81 years with community Pap
smear diagnoses (69% ASC-US, 31% LSIL).116 ALTS participants were primarily young (77.5%
younger than age 35 years) and were racially and ethnically diverse. Criteria for immediate
colposcopy referral was HSIL+ on repeat testing in either arm or positive HPV results in the
intervention group. All women received colposcopy at 2 years. The reported sensitivity of the
three arms for detection of CIN3+ was actually a calculation of the cases of CIN3+ detected
using each of the management strategies within the a priori-defined period for the strategy
(enrollment period for HPV arm and enrollment plus followup periods for conservative
management) out of the total CIN3+ detected in that arm over the 2-year study period. This
calculation focuses on comparing the efficacy of a single test event (HPV plus cytology) with
ongoing testing (with cytology alone).
Within the a priori-defined periods for each strategy, CIN3+ was detected in 6.3 percent
of women in the HPV-LBC triage arm and 5.1 percent in the cytology triage arm, for a relative
CIN3+ detection ratio of 1.24 (95% CI, 0.88 to 1.73) (Table 11). CIN3+ included two cases of
ICC and one case of AIS across all arms (one per arm) and similar cumulative CIN3+ cases (97
in immediate colposcopy arm, 101 in HPV triage, 109 in conservative management). HPV
testing diagnosed a greater percentage of the CIN3+ cases at baseline, rather than during
followup or at the exit visit (75.2% of all cases detected over the 2 years of the study), than
immediate colposcopy (59.8%) or followup cytology (40.7%). At a cytology threshold of
HSIL+, repeat cytology triage over 2 years referred significantly fewer women to colposcopy
than HPV-cytology triage (12.3% vs. 55.6%; p<0.001), with no colposcopy referrals in the HPV
arm based on cytology alone. Colposcopy compliance was reduced slightly when delayed
(90.1% after HPV triage, 98.7% with immediate colposcopy referral).
Among women with LSIL enrolled in ALTS, HPV testing diagnosed a greater percentage
of the CIN3+ cases at baseline, rather than during followup or at the exit visit (68.3% of all cases
detected over the 2 years of the study), than immediate colposcopy (62.7%) or followup cytology
(36.6%). HPV testing to triage LSIL, however, referred a vast majority of women (85%) to

Screening for Cervical Cancer 29 Oregon Evidence-based Practice Center

colposcopy. CIN3+ was detected in 12.1 percent of women in the HPV-LBC triage arm and 6.7
percent in the cytology triage arm. The HPV arm was closed early due to very high HPV
positivity, leading to an unequal number of women in each arm. Therefore, relative detection
ratios are not valid in women with LSIL.
The ALTS trial was rated as good quality, but had some limitations, particularly related
to applicability. The study design does not likely reflect current standard practice for ASC-US
cytology in U.S. practice. This study used a repeat cytology threshold of HSIL for referral to
colposcopy, while recent guidelines recommend referral of women to colposcopy if ASC-US or
worse is identified on repeat cytology.68 The results of the ALTS trial are reasonable estimates of
what the study arms would produce in real life. While theoretical estimates are reported by the
authors, the data provided do not allow for calculation of realistic estimates of comparative
referral rates for usual care. More women would potentially have been referred to colposcopy,
and sensitivity for CIN3+ might have been higher in the conventional management arm if a
lower cytology threshold for referral had been employed. Whether this would have differed from
the HPV triage strategy is unknown.
A second, smaller RCT compared HPV testing (HC2) plus repeat CC to repeat CC alone
in 674 women aged 23 to 60 years with ASC-US or LSIL Pap smears identified through the
Swedish national screening program.119 After one round of triage, 132 CIN3+ lesions (including
one ICC) were detected, and relative CIN3+ detection tended to be higher with HPV-CC triage
than CC triage alone (1.20 [95% CI, 0.88 to 1.63]) (Table 11). These results were very similar in
magnitude to the single round in ALTS, but nonstatistically significant. Although power was
limited, HPV-CC triage tended to improve relative CIN3+ detection primarily in women aged 30
years and older. HPV-CC triage significantly improved CIN2+ detection compared with CC
alone (1.32 [95% CI, 1.04 to 1.67]), with relatively greater detection of CIN2+ in younger
women. A very large proportion of women (62% in the HPV-CC triage arm and 41% of women
in the CC triage arm) were referred to colposcopy after triage. The relative false-positive
proportion for CIN3+ was 1.74 (95% CI, 1.38 to 2.20), meaning there were seven false positives
in the HPV-CC triage arm for every four in the CC-only triage arm. Age-specific results
suggested worse relative false-positive performance for women younger than age 30 years,
compared with older women.
This trial differed from ALTS in several important ways: 1) women were referred at a
threshold of ASC-US (and/or HPV positive results) after one triage test, rather than through a
program of repeat testing; and 2) all triage positive women were treated with LEEP, laser
conization, or hysterectomy, providing good histological confirmation of disease. While this trial
was rated as good quality, its small sample size limits its power. Additionally, the applicability of
this trial to U.S. practice is limited because the authors do not present results separately for
women referred with ASC-US versus LSIL cytology. As seen in the ALTS trial and the
observational studies discussed below, the HPV test does not perform well as a triage test in
women referred with LSIL cytology due to low specificity, whereas the specificity of HPV is
similar to repeat cytology in the triage of women with ASC-US cytology to colposcopy.
Three fair-quality studies136-138 and one good-quality study100 that included 2,299 women
aged 15 to 78 years with ASC-US on initial CC screening compared the absolute sensitivity and
specificity of HPV alone or combined with cytology to repeat cytology alone for the detection of
CIN2+ (Table 12). Studies primarily reported CIN2+ using a referral threshold of ASC-US+ or
HC2 >1 pg/ml. All but one of these studies trended toward higher sensitivity for HPV.136 The
confidence intervals, however, were wide, and the differences were not statistically

Screening for Cervical Cancer 30 Oregon Evidence-based Practice Center

significant.100,137,138 HPV tended to have similar100or worse specificity136,137 than repeat cytology
in all but one study that showed slightly improved specificity with HPV,138 although power was
an issue in most comparisons. HPV plus cytology tended to improve sensitivity but reduce
specificity (with limited power, because fewer than 1,000 women with ASC-US were evaluated
for these comparisons).136,138
The cohort studies were small (total n=2,299), but data could be pooled for three of the
studies (n=1,550) to provide combined test performance estimates for the comparison of HPV
testing to repeat cytology for the detection of CIN2+ among women with ASC-US referral
cytology (Figures 7 and 8).100,137,138 The pooled difference in sensitivity between HC2 and repeat
cytology was estimated to be 12 percent (95% CI, 0.2 to 23.9), suggesting a better sensitivity for
HC2. The confidence interval was wide even after pooling due to small sample sizes. No
difference in specificity between HC2 and repeat cytology was observed (P=0.65 for the
combined difference).
The fourth cohort study was not pooled because it provided cumulative test performance
over 1 year for detection of CIN2+ among women with ASC-US cytology results.138 In this
study, HC2 alone was more sensitive than cytology for the detection of CIN2+ (93.1% [95% CI,
91.3 to 94.9] vs. 74.1% [95% CI, 70.9 to 77.3]) and more specific (78.6% [95% CI, 75.7 to 81.6]
vs. 72.3% [95% CI, 69.0 to 75.6]). The combination of both cytology and HPV testing was 100
percent sensitive, but less specific (62.5% [95% CI, 58.9 to 66.0]) than either HC2 alone or
cytology alone. Age-specific results showed significantly better sensitivity and a tendency
toward better specificity (but worse PPV) with repeat cytology in women aged 35 years and
older, compared with younger women. In older women, HPV triage had a significantly higher
area under the curve (AUC) (0.92) than in younger women (AUC, 0.74).
One study confirmed worsened sensitivity of immediate colposcopy that ALTS also
found when compared to HPV testing (but not repeat Pap testing) in all women with ASC-US,
regardless of age.138 When data were reported for triaging initial LSIL results using HPV,137 with
or without repeat cytology,136 these studies confirmed findings from ALTS of very poor
specificity of HPV testing strategies for triaging LSIL.
Findings from observational studies generally represented older women (mean or median
age, 34 to 42 years) and confirmed an increased detection of CIN2+ with HPV triage of ASC-US
cytology (compared with repeat CC) and no further sensitivity advantage of adding CC to HPV
triage. Trial results suggest reduced specificity (more false positives and colposcopies) with an
HPV triage strategy, and most observational studies agree. In one small study (n=749) of ASC-
US only that reported age-specific results for women younger and older than age 35 years,
sensitivity for CIN2+ did not differ by age. However, in women aged 35 years and older,
specificity for HC2 was better than for repeat cytology (84.8% vs. 74.7%), while in women
younger than age 35 years, specificity for HC2 tended to be lower than for repeat cytology
(60.4% vs. 65.5%).138

Key Question 4. What Are the Harms of Liquid-Based

Cytology?
Potential harms of screening with LBC (which are also potential harms of CC) include
harm from collecting the cytologic sample itself, harm from unnecessary evaluation of false-
positive smears, psychological distress associated with a false-positive result, and the economic
burden related to recall for repeated sampling due to an inadequate or insufficient LBC

Screening for Cervical Cancer 31 Oregon Evidence-based Practice Center

specimen. We did not identify any studies that specifically addressed direct harm from collection
of the LBC sample or psychological distress. Additionally, we did not systematically review the
harms of diagnosis with colposcopy and biopsy.

Key Question 5. What Are the Harms of Using HPV Testing as

a Screening Test, Either Alone or in Combination With
Cytology?
Potential harms of HPV testing include harm from collecting the sample, psychological
distress associated with a false-positive result or unnecessary evaluation of a false-positive result,
partner discord, and the economic burden related to recall for repeated sampling due to an
inadequate or insufficient specimen. Seven of the studies included for KQ3 reported on
insufficient HPV test samples (Appendix C Table 3).112,113,115-117,122,132 The range of insufficient
HPV test samples from these studies (including both HC2 and PCR) ranged from 0.08 to 6.0
percent of samples taken. No studies reported direct harm from collection of the cervical sample
itself.
We found four fair-quality observational studies that examined the psychological impact
of HPV testing (Tables 13 and 14).139-142 Three were conducted in the United Kingdom, two
cross-sectional surveys140,141 and one consecutive series139 of patients evaluated from a
randomized trial of combined HPV and LBC testing, which included 4,155 women aged 20 to 64
years presenting for routine cervical screening. These three studies focused on the psychological
impact of knowing HPV test results. The fourth, a randomized trial of HPV triage of ASC-US
Pap smears conducted in Australia (n=314), evaluated the psychological impact of HPV triage
versus repeat cytology versus having an informed choice of either an HPV test or repeat
cytology.142 All study details are included in Appendix C.
Two of the three studies evaluating the psychological impact of knowing HPV test status
(known test positive versus test negative, known test result versus no test result) evaluated only
the immediate impact of the HPV test results.139,141 The third evaluated participants both at 1
week and 6 months after receiving test results.140 These studies found testing positive resulted in
short-term increases in anxiety and distress among women who knew their HPV test result, but
these findings resolved by 6-month followup (Table 14). Among women who did not know their
test results, there were no differences in anxiety and distress between women who tested
positive. In the fourth study that evaluated the short- and long-term psychological impact of HPV
triage of ASC-US cytology versus repeat cytology, long-term followup suggested greater
satisfaction with care and less distress among women undergoing HPV testing.142
A fair-quality study by McCaffery and colleagues evaluated adverse psychological
effects in 428 women attending routine cervical screening at a NHS well-woman clinic after
being given standard information about HPV (Table 13).141 Seventy-three percent of women
enrolled were included in the final analysis. The analysis compared psychological outcomes by
screening test results using four study groups: 1) normal cytology, HPV negative (n=185); 2)
normal cytology, HPV positive (n=46); 3) abnormal/unsatisfactory cytology, HPV negative
(n=17); and 4) abnormal/unsatisfactory cytology, HPV positive (n=23). Baseline State-Trait
Anxiety Inventory (STAI) scores did not differ.141 Among those with normal cytology results,
women who tested positive for HPV were significantly more anxious (mean STAI score, 43.5 vs.
29.8; F=39; p<0.0001) and distressed (mean Coping Strategy Questionnaire [CSQ] score, 13 vs.

Screening for Cervical Cancer 32 Oregon Evidence-based Practice Center

8.9; F=69; p<0.0001) than those whose tests were negative (Table 13).141 Among participants
with abnormal or unsatisfactory cytology, women who tested positive for HPV did not differ in
anxiety, but women who were HPV positive were significantly more distressed (mean CSQ
score, 17 vs. 14; F=8.8; p=0.002).141
A second study evaluated the short-term psychological impact of HPV testing in a
consecutive sample of women enrolled in the ARTISTIC trial with normal or mildly abnormal
cytology (Table 13).139 Women in the ARTISTIC trial underwent both cytology and HPV
testing, but in one arm the HPV test result was concealed. Overall, 2,700 women in the revealed
arm and 882 women in the concealed arm were mailed questionnaires assessing psychological
distress, anxiety, and sexual satisfaction at 2 weeks after they had received the results of their
baseline cytology. This study was rated as fair quality, with the primary concern that no baseline
General Health Questionnaire (GHQ), STAI, or Sexual Rating Scale (SRS) testing was assessed
for study participants prior to undergoing cervical cancer screening. In addition, the followup
questionnaire had a response rate of about 70 percent.139 The primary comparison was made
among women with normal cytology who either knew (revealed arm) or did not know (concealed
arm) they were HPV positive.139
The two groups did not differ in distress or anxiety (Table 14). Women in the HPV
revealed arm did indicate lower sexual satisfaction with their current partner (adjusted mean
difference in SRS score, -7.28 [95% CI, -12.60 to -1.96]). Planned subgroup analyses of women
who had borderline or mild abnormalities on cervical cytology revealed no significant
differences in distress, anxiety, or sexual satisfaction between the two groups. The study also
compared women within the revealed arm of the study who knew their HPV test result.139
Among women with negative cytology results, the odds of psychological distress (GHQ score
≥4) were increased (age adjusted OR, 1.70 [95% CI, 1.33 to 2.17]), and mean GHQ scores were
higher (mean difference, 1.43 [95% CI, 0.75 to 2.10]) for women who knew they were HPV
positive compared to women who knew they were negative. STAI scores indicated higher state
(mean difference, 2.90 [95% CI, 1.40 to 4.39]) and trait (mean difference, 1.53 [95% CI, 0.16 to
2.92]) anxiety levels for women who were HPV positive. There were no statistically significant
differences between HPV positive and negative women with mild or borderline cytology results,
except that women who were HPV positive had higher odds of sexual satisfaction with their
current partners than those who were HPV negative (mean difference, 8.66 [95% CI, 4.30 to
13.02]; p<0.0001).
The third study evaluating the psychological impact of HPV test results was conducted
by Maissi and colleagues,140,143 who evaluated 2,183 women attending routine cervical screening
at two of the three centers taking part in an English HPV/LBC pilot study (Table 14). In addition
to assessing distress and anxiety, they also assessed health-related quality of life (EuroQol EQ-
5D). Outcomes were assessed by mailed questionnaire within 1 week after women had received
their HPV and cytology results. Sixty-three percent of women returned the 1-week questionnaire,
and 74 percent completed a followup questionnaire at 6 months. No data were provided to assess
differences between responders and nonresponders. The analysis compared psychological
outcomes among four groups of participants: women with 1) normal cytology results and no
HPV test, 2) borderline or mildly abnormal cytology results and no HPV test, 3) borderline or
mildly abnormal cytology results and an HPV negative test, and 4) borderline or mildly
abnormal cytology results and an HPV positive test.140,143 The study groups varied significantly
in baseline characteristics; however, attempts were made to control for potential confounders in
multivariate analyses.140,143

Screening for Cervical Cancer 33 Oregon Evidence-based Practice Center

 Results from immediate followup showed that the groups differed significantly in anxiety
(F=4.44; p=0.004), distress (F=5.37; p=0.001), and concern about test result scores (F=242.46;
p<0.001) (Table 14).140,143 Women with abnormal cytology who were HPV positive had
significantly higher anxiety (mean, 39.6 vs. 37.6; p<0.00), distress (mean, 2.8 vs. 2.1; p<0.05),
and concern (mean, 9.7 vs. 8.8; p<0.05) than women who were HPV negative. There was no
difference in anxiety, distress, or concern between women who had negative HPV tests and
women who were not tested for HPV.
At 6 months, the groups still differed significantly in concern about test results (F=83.39;
p<0.001), but not in anxiety or distress (Table 14).140,143 Levels of anxiety, distress, and concern
did not differ significantly between the HPV positive and HPV negative groups. Groups did not
differ in health-related quality of life scores at baseline or followup. All four groups had low
scores on the Psychological Effects of Abnormal Pap Smears Questionnaire, indicating low
levels of sexual health worries, but women who were HPV positive had significantly higher
scores than women who were HPV negative (p<0.05).
The fourth study, by McCaffery and colleagues, evaluated the psychological impact of
HPV triage versus repeat cytology versus having an informed choice of either an HPV test or
repeat cytology among women from family planning clinics across Australia with ASC-US
equivalent cytology results (Table 13).142 Overall, this was a well-designed, pragmatic,
nonblinded RCT with good followup. Outcomes were assessed by questionnaire at baseline and
at 2 weeks, 3 months, 6 months, and 12 months after the triage test. The primary outcome
measure was health-related quality of life (36-Item Short-Form Health Survey, mental health
combined score). They also assessed cognitive measures (perceived disease severity and risk,
intrusive thoughts, worry, and satisfaction with care), emotional measures (anxiety, distress, and
concerns about infectivity and effects on relationships), and behavioral measures (effects on
sexual health, help seeking behavior, and visits to primary care physician).
At 2 weeks, no significant differences were seen between the three groups in
psychosocial outcomes, except in proportion reporting intrusive thoughts (57%, 43%, and 32%
for the HPV, informed consent, and repeat cytology groups, respectively; p=0.02) and
satisfaction with care (p=0.04). Over 1 year, however, distress was significantly less in the HPV
group than either the repeat cytology or informed choice groups, with mean CSQ scores of 16.6
in the HPV group, 18.4 in the cytology group, and 17.5 in the informed choice group (p<0.01).142
Mean satisfaction scores were highest among women randomized to HPV testing and informed
choice. The authors hypothesized that the longer wait for results in those who chose or were
assigned to cytology likely accounted for higher distress and lower satisfaction in this group.

Screening for Cervical Cancer 34 Oregon Evidence-based Practice Center

Chapter 4. Discussion

Summary of Review Findings

Cervical cancer screening’s impact on reducing cervical cancer rates has been well-
established by epidemiological evidence.144 Evidence to evaluate the most efficient and effective
screening approaches, however, has changed substantially since the 2003 USPSTF review and
recommendation.145 At that time, there was insufficient evidence to evaluate newer technologies,
including LBC and high-risk HPV DNA screening. Largely within the past 5 years, results from
eight RCTs evaluating HPV-enhanced screening strategies have been reported, with ongoing
results as additional screening rounds are completed.112-117,119,120 Another updated body of
evidence addresses whether LBC and CC are generally equivalent. A large RCT compared LBC
to CC,108 and another large RCT compared these two cytological approaches using data from an
HPV-cytology co-testing trial.107 Data from trials for newer technologies are supplemented by
well-done observational studies evaluating absolute test performance. When well-done,
observational studies can be viewed as superior in some ways, since they compare test
performance in the same women. However, since their results represent only cross-sectional
histological findings, longitudinal followup with rescreening (as in trials) is needed to determine
whether any differences in detected cervical lesions represent true (likely to progress) predisease.
The USPSTF began formulating its update in 2006 with a focus primarily on evidence for
newer cervical cancer screening technologies. This report also focuses primarily on studies
applicable to the United States or other countries with well-developed, population-based cervical
cancer screening. Thus, while some promising trials and studies have been performed in
India118,129 and China,130-132 their results have not been discussed, nor do they inform our
discussion and conclusions.
Table 15 presents a summary of evidence for each KQ in order, which we briefly discuss
next.

Initiation of Cervical Cancer Screening

The available evidence from five studies (four of fair quality and one of good quality)
cumulatively suggests no benefit to cervical cancer screening for women before the age of 21
years. The goal of cervical cancer screening is detecting and treating preinvasive lesions, and
incidence of CIN2 and CIN3 does not begin to peak until women reach their late 20s. The
findings of Woodman and colleagues106 and Peto and colleagues32 confirm the findings of other
studies146 indicating that the prevalence and incidence of HPV infections in women younger than
age 20 years is high, but most infections and cytologic abnormalities are transient. Moreover, a
study by Insinga and colleagues found that the risk of false-positive smears is higher for women
younger than age 25 years than for women aged 25 to 29 years (3.1 to 3.5% vs. 2.1%,
respectively).104 U.S. incidence data demonstrate that ICC is rare in women younger than age 20
years.17 Overall, between 2000 and 2008, the age-adjusted incidence rate of cervical cancer
among women younger than age 20 years was 0.05 cases per 100,000 U.S. women.17 By
comparison, the annual age-adjusted incidence rate for breast cancer in men of all ages was
1.1/100,000.147 The high prevalence of HPV, the transient nature of cytologic abnormalities, and
the rare occurrence of cervical cancer in adolescents argue against cytologic screening for

Screening for Cervical Cancer 35 Oregon Evidence-based Practice Center

women younger than age 20 years, irrespective of timing of coitarche or presence of high-risk
sexual practices. In fact, screening in this population may be harmful, as it could lead to
unnecessary intervention. Since CIN1 and CIN2 are likely to regress, overtreatment could
potentially occur.68 Colposcopy and biopsy, which are currently the gold standard for evaluation
of cervical cytologic abnormalities, and treatment of CIN may be associated with anxiety, pain,
and cervical bleeding.84,85,148,149 Furthermore, certain types of CIN treatment procedures may
affect subsequent reproductive outcomes. Two systematic evidence reviews of obstetric
outcomes in women with a history of CKC to treat CIN demonstrate a significantly increased
risk of preterm birth (at less than 30-, 34-, and 37-weeks’ gestation) and low birthweight in
infants (less than 2,000 grams and less than 2,500 grams).86,87 The two reviews differed in the
impact of LEEP on obstetrical outcomes. In one review, pooled estimates demonstrated a 1.7-
fold increased risk of preterm birth prior to 37 weeks and a 1.8-fold increased risk of birthweight
less than 2,500 grams.86 In the other, pooled estimates demonstrated no impact of LEEP on
preterm birth prior to 34 weeks or birthweight less than 2,000 grams.87 Other harms to consider
are the psychological impact of labeling a woman as HPV positive, especially in a population in
which HPV infections are highly prevalent and likely to regress.150-152
Whether initiation of screening in the United States should begin later than age 21 is
unclear. The UK NHS Cervical Screening Programme does not commence cervical cancer
screening until age 25. The large case-control study by Sasieni and colleagues was designed to
determine whether screening should begin prior to age 25 in the United Kingdom.23 While the
authors concluded that screening women aged 20 to 24 years would have little or no impact on
rates of ICC up to age 30, there was still some uncertainty regarding its impact on advanced
stage tumors (IB+) in women younger than 30.23 In June 2009, the UK Advisory Committee on
Cervical Screening reviewed the practice of initiation of screening at age 25 years, and there was
unanimous agreement that there should be no change in their current policy.153 However,
whether this practice should be adopted in the United States is uncertain. The Icelandic study by
Sigurdsson and colleagues105 supports initiation of screening in women in their early 20s,
whereas the UK study was limited in power to definitively determine whether screening among
this group of women is beneficial.23 Neither study provided sufficient detail to allow
determination of a specific age at which screening should be initiated. Furthermore, no studies
were identified that provided information on age at which to initiate cervical cancer screening
using U.S. data.

Liquid-Based Cytology Compared to Conventional Cytology

for Primary Cervical Cancer Screening
The studies we reviewed demonstrated that LBC and CC do not differ in relative
sensitivity or absolute sensitivity and specificity. False-positive rates varied among studies. They
were not significantly different between LBC and CC in the nonrandomized trials. False-positive
proportions in randomized trials were slightly lower in one study and slightly higher in the other,
and both results bordered on statistical significance. The randomized trials included over 130,000
women combined and, thus, were well powered to detect significant differences. Our findings
that LBC and CC do not differ in sensitivity and specificity are consistent with two recently
completed systematic evidence reviews of LBC with more liberal inclusion criteria.154,155
However, the systematic evidence review by Davey and colleagues performed in 2006, prior to
the release of data from the NTCC and NETHCON trials, found that LBC did not reduce the

Screening for Cervical Cancer 36 Oregon Evidence-based Practice Center

proportion of unsatisfactory slides compared to CC.155 Data from the NTCC and NETHCON
trials, in which thousands of women were randomized to LBC or CC, has since been published
and demonstrates that LBC yields fewer unsatisfactory slides than CC.107,108 We were unable to
identify any studies that identified direct harms resulting from collecting the cervical sample for
LBC.
Studies of clinical practice in the United States suggest that LBC has been widely
adopted despite lack of available data to support greater accuracy with LBC testing, compared to
CC.94 One potential reason for the adoption of LBC is the ability to add reflex HPV testing
without requiring an additional examination and specimen collection. Currently, the FDA has
approved HC2 for testing patients with ASC-US cytology to determine the need for referral to
colposcopy, and for use in women aged 30 years or older in conjunction with cytology to assess
the absence or presence of high-risk HPV types. Since specimens for HPV testing can be
collected at the time of cytologic testing without the use of LBC, sophisticated decision analysis
models would need to be developed to determine whether or not the use of LBC is preferable to
CC when HPV testing is desired, as there appears to be no advantage in terms of test
performance to the use of LBC over CC in the absence of HPV testing. An editorial commentary
by Schiffman and Solomon noted that other factors now influence the choice between LBC and
CC, including issues related to laboratory productivity (LBC specimen slides are easier and
quicker to scan under the microscope), slide adequacy (impact of fewer unsatisfactory slides),
relative cost (LBC is more expensive than CC), and ease of ancillary molecular testing.156

HPV-Enhanced Primary Cervical Cancer Screening

The most extensive new data for cervical cancer screening technologies evaluate four
potential roles for HPV in primary cervical cancer screening. However, despite recent detailed
reports from five large RCTs within national screening programs in Italy, England, Finland,
Sweden, and the Netherlands, available data are not yet complete, consistent, or relevant enough
to determine a clear role for HPV testing as a primary cervical cancer screening method in the
United States. One trial (NTCC Phase II) compared HC2 screening alone to CC alone (49,196
women screened; 27.9% younger than age 35 years),113 four trials (NTCC Phase I, POBASCAM,
Swedescreen, ARTISTIC) compared co-testing (with HC2 or PCR and CC or LBC) to CC or
LBC alone (127,149 women; 13.4% younger than age 30 to 35 years),113-115,117 and one trial
(Finnish trial) compared primary HPV screening with cytology triage to CC alone (71,337
women; 16.2% younger than age 35).120
While all but one120 of these trials of primary HPV-enhanced screening have reported
results after two rounds of screening, data needed to determine benefit, harms, and net benefit
remain incompletely reported. As shown in Table 5c, reported benefits (for CIN3+ detection,
Table 16) as a cumulative or second-screening round outcome (Table 17) are considered possible
surrogates for cancer; however, these data also represent incomplete followup of a significant
proportion of study participants in three of four co-testing trials (POBASCAM, Swedescreen,
ARTISTIC).114,115,117 In addition, a planned second screening round is not yet conducted or
reported in one trial (Finnish trial),120 and recent reporting of a third round in ARTISTIC does
not rectify data or other concerns affecting its validity.135
Regarding potential burden or harms, four of six trials (NTCC Phase I and II,
Swedescreen, Finnish trial) representing all types of HPV-enhanced primary screening do not
include data for each screening round and cumulative data, as would be necessary to interpret

Screening for Cervical Cancer 37 Oregon Evidence-based Practice Center

screening burden and potential harms (Table 18).112,113,115,120 Missing data include: proportion
referred and receiving colposcopy immediately or after retesting protocols, proportion referred
for retesting, compliance with retesting referrals, proportion receiving treatment, and, ideally,
proportion experiencing diagnostic and treatment-related harms. Because age-specific data are
critical in HPV-enhanced screening, lack of complete age-specific reporting for important benefit
and harm-related measures in two of three trials including women younger than age 30 or 35
years (ARTISTIC, Finnish trial) further limits their current interpretation.117,120 Reporting of
these data will more fully inform the balance between potential benefits and harms from HPV-
enhanced primary screening strategies, which will be particularly important since some available
metrics (i.e., colposcopy) may appear ― worse‖ after one round of HPV testing (compared with
cytology), but may look better over time if the more sensitive HPV test detected and treated
earlier disease. It will also be particularly important to consider these trials’ applicability, since
none of their screening strategies mimics recommended U.S. practice.
How can we have so much data and yet still not know enough? The answer lies in our
inability to answer two critical questions: 1) how much benefit does incorporating the more
sensitive HPV test into routine screening approaches for cervical cancer provide? and 2) what are
the tradeoffs in order to achieve this benefit? These issues also must be framed in a
programmatic screening perspective focused specifically on cervical cancer. We illustrate these
considerations using one trial, NTCC Phase II (Appendix E).

The Rationale and Potential Pitfalls of HPV-Enhanced Screening

Fair- or good-quality test performance studies (without verification or other serious
biases) of one-time screening test performance clearly indicate that HC2 testing is much more
sensitive than cytology alone for detecting CIN2+ (and CIN3+, based on more limited data).
These data come primarily from women aged 30 to 69 years, within countries with well-
developed cervical cancer screening programs. In the case of one-time co-testing (combined
HPV-cytology screening), sensitivity is also superior to cytology alone, but not clearly better
than HPV alone. For co-testing, test performance studies are fewer and more variable, and each
study reflects a somewhat different test combination for a positive result (Table 9). There is also
a potential bias toward inflated sensitivity when an adjunctive test is added to a conventional test
and this combination is compared to the conventional test in the same women.14 Therefore, based
on test performance studies alone, some improvement in sensitivity compared with cytology is
likely if HPV testing were substituted for (or added to) cytology in primary cervical cancer
screening, but the magnitude of increase is uncertain.
While some improvement in sensitivity with primary HPV screening may be likely, the
degree of benefit in preventing invasive cancer cannot be determined from test performance
studies alone for a number of reasons.14 First, the cross-sectional data suffer from determining
sensitivity, specificity, and related predictive values for a surrogate outcome (CIN2+) and not
true disease (ICC). Cervical cancer has a long preclinical period with predisease (CIN)
regression, as well as progression that cannot be easily or directly studied. Regression can
happen in any preclinical lesion, but appears much more likely in CIN2 or milder abnormal
histological findings than in CIN3.55 If a disease that is destined to regress is detected, it
represents true overdiagnosis and potentially overtreatment. As a surrogate, we can be more
confident in the detection of CIN3+, given that it includes carcinoma in situ, adenocarcinoma, or
ICC, and is more likely to progress and less likely to regress than CIN2+.55 Nonetheless, all
CIN3+ is not clearly destined to quickly progress, leaving some uncertainty about whether

Screening for Cervical Cancer 38 Oregon Evidence-based Practice Center

increased detection and treatment confers a clear benefit in preventing ICC.55 Since cervical
cancer screening consists of a program of repeated screening over time, earlier detection of
precancerous lesions that would not have progressed and could be detected at a subsequent
screening is not a clear benefit. Thus, for many reasons, one-time comparative test performance
studies cannot provide full information on benefit, and complete data from repeated screening
over time are needed. On the other hand, very high sensitivity (and corresponding negative
predictive value [NPV]) is informative when considering screening interval. This concept will be
covered more thoroughly in the section titled ― Potential Subgroup Considerations With HPV-
Enhanced Cervical Cancer Screening.‖
While we are confident there is a meaningful potential benefit from HPV screening, we
also recognize the potential for harms. The same test performance studies suggesting increased
sensitivity also show specificity is generally reduced (between 2.8 and 4.5%). Given that
screening test specificity is critically important when the prevalence of disease is low (as is the
case with cervical cancer overall, but particularly in younger age groups),17 test performance
studies suggesting any decrease in specificity demand further research.157 For example, even a 2
percent decrease in specificity for a one-time screening test in 10,000 U.S. women (with
0.8/1,000 CIN2, 0.7/1,000 CIN3, 0.1/1,000 cervical cancer) would result in 200 additional
women receiving further unnecessary and even harmful testing and/or treatment, compared with
cytology alone.104 No more than one case of cervical cancer could be detected (even with
increased sensitivity), although more predisease would be detected and treated. Given that the
reduced specificity with HPV testing is for a surrogate outcome (CIN2), it cannot be determined
whether any (or how much) of the presumed false-positives actually represent predisease that
was appropriately detected and prevented through ongoing enhanced surveillance stimulated by a
positive screening test and negative colposcopy. This is particularly possible since colposcopy is
also an imperfect test. Colposcopy is the accepted reference standard, but one that can generate a
false-negative or false-positive result, leading to overtreatment. A study of 1,176 community
histology CIN1 or CIN2+ diagnoses from the NTCC trial suggested a 15 percent estimate of
overtreatment, since 15 percent of CIN2 or worse diagnoses were downgraded to CIN1 or better
after blinded review of all surgical and histological samples available within 1 year of
colposcopy referral.158 Similarly, in the United Kingdom, possible overtreatment occurred in 26
percent of histologically confirmed CIN1 and in 18 percent of women with biopsy showing less
than CIN1 findings.159 Thus, additional cumulative disease detection results, along with more
complete reporting of retesting, colposcopies, treatments, and related harms from RCTs could
help answer important questions about the comparative impact on benefits and harms of different
screening strategies for cervical cancer in a program of repeated screening.

Interim Conclusions About HPV-Enhanced Screening From Available

Data
While incomplete, trial results to date—in combination with results from rigorous test
performance studies in applicable populations—allow us to draw a few conclusions and point out
some important caveats to interpreting trial results as they are reported going forward
First, HPV-enhanced primary screening strategies appear most promising when focused
in women aged 30 or 35 years and older, but not younger women. Women older than age 30 or
35 years represent the primary age of study participants, and also show a better balance between
improved test sensitivity and reduced test specificity than do younger women (Appendix E).

Screening for Cervical Cancer 39 Oregon Evidence-based Practice Center

 Second, some HPV-enhanced screening strategies look more promising and more
relevant to U.S. practice than others. Although it is premature to determine which HPV-enhanced
protocol(s) might be preferable, some trial designs are more directly relevant to U.S. practice
(NTCC Phase I and II, Finnish trial), primarily due to the colposcopy referral thresholds
employed. According to NTCC Phase II, HPV screening alone in women aged 35 years and
older may provide a benefit relative to a cytology-only strategy, but this benefit would require
some initial increase in colposcopy (Appendix E). Whether some of this increase will be offset
by fewer tests in subsequent screening rounds, and determining what proportion of excess
colposcopy is due to increased false positives (and their related harms), cannot be determined
with available data (Table 18). Also, it remains to be determined whether proportional benefits
and harms reported from this trial will be directly applicable to the United States, given this
study tended to use a lower cytology threshold for immediate colposcopy referral and also
referred all women to colposcopy for a single HPV positive test. Based on possibly reducing the
degree of relative increase in colposcopy in HPV screening versus cytology, HPV testing
followed by cytology triage appears promising given its superior specificity for CIN2+ or CIN3+
lesions, compared to cytology screening alone, in women of all ages. For women aged 35 years
and older only, simulations suggest relative PPV for HPV with cytology triage was the same or
significantly greater than with cytology alone, while HPV screening showed significantly
reduced relative PPV.121,133,160 These simulated data are interesting but preliminary, since they
reflect only baseline screening results and not a full screening round (with ongoing rescreening
and colposcopy referral) or cumulative screening rounds. Also, data from the HPV-cytology
triage trial come from cytology referral protocols that are similar but not identical to U.S.
practice—that is, immediate colposcopy referral threshold for LSIL+ cytology with HPV+
(ASC-US or normal cytology) managed through repeat testing. Thus, more complete results from
this trial could be relatively applicable to the United States.
Third, and in contrast to the other HPV-enhanced strategies, it is not clear if any co-
testing strategy reviewed here offers a clear potential for additional benefit, particularly
compared with primary HPV screening (alone or followed by cytology triage). Test performance
data suggest no additional benefit above primary HPV screening alone for co-testing using
cytology thresholds similar to U.S. practice, although increased cost would be expected for the
additional test. European trials compared co-testing strategies to cytology alone (never to HPV
screening), although indirect comparisons in the NTCC Phase I and II trials in women older than
age 35 years suggest HPV-cytology co-testing did not detect more CIN that HPV testing alone,
but did require twice the number of colposcopies at baseline. Finally, none of these trials
employed strategies to directly evaluate the other main potential benefit from co-testing, which
would be a prolongation in screening interval for cytology negative, HPV negative women (as
recommended in U.S. practice). Unless co-testing is completely superior to HPV testing in
appropriately determining those at lowest risk for prolongation in screening interval, it is difficult
to see how administering both tests will ultimately be more valuable than other HPV-enhanced
screening strategies. The issue of NPV is discussed more thoroughly below (― Potential Subgroup
Considerations With HPV-Enhanced Cervical Cancer Screening‖).
Fourth, there is no current consensus on how to interpret these comparative effectiveness
trials of cervical cancer screening. Their interpretation is impacted by the many years and large
sample sizes necessary to determine true disease outcomes (cancer). Thus, available data
primarily represent surrogate outcomes (precancer or combined precancer and cancer). The
European trials have offered considerable expertise and perspective on the acceptability and

Screening for Cervical Cancer 40 Oregon Evidence-based Practice Center

hierarchy of program outcomes—including surrogates—which is informative (Table 17). These
experts suggest that reduced CIN3+ in Round 2 or beyond may be an acceptable surrogate
measure for screening program benefit,161 while also clearly acknowledging the preference for
demonstrating an impact on invasive cancer incidence or mortality.162 However, these
perspectives may be most applicable in countries with uniform national screening policies. The
degree of confidence that U.S. clinicians and policymakers are willing to place in surrogate
outcomes is key.
Similarly, interpretation of round-specific and cumulative trial results is complex. As
suggested by experts, Round 1 of screening detects prevalent disease and predisease, and
increased detection of predisease in one strategy relative to another may represent early
diagnosis and/or overdiagnosis of regressive predisease.117 In Round 2 of screening, incident,
missed, or progressive disease and predisease are detected.117 Over at least two rounds, therefore,
there is some way to compare the patterns of disease and predisease detection and infer overall
program performance, as well as to compare round-specific patterns between trials to explain
different results. Longer followup of Round 2 results (or additional screening rounds) may be
necessary, particularly to allow for more complete ascertainment in both arms and to detect an
impact on cancer. Some experts evaluate the pattern of screening results by round, suggesting
that increased relative CIN2+ detection in Round 1 followed by decreased relative CIN3+ in
Round 2 suggests prevention of disease progression.163 Others suggest that similar cumulative
CIN2+ disease detection between arms after at least two screening rounds would indicate lack of
overdiagnosis144 if the same screening test (ideally including HPV) was applied in both study
arms at Round 2 and after.163 Only one trial applied HPV testing using PCR to both arms in the
second screening round.114 Many other differences between trials (besides whether the second
round applied HPV testing or not)—including type of HPV screening strategy, colposcopy
referral and repeat screening protocols, and approaches to compiling and reporting outcomes—
complicate applying these types of theoretical interpretations to the current body of evidence.
Some commentators point out that the co-testing trials (with the exception of NTCC Phase I)
actually test primary HPV screening with cytology triage, since all the trials use a cytological
referral threshold only for immediate colposcopy.163 However, these trials actually have a safety-
net in place for women with HPV-cytology-positive lesions, since all women receive both tests
with referral for high-grade cytology alone.
Fifth, there are a number of important potential biases that will need to be carefully
considered when interpreting more complete reporting from trials. Large comparative
effectiveness trials of cervical cancer screening embedded in national screening programs use a
pragmatic design that offer many advantages.164 However, there are several important biases to
consider in their ultimate interpretation. As is well recognized, there is a potential for verification
bias in any screening study that does not apply the gold standard to all who are screened,
regardless of outcome.102 In these real-world trials, only those screening positive possibly receive
the diagnostic colposcopic evaluation. Therefore, as with observational studies, their main value
in terms of estimating test performance is limited to relative test performance results. Similar,
any outcome interpretation is affected by the proportion receiving the diagnostic test. Possible
ascertainment bias could occur if there are between-arm differences in the proportion complying
with the recommended diagnostic test. Sufficient time for followup is also critical, given that
diagnostic tests can be recommended immediately after screening or after a year or so of
retesting and confirmation of initially abnormal screening results. Finally, the comparison of two
tests (HPV vs. cytology) or the use of adjunctive tests (HPV plus cytology vs. cytology) in a

Screening for Cervical Cancer 41 Oregon Evidence-based Practice Center

randomized design can still be complicated by asymmetry bias in ascertainment if results do not
represent sufficient long-term followup.14 Between-arm differences in predisease detection can
occur even if the new test performs at random, when more women are selected for colposcopy
due to the detection of incipient lesions that would not otherwise have been found. Thus,
sufficient long-term followup and use of outside registry data to get a better estimate of the rates
of true disease and predisease is important.

Potential Subgroup Considerations With HPV-Enhanced Cervical

Cancer Screening
Beyond the impact on disease detection, there may be other subgroup considerations for
an HPV-enhanced screening strategy. HPV screening introduces potential individual patient-
level as well as population-level benefits, such as using negative test results to stratify women
into low-risk groups in which screening intervals may be safely lengthened. International experts
have noted that the NPV of adding an HPV test to cytology (or substituting HPV for cytology)
may be a major utility of HPV-enhanced primary screening.165 Thus, this is an important
endpoint for ongoing European trials, which has been partially reported to date.166 On the other
hand, issues of how to best manage women with mixed results—particularly those who are HPV
positive but cytology negative—are equally critical. For all women with inconclusive testing
results, safety of any tailored screening strategies along with data on psychological effects,
including compliance with rescreening, will be critical.
HPV negative/cytology negative subgroup considerations (Table 19). Meta-analyses
of cross-sectional results have confirmed the high NPV of negative results for combined
HPV/cytology testing.165,166 Some European trials have reported longitudinal results for this
subgroup. The POBASCAM trial estimated that after a combined negative high-risk HPV test
result and negative cytology, the 5-year cumulative risk of CIN3+ lesions per woman screened
was 0.1 percent (95% CI, 0.1% to 0.2%), which was lower than the risk for women who did not
receive an HPV test at baseline but had negative cytology (0.8% [95% CI, 0.6 to 1.0]).114 Almost
half of CIN3+ cases (3/8) detected in the subsequent screening round 5 years later in those
initially HPV negative/cytology negative were in women who tested HPV+ in the second
round.114 Post hoc analyses demonstrated little prognostic benefit for co-testing above HPV
testing alone, since the 5-year cumulative risk of CIN3+ after a negative high-risk HPV test was
0.2 percent (95% CI, 0.1 to 0.3). Two other trials (ARTISTIC, Swedescreen) have reported
interim data that are consistent with a very low risk of CIN3+ in those negative for HPV and
cytology at rescreening after 2 to 3 years.115,117 However, a lower proportion of HPV
negative/cytology negative women completed Round 2 screening in ARTISTIC (60%) than
women with at least one positive test did. This affects assessment of true CIN3+ risk, but also
raises questions about whether women who test double-negative might not comply with future
screenings. Reporting from a third screening round in ARTISTIC confirms a longer-term (6-
year) reduced risk of CIN3+ (0.28%) in those women who were HPV negative that is
indistinguishable from those who were HPV negative/cytology negative.135 Since these data are
reported only in those women undergoing three rounds of testing, however, they represent only
36.2 percent of the original cohort, and could represent selective ascertainment due to
incompletely reported data.
These short-term, trial-specific data are supplemented by large, longitudinal cohort
studies and pooled data. A multinational European joint cohort study with pooled data on 24,295

Screening for Cervical Cancer 42 Oregon Evidence-based Practice Center

women examined cumulative incidence of CIN3+ among women with adequate cytology and
HPV testing at baseline and at least one followup cytological or histological test.167 During 6
years of followup, 1.6 percent of women developed histologically-confirmed CIN3+. The
cumulative CIN3+ incidence rate among women that tested negative for HPV (generally HC2)
and on cytology (less than ASC-US) was 0.28 percent (95% CI, 0.12 to 0.45). There was little
difference in CIN3+ development between women with negative results on both tests and
women negative for HPV only. The rate of CIN3+ development over 6 years in women who
were HPV negative was significantly lower than among women who had negative cytology
results (0.97% developed CIN3+ over 6 years). Results for CIN2+ were essentially the same, but
with a higher number of cases. These data are limited by verification bias (only test positives
according to initial and rescreening protocols were uniformly assessed for disease outcomes),
with between-study differences in protocol, as seen in trials in this review. Nonetheless, CIN3+
detection rates were generally consistent and low across studies in HPV negative/cytology
negative women, despite their likely participation in ongoing cervical cancer screening.
In a prospective study of 20,810 women (mean age, 35.9 years) in Kaiser Permanente
Northwest, the risk of CIN3+ was 0.16 percent (95% CI, 0.08 to 0.24) after almost 4 years of
followup in 17,592 women with negative cytology and high-risk HPV tests.168 In women who
were HPV negative, the 10-year cumulative incidence of CIN3+ was 0.87 (95% CI, 0.62 to 1.12)
and lower than the cumulative incidence in women with ASC-US+ baseline cytology (1.38 [95%
CI, 1.10 to 1.67]).
Among Danish women who tested negative for high-risk HPV, only 8 percent of those
aged 22 to 32 years and 7 percent of those aged 40 to 50 years developed an abnormal Pap smear
over 10 years, with each woman receiving a median of three tests. For both age groups, most
abnormal smears were atypia only, with about one-third reflecting severe dysplasia.169 The
absolute risk of CIN3+ in HPV negative/cytology negative women at 3 years was 0.2 percent in
younger women and 0.08 percent in older women, at 5 years it was 0.8 percent in younger
women and 0.4 percent in older women, and by 10 years it was 3.1 percent in younger women
and 1.7 percent in older women. Compared with women with two negative tests, age cohorts that
were cytology negative but HPV positive had markedly increased relative risk for CIN3+ at 3
years (younger women: RR, 11.0; older women: RR, 53.8), 5 years (younger women: RR, 6.9;
older women: RR, 23.3), and 10 years (younger women: RR, 4.4; older women: RR, 12.5).
Among 8,735 women aged 30 to 60 years participating in the United Kingdom HPV in
Addition to Routine Test (HART) trial, a randomized evaluation of management strategies for
women who tested positive after co-testing, the high NPV of a negative HPV test was
confirmed.159 After a minimum of 5 years, cumulative CIN2+ was about half as common in
women who were HPV negative at baseline compared with those who were cytology negative
(0.23% and 0.48%, respectively). Since most differences between the two tests occurred in the
first year, differences may reflect poorer sensitivity of cytology. The hazards ratio for cumulative
CIN2+ increased dramatically with the HPV relative light unit (RLU) levels. Compared with a
typical negative result (<1 pg/ml), the hazards ratio for an HPV RLU of 1-10 pg/ml was 5.4
(95% CI, 1.7 to 18.2) and 25.2 (95% CI, 13.6 to 47.9) for an HPV RLU >10 pg/ml (p<0.00l for
trend). Data were not reported for CIN3+.
These trial and cohort data clearly indicate that one potential value of a screening
program with initial HPV testing could be reduced screening intervals for the majority of women
who test negative. Among participants in co-testing trials, this group represents a very significant
proportion of those screened at baseline: from 78 percent in both arms (combined) in ARTISTIC,

Screening for Cervical Cancer 43 Oregon Evidence-based Practice Center

to 88 to 93 percent in the co-testing arms of Swedescreen, NTCC, and POBASCAM. Thus, if a
reduced interval for repeat screening is shown to be safe and effective—as well as workable
within the clinical, social, and political realities of cervical cancer screening in the United
States—it would be appropriate for the vast majority of women aged 35 years and older after a
single round of screening that included HPV testing.24
HPV negative subgroup considerations. Based on the data discussed above, women
screening negative on HPV testing have a nearly identical reduced long-term risk of developing
CIN3+ as women that are HPV negative/cytology negative. The high NPV associated with HPV
negative testing alone, particularly in older women, might inform extended screening intervals
for such women, with no need for cytology testing at all in HPV negative women.
HPV positive/cytology negative subgroup considerations. A concern among programs
that involve combined HPV-cytology screening initially or in sequence is how best to manage
HPV positive/cytology negative individuals. Data from large cohort studies show that women
with HPV positive/cytology negative results experience a continuously increasing cumulative
incidence rate that reaches 10 percent (95% CI, 6.2 to 15.1) after 6 years.167 As indicated in
Table 5b, trials varied in their approach to management of these individuals in terms of timing of
repeat screening, rescreening tests utilized, and colposcopy referral thresholds. A detailed
analysis and comparison of these differences and associated outcomes in this important subgroup
would be important, but our review (consistent with others’ findings)170 suggests that additional
details beyond those currently published would be needed to fairly compare different protocols.
Any modeling of co-testing would need to carefully consider between-study details about
rescreening protocols, compliance, and the impact on results. Furthermore, research continues to
identify the role of specific HPV subtypes (particularly 16, but also 18, 31, and 33) and persistent
infection by these types in further specifying high risk for CIN3+.171 More specific management
of this subgroup could be informed by better risk prediction. Similarly, genotyping may also play
an important role in the future for risk-stratification into tailored screening strategies.172

Cytology Screening With HPV Triage (Reflex HPV) for ASC-US or LSIL
Cytology
Overall, results from observational studies suggest that HC2 is somewhat more sensitive
than repeat cytology at a colposcopy referral threshold of ASC-US+ for the detection of CIN2+
(but not clearly CIN3+) lesions among women with ASC-US referral cytology, with no further
advantage when CC is added to HPV triage, but a possible increase in false positives. Age-
stratified results were generally not available, but many studies (besides ALTS) represent women
primarily older than age 30 years. Our findings from a much more limited meta-analysis agree
with previous meta-analysis results reported by Arbyn and colleagues.173,174 HPV testing was
more sensitive and equally specific for detection of CIN2+ for the triage of ASC-US+ results,
compared to repeat cytology, with no benefit for HPV triage of LSIL+ cytology.
Trial results suggest reduced specificity (more false positives and colposcopies) for
CIN2+ or CIN3+ with HPV compared with CC triage—particularly, but not exclusively, in
women younger than age 30 years. The higher prevalence of transient HPV infections in younger
women may play a role here. In contrast, the use of an HPV triage test clearly provided no
substantial advantage for referring women with LSIL to colposcopy. This may reflect a high
prevalence of HPV among women with LSIL cytology results (58.9 to 94.8%). Other studies
have suggested potential value for HPV triage of LSIL in women older than ages 45-50 years, if

Screening for Cervical Cancer 44 Oregon Evidence-based Practice Center

they represent a group in whom the co-occurrence of HPV is lower and if the HPV negative
group has a low-risk of CIN3+ over the time period until the next screening.175 In women aged
30 years and older, one small study suggests an HPV triage strategy for ASC-US or LSIL would
produce three false positives for every two with repeated cytology, and four false positives with
HPV triage for every two with cytology in younger women (Appendix C Table 3).119 These
estimates are imprecise due to the small number of women in the study and because the authors
include both ASC-US and LSIL triage in their calculation, which inflated the number of referrals
in the HPV arm. Trials reviewed here reported simulations of various triage and repeat testing
strategies following primary HPV screening or primary cytological screening.117,119,121 None of
these had (or reported) cumulative screening round data to simulate different triage strategies
within a program of screening.
The studies we included to evaluate HPV triage of abnormal cytology included women
from a broad age range (range, 15 to 78 years; mean or median range, 27 to 35 years), but
provided minimal age-stratified data. While these studies found that overall HPV testing was not
useful for the triage of LSIL cytology due to the high prevalence of HPV among women with
LSIL cytology, one might postulate that the low HPV prevalence among older women could
potentially render HC2 useful for triage of LSIL cytology in the older age groups. However, the
study by Peto and colleagues, included for KQ1, demonstrated that there was no trend of
decreasing high-risk HPV prevalence with age among women with abnormal cytology.32 In an
article from the ALTS trial, the authors concluded that HPV triage of LSIL cytology was not
useful at any age range, since the proportion of HPV positivity among women with LSIL did not
decline dramatically with age.176

Harms of HPV Testing

In addition to concerns about false-positive testing and related harms, we identified four
studies that described potential psychological harm from HPV testing.139-142 In the short term
(first few weeks after receiving test results), women who test positive for HPV had higher levels
of anxiety and distress and greater concerns about their health and health risks. In the long term,
however, these results did not persist. In fact, when considering triage of ASC-US cytology with
an HPV test versus repeat cytology, long-term followup suggests greater satisfaction with care
and less distress among women undergoing HPV testing. This may be because women who
undergo repeat cytology have to wait for additional results before it is determined whether or not
they need colposcopy, whereas women undergoing HPV testing are triaged much more quickly.
The evidence about harms of HPV testing is limited. Only two of the four included
studies present long-term followup, there was a small number of women included in the
followup, only one study administered questionnaires prior to cytology and HPV testing, and all
studies had large proportions of women who did not return the study questionnaires. Larger
studies with longer-term followup, assessment of psychological measures pre- and post-test, and
adjustment for baseline psychological measures and appropriate confounders are needed to
determine the psychological impact of HPV testing.

Are All HPV Tests the Same?

HPV testing has been approved by the FDA for cervical cancer screening in women older
than age 30 years as co-testing and for triage of ASC-US cytology. Whether HPV testing was a

Screening for Cervical Cancer 45 Oregon Evidence-based Practice Center

more sensitive indicator than cytology for recurrent or residual CIN following treatment was not
included in this review.166
The vast majority of data reviewed in this report, from both trials and observational
studies, reflects a clinically validated commercial assay, HC2, with a much smaller body of
evidence evaluating PCR testing using GP5+/6+ probes. Newer FDA-approved tests were not
part of our original scope, although we did not exclude any trials for that reason. As evidence on
HPV testing is translated into practice—particularly into screening programs—users should
consider whether tests other than HC2 will produce similar results as shown in research. In
widespread screening, even small differences in test performance may have large detrimental
impact.177 HPV is a very complex molecular diagnostic assay whose analytic and clinical validity
are affected by issues such as the number of HPV genotypes tested,177 number of viral copies
required, and other factors.178 Users should be aware of potential differences in expected test
performance between validated well-studied tests and other, less-well-studied tests. Those
choosing to use a less-well-studied test should ensure the minimal performance standards of
these tests, as discussed below.
Some data suggest that PCR may not be equivalent to HC2 in absolute test
performance122 or have shown heterogeneous sensitivity and specificity estimates when pooled,
perhaps due to use of different primers in detection of amplified sequences.144 Although
differences may be amenable to better quality control, care should be taken to ensure expected
test performance before substituting another HPV assay for proven tests in large-scale screening
programs. Furthermore, as outlined in a recent article, FDA approval of newer HPV technologies
may not always include a complete consideration of its comparative performance relative to
HC2, or its overall clinical performance (both sensitivity and specificity) in a program of
screening.179 Kinney provides a cogent argument, with examples taken from package insert data
for one recently approved HPV test, illustrating that HPV tests with good analytic sensitivity
should not be assumed to have clinically equivalent test performance as HC2, and that
differences in clinical performance, particularly related to specificity, could have a large impact
on cervical cancer screening programs in terms of costs and potential harms.179
An international group of experts has proposed minimum relative sensitivity (0.90) and
specificity (0.98) thresholds to be determined in direct test performance comparisons with HC2
before clinical use of newer high-risk HPV tests in cervical cancer screening. Newer tests should
also be highly reproducible (agreement >87%, minimum 500 samples).162,180 U.S. experts have
made similar recommendations.163 Criteria have also been articulated to guide policymakers
about when good clinical test performance data can allow substitution of a diagnostic test into
proven clinical use without new RCTs.157,162 These same standards should apply to the
substitution of different screening tests than those proven in RCTs or convincing epidemiological
evidence.

Age at Which to Stop Cervical Cancer Screening

We did not systematically evaluate the literature regarding the age at which cervical
cancer screening should be discontinued. This topic was systematically reviewed in the previous
USPSTF evidence review.99 Based on fair-quality evidence obtained from 12 cohort studies, the
review reported the following conclusions.
1. The incidence and prevalence of high-grade cervical lesions and cancer decreased
with age. The peak incidence or prevalence varied with type of lesion (e.g., CIN1 and

Screening for Cervical Cancer 46 Oregon Evidence-based Practice Center

 CIN2 versus CIN3), but in general, women older than age 65 years had the lowest
burden of disease.
2. The age-related decrease in cervical disease was similar in previously unscreened
women.
3. There was no difference in the aggressiveness of invasive cancer in older women
compared with younger women.
4. Repeat screening after negative smears was associated with a reduced risk of high-
grade cytologic abnormalities.
Evidence identified during the course of our review confirms the previous review’s
findings of reduced rates of abnormal cytology and detection rates for CIN3+ as women age and
with subsequent screenings.32,104,181 Data from two rounds of cervical cancer screening (750,591
cytology tests from the first round and 373,851 from the second) from the CDC’s National
Breast and Cervical Cancer Early Detection Program (NBCCEDP) demonstrate that the
percentage of abnormal cytology results decreases with age and with subsequent screenings.181
The percentage of cytology results that were classified as abnormal on first screening decreased
fairly linearly with increasing age, from 33 percent of cytology tests in women aged 18 to 29
years to 14 percent in those aged 65 years and older. The percentage with HSIL or SCC also
decreased with age from a high of 2.4 percent in 18- to 29-year-olds, but plateaued and was
similar among those aged 40 years and older (0.4 to 0.6%). Age-specific detection rates for
CIN3+ decreased linearly with age from 14.6 per 1,000 cytology tests in women aged 18 to 29
years to 2.0 per 1,000 in those aged 65 years or older. CIN3+ rates were fairly similar among all
women aged 50 years and older. For all ages, rates of abnormal cytology or histology were
reduced on second screening, but the age gradient was maintained, with relatively higher rates of
cervical abnormalities in younger women than older women. Women aged 40 years and older,
particularly those aged 65 years or older, experienced a smaller proportional reduction from first
to second screening in rates of abnormal cytology and biopsy-confirmed CIN than younger
women.
In a study from a UK cohort screened between 1988 and 1993 and less than 5 years after
a normal screening smear, the annual incidence of CIN3+ decreased as women aged, from a high
of 4.07 per 1,000 per year for ages 25 to 29 years to 0.19 per 1,000 per year for ages 60 to 64
years.32 Incidence of CIN3+ in those women aged 65 to 69 years was somewhat higher (1.39 per
1,000 per year), but was comparable to the incidence in young women aged 15 to 19 years (1.56
per 1,000 per year). Similarly, in the Kaiser Permanente Northwest population, the highest
incidence of CIN3 (6 per 1,000 routine smears) was in women aged 25 to 29 years, with 0 to 1
CIN3 cases per 1,000 routine smears in women aged 60 to 79 years, which was lower than the
15- to 19-year-olds (2 per 1,000).104 In this study, there was a sharp decline in the yield of CIN2
and CIN3 with screening in women older than age 30 years, with only 2 cases of high-grade CIN
identified in 5,488 routine smears in women aged 60 years and older.104 Incidence of cervical
cancer after three consecutive negative screening tests was found to be the same after 10 years
followup in 445,000 women aged 30 to 44 years compared to 219,000 women aged 45 to 54
years, suggesting that the risk among well-screened women is the same among middle-aged
women (30 to 65 years).182
At present, there remains no consensus regarding the age at which to discontinue cervical
cancer screening,183,184 and countries with screening policies recommend stopping after an
adequate screening history at different ages: ages 59 to 60 years (Sweden, Finland, Japan), ages
64 to 65 years (England, Spain), and age 69 years (Australia, Canada, Norway).183 The United

Screening for Cervical Cancer 47 Oregon Evidence-based Practice Center

States may be the only country consistently screening some women older than age 65 years (an
estimated 43 to 66% during one 3-year period), and one epidemiologist has recently noted that
ecologic data from all of these countries suggest that the United States is also the only one of
these countries that has achieved a relative downward trend in the incidence of cervical cancer in
women older than age 65 years.183
However, improving the burden of cervical cancer on older women is likely best
achieved by focusing on screening those who have not been adequately screened. In a recent
review on screening intervals and age limits, Sasieni and Castanon note that a Markov model for
disease progression produced by Fahs and colleagues determined that screening women older
than age 65 years with previously adequate screening history would be inefficient;185 in contrast,
screening women who have not been adequately screened triennially would reduce mortality by
74 percent.183 Sasieni and Castanon state that the inefficiency is primarily because more smears
are required, less CIN is detected as women age, and there are other competing causes of death.
In addition, disease progression from CIN to cancer is believed to be relatively slow, and only a
proportion of CIN cases will progress to cancer (20 to 30% within 5 to 10 years).183 These
authors point out that most guidelines around the world suggest that screening should cease by
age 65 years, provided women have an adequate screening history.183
Defining an ― adequate screening history‖ is not entirely clear-cut, except among those
who have never been screened. Published reviews suggest that about half of all invasive cervical
cancer cases are diagnosed in women who have never been screened or have not been screened
within 5 years.18,186,187 Given this, the NBCCEDP program has shifted its focus to target women
older than age 40 years who are at greater risk for never or rarely having been screened.181
Among the 465 cases of ICC detected between 1995 and 2001 in the NBCCEDP program, 31
percent reported no prior screening before entry into the program. Among women aged 18 to 29
years, 25 percent reported no previous screening, compared to 42 percent among those aged 65
years and older. Data from the UK Audit of Screening Histories also suggest that older women
with cervical cancer are less likely to have ever been screened than younger women with cervical
cancer or age-matched controls.183 According to the UK data, approximately 70 to 80 percent of
women aged 20 to 49 years with cervical cancer had ever been screened, compared to fewer than
50 percent of women aged 60 to 69 years. The proportion ever screened among the young
women with cervical cancer did not appear to differ from their age-matched controls, whereas
the proportion of women aged 60 to 69 years with cancer who had ever been screened was 20
percent less than age-matched controls. Only about 25 percent of women aged 60 to 69 years
with invasive cancer had a negative smear within 5 years, compared with 60 percent of age-
matched controls.
The results of previous screening episodes may also be associated with risk. As already
discussed, a large observational study in the Netherlands found the same cumulative incidence of
ICC after three consecutive negative smears in women aged 45 to 54 years as in women aged 30
to 44 years.182 Another observational study in Italy found nearly an eight-fold lower cumulative
risk of CIN2+ in women aged 50 to 64 years compared to those aged 25 to 49 years after three
previous negative screens.188 The effect of a history of negative screening results on risk in older
women is not clear from these studies, although differences between older and younger women
may be less for cervical cancer than for precancerous lesions. Researchers are beginning to factor
in considerations such as new sexual partners in increasing risk for HPV infection (or re-
infection) in older adults.189

Screening for Cervical Cancer 48 Oregon Evidence-based Practice Center

 Women previously treated for CIN have a higher risk of later cervical cancer. A cohort
study in Finland found increased risk of cervical cancer in women treated for any CIN, compared
to a standard population (standardized incidence ratio, 2.8 [95% CI, 1.7 to 4.2]),83 although no
increase in cervical cancer mortality was found in the same cohort.190 Another cohort study in
Sweden found increased cervical cancer risk after CIN3 treatment (standardized incidence ratio,
2.34 [95% CI, 2.18 to 2.50]), with greater risk for women aged 50 years and older, compared to
younger women.191
Older women are currently disproportionately represented in the unscreened and
underscreened population—with 83.1 percent of those aged 60 to 64 years receiving
recommended screening versus 87.6 percent overall, according to 2008 Behavioral Risk Factor
Surveillance System data—as are some minority (American Indian/Alaska Native and
Asian/Pacific Islander) and non-English speaking women.184,192 Black women, despite having
slightly higher than average rates of compliance with recommended cervical screening,192 have
increased age-specific cervical cancer incidence that does not peak but continues to increase with
age193,194 to about 26 per 100,000 women at ages 85 years and older (Table 2 and Figure 1). Both
black and Hispanic women have higher age-adjusted incidence rates for cervical cancer than
nonHispanic whites,17,193,194 and these minority groups, along with American Indian/Alaskan
Natives, also have higher age-adjusted cervical cancer death rates.17 Therefore, these groups
remain important populations in which to ensure adequate screening, both for older and younger
women. Age-adjusted incidence rates for Asian and Pacific Islander women were somewhat
higher than for nonHispanic white women from 2000 to 2008, but mortality was similar between
the two groups.17
In summary, newly available data do not contradict current USPSTF recommendations to
discontinue routine cervical cancer screening for women older than age 65 years who have had
adequate screening with negative results and who are not otherwise at high risk for cervical
cancer. Older women with a history of treatment for CIN represent one high-risk group who
could continue screening. In the future, factors such as the use of HPV testing, HPV genotyping,
and sexual history might help further define a cohort of older HPV negative women for whom
screening could be safely discontinued.32,195,196

Limitations
This review has several limitations. While our literature search was extensive and the
included studies covered an international population of women, we only included studies that
were written in the English language. We further focused our results and discussion to primarily
consider studies most relevant to the United States, which excluded countries without well-
developed population screening for cervical cancer in place. Most included studies addressed
women aged 30 to 60 years, with almost no data in women older than age 65 years and limited
data in younger women. Age-specific data were not always reported or did not always use the
same thresholds when reported. Thus, women aged 30 to 34 years were variously grouped with
older or younger women, depending on study reporting. We did not systematically review data
related to screening intervals, age at which to stop screening, or automated cytologic screening
technologies, of which the latter two were covered in the previous review by Hartmann and
colleagues.99 Automated cytologic screening technologies were excluded from this review due to
the limited audience for these data among primary care providers. Furthermore, HC2 was the

Screening for Cervical Cancer 49 Oregon Evidence-based Practice Center

only HPV test available in the United States when the scope of this review was determined, and
thus we limited our review to use of HC2 and PCR only.
Two large studies, one evaluated for inclusion in KQ2 (Guanacaste study) and one for
KQ3 (HART), did not meet eligibility criteria for this review. Appendix D delineates the
rationale for their exclusion. Briefly, the final histologic diagnosis in the Guanacaste study
included results of the screening tests. Additionally, the reference standard of colposcopy and
biopsy was not systematically applied. The main limitation of the HART study is that it is a
randomized trial of management options after co-testing or HPV with cytology triage rather than
a test of an HPV-enhanced screening strategy compared with cytology. HART also has risk of
verification bias, given that there was differential loss to followup for colposcopy referral among
the study arms. Other issues in using results to estimate absolute test performance include
uncertainty about the timeframe within which colposcopy and biopsy were provided and lack of
blinding of colposcopists to cytology results (with perhaps the ability to guess HPV results).
Longer-term followup with linkage to registries can overcome some of these limitations,
particularly for examining NPV.
Our review made a dedicated effort to consistently analyze and report the most policy-
relevant data from recent trials of screening programs involving HPV for the USPSTF’s
recommendation process. However, there are many publications associated with each of these
trials, with updated results coming out over time. Some of the data that we indicate as not
reported might have been missed in an ancillary publication or could become available through
author requests or soon-to-be-available publications. Thus, findings from this report will need
frequent updating with more complete data from trials. We found little data on age at which to
begin screening or risk factors that may modify when screening should begin, such as age at first
intercourse. While the available studies did not present data with sufficient granularity to make a
specific age recommendation at which to commence screening, they do suggest that screening
women younger than age 20 years is of little value, given the low incidence of cervical cancer in
this age group and the potential harms of unnecessary evaluation and treatment.
Providing data related to the cost-effectiveness of HPV in any screening strategy was
beyond the scope of our review. ARTISTIC investigators have conducted an extensive economic
evaluation associated with that trial.197 Results suggest it would not be cost-effective to screen
with cytology plus HPV (co-testing) compared with cytology alone. In this analysis, however,
simulated primary HPV screening with cytology triage (or HPV triage of cytology) was cheaper
than cytology screening without any HPV. A head-to-head trial comparing these two strategies is
currently under way in Canada, with results expected in 2014 (Appendix F).198 Studies of HPV
triage of ASC-US and LSIL cytology were limited by the lack of age-stratified results, and only
two studies provided data for the outcome of CIN3+. The results of the ALTS trial were limited
by a study design that does not mirror current clinical practice. In the ALTS trial, women were
referred for colposcopy if their cytologic diagnosis was HSIL, which is a higher threshold for
referral than what is commonly used in clinical practice.68 In addition, the immediate colposcopy
arm would represent the results of colposcopy after one abnormal cytology result. In the clinical
setting, among women with no prior history of CIN, colposcopy is usually performed after two
ASC-US cytology results have occurred.
Another potential limitation of this review is that most trials and studies used colposcopy
and/or biopsy as the reference standard. In some included studies, the biopsy was taken at
standard cervical positions, but in many studies only abnormalities visible on colposcopy were
biopsied, with a negative colposcopy interpreted as absence of disease. Colposcopically-directed

Screening for Cervical Cancer 50 Oregon Evidence-based Practice Center

biopsy is not 100 percent sensitive for the detection of preinvasive disease. The Shanxi Province
Cervical Cancer Screening Study, for example, found that colposcopically-directed biopsy was
more accurate in detecting large lesions compared to small ones, and identified 62.5 percent of
lesions covering zero to two quadrants of the cervix and 100 percent of lesions involving three to
four quadrants.199 In addition, only 62 of 83 women with CIN2 were detected by
colposcopically-directed biopsy: 19 were detected by random biopsy and 2 solely by
endocervical curettage. Analysis of data from the placebo arms of Merck’s GARDASIL trials
also showed low correlation between results of colposcopically-directed biopsy and excisional
specimens. The trial included women who were referred based on concerning cytology, biopsy
and/or endocervical curettage results for LEEP, or other definitive therapy, and who had a
cervical biopsy taken within 6 months before treatment (about 7% of all those in the placebo
arms). The biopsy and definitive diagnosis (negative, CIN1, CIN2, or CIN3/AIS) coincided for
just 42 percent of these participants; biopsy underestimated disease for 21 percent and
overestimated (or removed) disease for 36 percent.200
Finally, the use of detected disease without full ascertainment of undetected disease does
not accurately reflect sensitivity or true test performance. However, in the context of trials, it
reflects real-world impact. Almost all trials reported results without using an intention-to-screen
analysis, in which all women in the randomized arm are in the denominator for all calculations.
Thus, for comparability, we used the number of women screened (or other comparable measures)
for the denominator in our calculations. For trials nested within ongoing screening programs,
either denominator has a rationale, although intention-to-screen would be most conservative. It is
reassuring, however, that long-term disease detection was not substantially different using
intention-to-screen analysis than when calculated using only women screened in one study
reporting both.134

Emerging Issues/Next Steps

An international effort to pool data from HPV-based primary screening trials has been
recently announced, recognizing the need to provide complete, uniformly reported, age-stratified
data to inform evidence-based guideline development.201 These efforts are critical and could
provide the best simulations of various possible HPV-based screening strategies, considering
between-trial differences in screening and rescreening protocols. When available, their results
will greatly enhance what we found through our systematic review.
Studies under way could impact the findings of this review and perhaps necessitate an
update. These include a Canadian RCT comparing HPV with cytology triage to cytology
followed by HPV triage among women aged 25 to 65 years.198 Results after two rounds of
screening after implementation of the FDA-approved co-testing strategy in Kaiser Permanente
Northern California in over 300,000 women are also expected.202 Initial HMO experience
suggests that co-testing every 3 years is acceptable to both patients and providers,24 and that the
average interval between negative tests is appropriately lengthened.203 Data from a nationally
representative sample, however, suggests that U.S. primary care providers are not likely to
extend the screening interval to 3 years, as suggested.203
This review excluded several emerging HPV testing methods, including tests that detect
HPV-16 and HPV-18 only, p16 immunostaining, in situ hybridization, tests of mRNA or protein
expression, and tests of viral load, which we felt to be of less clinical significance to the primary
care setting when our review started. Since that time, more data are emerging to suggest that

Screening for Cervical Cancer 51 Oregon Evidence-based Practice Center

these may be important strategies to evaluate in the future. Recently, additional new technologies
beyond the scope of our review have been approved by the FDA. These include the Cervista
HPV HR and Cervista HPV 16/18 tests and Roche Diagnostics’ Cobas 4800 HPV test. Cervista
HPV HR tests for 14 high-risk HPV types and Cervista HPV 16/18 individually identify two
high-risk HPV types. The Cobas 4800 HPV Test simultaneously detects 14 high-risk HPV types
(the same as those detected by Cervista HR HPV) and specifically identifies types 16 and 18.74
We found no studies on the Roche technologies that met our inclusion criteria. However, this test
is in use abroad and approved in early 2011 for as yet undocumented indications. Triage
strategies that allow immediate colposcopy referral for the highest-risk women, such as HPV
genotyping and/or p16 immunostaining in HPV positive women, could improve overall
compliance with colposcopy and potentially improve HPV-based screening program
performance.170 Emerging technologies such as Roche Diagnostics’ Amplicor HPV test and
Linear Array HPV genotyping test and Gen-Probe’s APTIMA HPV test will require future
consideration, if submitted to and approved by the FDA. Gen-Probe’s APTIMA HPV, which
detects 14 high-risk HPV types and also mRNA from viral oncogenes E6 and E7, is approved for
use in Europe and has been submitted for FDA approval.

Future Research
Future research and future reviews will need to address the long-term impact of the HPV
vaccine on the incidence of CIN and cervical cancer and on cervical cancer screening strategies.
Reports from trials of GARDASIL and CERVARIX include about 3 years of followup, but
longer-term efficacy is unknown.92,204 Brisson and colleagues used a cohort model of the natural
history of HPV infection to estimate the number needed to vaccinate to prevent HPV-related
disease and death, and found that results were highly dependent on the vaccine’s duration of
protection.205 As discussed earlier, none of the HPV screening studies included in this review
included HPV-vaccinated women; therefore, the impact of HPV vaccines on the effectiveness of
cervical cancer screening programs is also currently unknown. Similarly, whether screening
strategies should be modified in the face of known (or uncertain) vaccination histories will need
study.
Additional research on the appropriate age at which to start screening (with year-specific
data reported for younger women rather than 5-year age groups) and exploration of risk-
stratification tools for targeted, earlier screening would extend the limited findings from this
report. Similarly, given the relatively high proportion of women aged 65 years and older who are
unscreened or underscreened and the apparent downward trend in cervical cancer screening (as
recommended) among this age group, continuing research to determine screening history and
other characteristics of women who develop ICC before and after age 65 years will be
informative.
Ongoing population screening program research in Canada is under way to directly
compare the efficacy of primary HPV screening (with cytology triage using LBC) to primary
LBC with HPV triage, using tests and protocols similar to those in current use in North
America.198 Results could help inform screening policy in the United States and Canada,
including safety of an HPV primary screening approach and prolonged intervals for HPV
negative women. Other research confirming the long-term low risk of high-grade cervical lesions
in screening-negative women, along with research and modeling studies which incorporate
sociodemographic and medical factors, may help further risk stratify women for more or less

Screening for Cervical Cancer 52 Oregon Evidence-based Practice Center

aggressive cervical cancer screening regimens. Ongoing research evaluating type-specific high-
risk HPV testing, mRNA, or p16INK4A and other molecular markers has the potential to further
clarify future risk in women and to improve the specificity of targeted screening approaches.144
Additionally, other future research should continue to address means to encourage screening in
women who often ignore invitations to screening visits; one promising approach could be self-
sampling for HPV testing, among other innovations.206

Conclusions
In summary, our systematic review supports the following conclusions:
1. Due to the high prevalence of HPV, the regressive nature of prevalent cervical
abnormalities, and the low prevalence of cervical cancer in women younger than age 21
years, cervical cancer screening in women younger than age 21 years does not appear to
offer substantial benefit. No studies provided specific information on which risk factors
beyond age should influence the decision of when to start screening, and we found no
sufficient data on screening interval specific to younger women.
2. In terms of cervical cytology approaches, LBC did not differ from CC in absolute test
performance (sensitivity, specificity) or improve relative CIN detection. Most data
suggest that LBC yields a lower proportion of unsatisfactory slides compared to CC and
also allows for several different screening strategies with one specimen (i.e., reflex HPV
after an ASCU-US cytology result, co-testing with both LBC and HPV, or reflex
cytology after a positive HPV result). Cost and feasibility were not part of our review, but
may be considerations, along with other local factors.
3. The use of the HC2 HPV test as a primary cervical cancer screening tool appears very
promising in women aged 30 years and older, particularly when coupled with cytology
triage of HPV positive results. HC2 clearly is more sensitive for the detection of CIN2+
or CIN3+, compared with cytology alone, but somewhat less specific, with some
uncertainty about overdiagnosis of regressive lesions. Use of cytology triage may reduce
the increase in false positives (and their related harms) seen with HC2 testing alone. The
net benefit of a primary HPV-screening strategy (with or without cytology triage) appears
promising, but the net impact of such a program remains to be confirmed through more
complete reporting of cumulative program results and requirements and modeling
exercises.
4. HPV testing in combination with cytology for women aged 30 years and older is also
more sensitive than cytology alone for the detection of CIN2+ and CIN3+, but round-
specific and cumulative impact on CIN3+ detection is still incompletely reported in
RCTs, with mixed results at present. An acceptable measure of comparative benefit for a
cervical cancer screening program has not been specified, although some European RCTs
suggest decreased CIN3+ in a second screening round. However, available RCTs
primarily test protocols that may not be very applicable to current U.S. practice. Also,
through indirect comparisons and observational studies, HPV-cytology co-testing appears
to be no more sensitive than HPV alone, and is possibly less specific; current RCTs do
not completely report round-specific and cumulative colposcopy or related harms. Thus,
from available data, there appears to be no additional advantage of HPV testing in
combination with cytology compared to HPV testing alone, unless an advantage is
conferred by assigning a subgroup of women who are negative on both tests to a program

Screening for Cervical Cancer 53 Oregon Evidence-based Practice Center

 of less-intensive screening. Modeling would be needed to inform this possibility, also
considering the similarly high NPV of HPV negativity alone.
5. A single HC2 HPV test is more sensitive but equally or slightly less specific than repeat
cytology for the detection of CIN2+ among women with ASC-US cytology. There is no
benefit to combined cytology and HPV triage over HPV triage alone, and this strategy is
associated with more false positives. Two trials (that actually tested HC2 plus CC triage)
suggest non-significantly increased detection of CIN3+ with HC2 HPV triage; results
apply particularly to women aged 30 or 35 years and older, with less data in younger
women. HPV testing is not useful for the triage of LSIL or higher grade cytology, and
HPV testing in women younger than age 21 years is clearly not advised.
6. The best studied test for any HPV-enhanced screening program is HC2. Data reported
here primarily refer to results with HC2 at a positive threshold of 1 pg/ml, and to a lesser
extent, PCR GP5+/6+. Some trials simulate screening program results using a 2 pg/ml
threshold for HC2 screening. In the absence of adequate RCT data, substitution of other
types of HPV testing in cervical cancer screening programs based on these trials should
be based on careful consideration of clinical test performance (test positivity, sensitivity,
and specificity) when directly compared with HC2, on evidence of test-retest and inter-
laboratory test reliability, other quality control issues, and cost.

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Figure 1. U.S. Age-Adjusted Cervical Cancer Incidence Rates By Age and Race/Ethnicity (SEER
2000-2008)17

35
Black
American Indian/Alaska Native
Asian or Pacific Islander
30 Hispanic
White Non-Hispanic
Cervical cancer incidence (cases per 100,000)

25

20

15

10

0
00-19 20-29 30-39 40-49 50-59 60-69 70-79 80+
Age at Diagnosis (years)

Rates are expressed as cases per 100,000 women; age-adjusted to 2000 US Standard Population
*American Indian/Alaska Native statistics only include cases from the Contract Health Service Delivery Area (CHSDA) counties.
†Hispanic and NonHispanic are not mutually exclusive from white, black, American Indian/Alaska Native, and Asian or Pacific Islander.

Screening for Cervical Cancer 70 Oregon Evidence-based Practice Center

Figure 2. U.S. Age-Adjusted Incidence and Death Rates of Invasive Cervical Cancer By Age
(SEER 2000-2008)17

18
Incidence
Mortality
16

14

12
Rates per 100,000

10

0
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
Age (years)

Screening for Cervical Cancer 71 Oregon Evidence-based Practice Center

Figure 3. U.S. Age-Adjusted Cervical Cancer Mortality Rates By Age and Race/Ethnicity (SEER
2000-2008)17

25

Hispanic
Black
American Indian/Alaska Native
Asian or Pacific Islander
20
White Non-Hispanic
Age-adjusted mortality rate (cases per 100,000)

15

10

0
00-19 20-29 30-39 40-49 50-59 60-69 70-79 80+
Age (years)

Rates are expressed as cases per 100,000 women; age-adjusted to 2000 U.S. Standard Population. Data not yet updated for 2008.
*American Indian/Alaska Native statistics only include cases from the Contract Health Service Delivery Area (CHSDA) counties.
†Hispanic and nonHispanic are not mutually exclusive from white, black, American Indian/Alaska Native, and Asian or Pacific Islander.

Screening for Cervical Cancer 72 Oregon Evidence-based Practice Center

Figure 4. Prevalence of High-Risk Human Papillomavirus By Age34

40

35

30

25
Prevalence (percent)

20

15

10

0
14-19 20-29 30-39 40-49 50-65
Age (years)

Screening for Cervical Cancer 73 Oregon Evidence-based Practice Center

Figure 5. Analytic Framework and Key Questions

Screening Evaluation Early detection of: Treatment

Females at
Abnormal Improved length
risk CIN1-3 (carcinoma in
2 3 screening and/or
for cervical situ)
results quality of life
cancer Invasive cancer

1 4

Harms Adverse effects

of of
screening evaluation

Key Questions
KQ1: When should cervical cancer screening begin, and does this vary by screening technology or by age, sexual history, or other patient characteristics?
KQ2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic yield and reduce indeterminate results and inadequate samples
compared to conventional cervical cytology?
KQ3: What are the benefits of using HPV testing as a screening test, either alone or in combination with cytology, compared with not testing for HPV?
KQ4: What are the harms of liquid-based cytology?
KQ5: What are the harms of using HPV testing as a screening test, either alone or in combination with cytology?

Screening for Cervical Cancer 74 Oregon Evidence-based Practice Center

Figure 6. High-Risk HPV Prevalence and CIN3+ Incidence32

25 5

High-risk HPV Prevalence

CIN3+ Incidence

20 4

CIN3+ incidence per 1000 women per year

Prevalence of High-risk HPV

15 3

10 2

5 1

0 0
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54
Age (years)

32
High-risk HPV types: 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66 and 68

Screening for Cervical Cancer 75 Oregon Evidence-based Practice Center

Figure 7. Comparison of HC2 and Repeat Cytology Sensitivity for the Detection of CIN2+ Among
Women Referred With ASC-US Cytology

Difference in sensitivity
Study - Year % Weight
(95% CI)

Bergeron, 2000 0.17 (-0.17,0.51) 14.0

Manos, 1999 0.13 (0.00,0.26) 74.4

Andersson, 2005 0.00 (-0.43,0.43) 11.6

Overall (95% CI) 0.12 (0.00,0.24); p=0.046

Test of heterogeneity: p=0.82

-0.4 -0.2 0 0.2 0.4 0.6

Difference in sensitivity

ASC-US: atypical squamous cells of undetermined significance; CI: confidence interval ; CIN: cervical intraepithelial neoplasia; HC2: Hybrid
Capture 2

Screening for Cervical Cancer 76 Oregon Evidence-based Practice Center

Figure 8. Comparison of HC2 and Repeat Cytology Specificity for the Detection of CIN2+ Among
Women Referred With ASC-US Cytology

Difference in specificity
Study - Year % Weight
(95% CI)

Bergeron, 2000 -0.10 (-0.23,0.03) 9.5

Manos, 1999 0.00 (-0.04,0.05) 86.5

Andersson, 2005 -0.07 (-0.28,0.13) 4.0

Overall (95% CI) -0.01 (-0.05,0.03); p=0.649

Test of heterogeneity: p=0.28

-0.25 -0.125 0 0.125 0.25

Difference in specificity

ASC-US: atypical squamous cells of undetermined significance; CI: confidence interval; CIN: cervical intraepithelial neoplasia; HC2: Hybrid
Capture 2

Screening for Cervical Cancer 77 Oregon Evidence-based Practice Center

Table 1. Cervical Pathology: Comparison of Cytologic and Histologic Test Results10 and Current
U.S. Guidelines for Management of Cytologic Abnormalities
Abnormal cervical cytology: the Bethesda System, 2001 Corresponding cervical histology
1
ASC-US
(Atypical Squamous Cells of Undetermined Significance)
2
ASC-H
(Atypical Squamous Cells – cannot exclude HSIL)
3
LSIL CIN1
(Low-Grade Squamous Intraepithelial Lesion) (Cervical Intraepithelial Neoplasia 1)

Previous terminology: mild dysplasia

HSIL
2 CIN2
(High-Grade Squamous Intraepithelial Lesion)
CIN3
Previous terminology: moderate dysplasia (CIN2)
Severe dysplasia and carcinoma in situ (CIN3)
2
SCC
(Squamous Cell Carcinoma)
2
AGC
(Atypical Glandular Cells; specify endocervical or not otherwise specified)
Atypical Glandular Cells, favor neoplastic
(specify endocervical or not otherwise specified)
2
AIS
(Adenocarcinoma in Situ [endocervical])
2
Adenocarcinoma
207
Management options and referral thresholds (based on ASCCP guidelines ):
1. Women ≤ 20 years : Repeat cytology
Women ≥ 20 years: Colposcopy is one option
2. All women: Receive at least immediate colposcopy
3. Women ≤ 20 years: Repeat cytology
Women ≥ 20 years: Colposcopy

Screening for Cervical Cancer 78 Oregon Evidence-based Practice Center

Table 2. U.S. Age-Specific Crude Invasive Cervical Cancer Incidence Rates By Race, 2000-2008208
American Asian or Pacific
Age-Group White NonHispanic Black Hispanic†
Indian/Alaska Native* Islander
00 0 0 0 0 0
01-04 0 0 0 0 0
05-09 0 0 0 0 0
10-14 0 0.1 0 0 0
15-19 0.1 0.2 0 0 0.2
20-24 1.5 1.9 3.8 0.5 1.6
25-29 6.4 5.2 6.0 1.8 5.2
30-34 12.4 9.6 12.9 5.6 11.2
35-39 13.9 12.5 9.2 8.3 16.9
40-44 13.8 16.9 12.3 12.2 21.5
45-49 12.6 16.6 11.6 15.5 20.7
50-54 11.8 17.3 8.9 14.0 21.0
55-59 11.1 18.7 15.2 14.5 22.5
60-64 10.7 23.3 10.4 17.3 24.1
65-69 11.4 24.3 10.8 17.1 26.7
70-74 10.3 21.7 12.3 16.1 24.1
75-79 9.0 24.1 19.8 18.4 21.9
80-84 9.4 24.7 8.7 16.7 17.8
85+ 8.3 28.9 14.5 15.1 18.0

Rates are expressed as cases per 100,000 women.

*American Indian/Alaska Native statistics only include cases from the Contract Health Service Delivery Area (CHSDA) counties.
†Hispanic and nonHispanic are not mutually exclusive from white, black, American Indian/Alaska Native, and Asian or Pacific Islander.

Screening for Cervical Cancer 79 Oregon Evidence-based Practice Center

Table 3. Characteristics of Liquid-Based Cytology Studies (RCTs and Observational Studies)
(KQ2)
108 107 109 110
NETHCON NTCC Taylor 2006 Coste 2003

Setting The Netherlands Italy Periurban South Africa France

Cluster RCT, randomized) to LBC RCT: HPV (HC2) & LBC vs. Cytology method (LBC vs. Consecutive series, split
Design
vs. CC CC CC) rotated on 6 month basis sample
Years of Study April 2004 to January 2008 February 2002 to 2005 June 2000 to December 2002 September 1999 to May 2000
Sample Size (N) 88,988 45,174 5,647 1,757
<30 ≥30 35-39 40-49 50-65
Patient Age LBC 0.7% 99.3% Median: 41 LBC 39.4% 41.4% 19.3% Mean (SD): 33.3 (11.1)
CC 0.6% 99.4% CC 37.5% 43.7% 18.8%
Primary Screening
ThinPrep ThinPrep ThinPrep ThinPrep
Test Evaluated
Primary Outcomes CIN2+, CIN3+ CIN2+, CIN3+ CIN2+, CIN3+ CIN2+
LBC (ASC-US/AGUS+): 2.7% LBC (ASC-US/AGUS+): 6.3% LBC (ASC-US+): 16.4% LBC (ASC-US+): 13.4%
Test Positivity Rate
CC (ASC-US/AGUS+): 2.8% CC (ASC-US/AGUS+): 3.8% CC (ASC-US+): 16.4% CC (ASC-US+): 12.4%
CIN2+ CIN3+ ICC CIN2+ CIN3+
CIN2 1.0% CIN2 or CIN3: 2.0%
Disease Detection LBC 0.71% 0.52% 0.06% LBC 0.44% 0.20%
CIN3+ 1.2% Invasive cancer: 0.3%
CC 0.70% 0.47% 0.03% CC 0.37% 0.24%
USPSTF Quality Good Fair Fair Fair

ASC-US: atypical squamous cells of undetermined significance; AGUS: atypical glandular cells of undetermined significance; CC: conventional cytology; CIN:
cervical intraepithelial neoplasia; HPV: human papillomavirus; LBC: liquid-based cytology; SD: standard deviation; RCT: randomized controlled trial; USPSTF:
United States Preventive Services Task Force

Screening for Cervical Cancer 80 Oregon Evidence-based Practice Center

Table 4. Liquid-Based Cytology Test Performance Characteristics for Studies (RCTs and
Observational Studies) (KQ2)
Sensitivity/ Relative
Cytology Specificity Positive Predictive False Positive Rate Unsatisfactory
Study ID Detection Ratio
Cutoff (95% CI) Value (95% CI)* (95% CI)* Samples†
(95% CI)*
LBC CC LBC CC LBC CC LBC CC LBC CC
Detection of CIN3+
NETHCON ASC-US+ 1.05 (0.86-1.29) (adjusted) NA 1.17 (0.99-1.39) 0.89 (0.82-0.98)
108 0.37% 1.09%
LSIL+ NR NA 1.17 (1.01-1.36) NR
107 ASC-US+ 0.84 (0.56-1.25) NA 0.42 (0.29-0.62) 1.93 (1.72-2.21)
NTCC 2.6% 4.1%
LSIL+ 0.72 (0.46-1.13) NA 0.40 (0.26-0.62) 1.72 (1.42-2.07)
75.8 87.9 84.2 84.5 4.9 7.2 15.8 15.5
ASC-US+
(57.7-88.9) (71.8-96.6) (82.9-85.5) (83.0 -86.0) (3.2-7.1) (4.9-10.2) (14.5-17.1) (14.0-17.0)
Taylor 66.7 72.7 93.6 93.9 10.0 14.1 6.4 6.1
109 LSIL+ 2.2% 0.8%
2006 (48.2-82.0) (54.5-86.7) (92.6-94.4) (92.9-94.9) (6.4-14.7) (9.3-20.3) (5.6-7.4) (5.1-7.1)
54.5 63.6 97.8 97.1 21.2 23.3 2.2 2.9
HSIL+
(36.4-71.9) (45.1-79.6) (97.2-98.3) (96.4-97.8) (13.1-31.4) (15.1-33.4) (1.7-2.8) (2.2-3.6)
Detection of CIN2+ -- --
NETHCON ASC-US+ 1.00 (0.84-1.20) (adjusted) NA 1.09 (0.95-1.25) 0.90 (0.82-0.99)
108 -- --
LSIL+ NR NA 1.04 (0.93-1.15) NR
107 ASC-US+ 1.11 (0.81-1.52) ‡ NA 0.65 (0.49-0.88) ‡ 1.97 (1.75-2.21)
NTCC -- --
LSIL+ 1.03 (0.74-1.43) NA 0.58 (0.43-0.78) 1.80 (1.48-2.19)
70.6 83.6 84.8 85.1 9.4 11.4 15.2 14.9
ASC-US+
(58.3-81.0) (71.2-92.2) (83.5-86.1) (83.6-86.5) (7.0-12.3) (8.5-15.0) (13.9-16.5) (13.5-16.4)
Taylor LSIL+ 60.3 69.1 94.1 94.5 18.6 22.4 5.9 5.5
109 -- --
2006 (47.7-71.9) (55.2-80.9) (93.2- 94.9) (93.5-95.4) (13.7-24.4) (16.3-29.4) (5.1-6.8) (4.6-6.5)
HSIL+ 44.1 58.2 98.2 97.6 35.3 35.6 1.8 2.4
(32.1-56.7) (44.1-71.3) (97.7-98.6) (96.9-98.2) (25.2-46.4) (25.7-46.3) (1.4-2.3) (1.8-3.1)
ASC-US+ 87.5 87.8 88.3 89.4 14.9 16.6 11.7 10.6
(73.2-95.8) (73.8-95.9) (86.7-89.8) (87.9-90.9) (10.6-20.1) (11.9-22.2) (10.2-13.3) (9.1-12.1)
Coste LSIL+
110
80.0 73.2 93.1 94.6 21.3 24.4 6.9 5.4 0.4% 0.1%
2003 (64.4-90.9) (57.1-85.8) (91.8-94.3) (93.4-95.6) (15.1-28.8) (17.1-33.0) (5.7-8.2) (4.4-6.6)
HSIL+ 65 60 98 99 49.1 58.5 1.6 1.0
(50-80) (45-75) (98-99) (99-99) (35.1-63.2) (42.1-73.7) (1.0-2.3) (0.6-1.6)
*Relative detection ratio, relative PPV, and relative false positive proportion for RCTs
†Unsatisfactory samples across all, not specific to CIN diagnosis
‡Restricted to centers with ASC-US+ referral criteria
ASC-US: atypical squamous cells of undetermined significance; CC: conventional cytology; CI: confidence interval; CIN: cervical intraepithelial neoplasia; HSIL:
high-grade squamous intraepithelial lesion; LBC: liquid-based cytology; LSIL: low-grade squamous intraepithelial lesion; NA: not applicable; NETHCON;
Netherlands ThinPrep vs. Conventional Cytology; NTCC: New Technologies for Cervical Cancer; NR: not reported

Screening for Cervical Cancer 81 Oregon Evidence-based Practice Center

Table 5a. Population and Screening Program of RCTs of HPV Screening Strategies for Cervical
Cancer Screening (KQ3)
117,197,216-
NTCC Phase Finnish NTCC Phase 114,214 115,160,215 ARTISTIC
112,113,209-211 120,133,134,212,213 112,113,210,211 POBASCAM Swedescreen 218
II Trial I
Country Italy Finland Italy The Netherlands Sweden UK
Total randomized
49,196 71,337 45,174 44,938 12,527 24,510
and screened
Ages recruited 25-60 25-65 25-60 30-56 32-38 20-64
Older women 35,471 59,757 33,364 44,938 12,527 19,344
Younger women 13,725 11,580 11,810 NA NA 5,166
Number of Rounds 2
1 2 2 2 2
Round Interval (y) 3 2-4 3 5 3 3
Followup (y) 3.5* 3.3 (mean) 3.5* 6.5† 4.1 (mean)‡ 7§
Screening
HC2 with cytology
Approach HC2 vs. CC HC2+LBC vs. CC PCR+CC vs. CC PCR+CC vs. CC HC2+LBC vs. LBC
triage (CC) vs. CC
Round 1
Screening
Approach CC vs. CC NA CC vs. CC PCR+CC vs. PCR+CC PCR+CC vs. CC HC2+LBC vs. LBC
Round 2
Difference between All women had CC NA All women had CC At Round 2, all women Second (―i ncidence‖) Women with CIN2+
rounds alone in Round 2 alone in Round 2 (both arms) had IG round screening histology at Round 1
protocol (HPV & CC co- occurred in the next excluded from
No women were No women were testing) screening round under analyses of Round 2
excluded from excluded from the Swedish cervical results
Round 2 based on Round 2 based on Women with CIN2+ cancer screening
Round 1 histologic Round 1 histologic histology at Round 1 program, scheduled 3
outcomes outcomes excluded from analyses years after baseline, or
of Round 2 results other screening not
Some women who Some women who complying with the
did not comply with did not comply study protocol
repeat screening or with repeat
post-colposcopy screening or post- No exclusions from
followup in Round colposcopy second round reported
1 were not invited followup in Round based on first-round
to Round 2 1 were not invited histologic outcomes
to Round 2

Screening for Cervical Cancer 82 Oregon Evidence-based Practice Center

Table 5b. Colposcopy Referral, Retesting, and Treatment Protocols of RCTs of HPV Screening
Strategies for Cervical Cancer Screening (KQ3)
117,197,216-
ASCCP║ NTCC Phase Finnish NTCC Phase 114,214 115,160,215 ARTISTIC
112,113,209-211 120,133,134,212,213 112,113,210,211 POBASCAM Swedescreen 218
II Trial I
Criteria for LSIL+ IG: HPV+ IG: HPV+&LSIL+ IG: HPV+ IG: HSIL+ IG: ASC-US+ IG: HSIL+
immediate (includes IG: ASC- IG: HSIL+††
colposcopy LSIL, HSIL, US+**
referral ASC-H)¶ CG: ASC- CG: LSIL+ CG: HSIL+ CG: ASC-US+ CG: HSIL+
US+ CG: ASC-US+ CG: HSIL+††
# #
Immediate CG: LSIL+ CG: LSIL+
colposcopy
also
acceptable
for ASC-US
Repeat ASC-US → IG: None IG: Baseline HPV+ IG: Baseline IG: Baseline HPV+, IG: Baseline HPV+ IG: HPV+ (LBC-):
testing either and CC- or ASC- HPV+ and ASC-US, ASC-H or (CC-) → repeat HPV Baseline, repeat
protocol immediate US → repeat cytology LSIL → repeat testing and CC annually, only HPV at 12
colposcopy, screening negative → at 6 and 18 months, persistent HPV+ (type months, if HPV+ →
repeat cyto (including HPV) at repeat HPV at 6 months- if specific) → patient choice of
at 6 and 12 months → and cytology in abnormal CC and colposcopy; CC: colposcopy at 12
12m, or HPV repeat ASC-US, or one year, if HPV+, or for HSIL+ Baseline ASC-US or months or repeat
test→ if ≥ three consecutive HPV+ or ASC- alone → colposcopy, LSIL → repeat CC only HPV at 24 months,
ASC or HPV+ results if US+ → at 18 months- HPV+ or (timing and referral if HPV+ at 24
HPV+ → CC- → colposcopy colposcopy‡‡ HSIL+ → colposcopy criteria NR) months →
colposcopy colposcopy; LBC:
HPV testing Same as CG
in women ≥
30y: CG: Baseline ASC-US,
Cyto- → CG: Baseline CG: Baseline CG: Baseline ASC-H or LSIL → CG: Baseline ASC-US
HPV test, if ASC-US (2 ASC-US → repeat ASC-US (2 repeat CC at 6 and 18 or LSIL → repeat CC
HPV+ → sites) → screening at 12 sites)→ repeat months, only (timing and CG: Baseline ASC-
repeat repeat months (referral cytology at repeat any referral criteria NR) US or LSIL →
cytology and cytology criteria NR) (timing NR), abnormality → repeat LBC at 6 and
HPV at 12m, (timing NR), if LSIL+ → colposcopy 12 months,
if cytology- & if LSIL+ → colposcopy if 3 consecutive
HPV+ → colposcopy ASC-US →
colposcopy colposcopy,
or if 2 consecutive
LSIL → colposcopy
Treatment CIN2+ CIN1+ CIN2+ NR High-grade CIN CIN2+
threshold CIN2+§§
Treatment NR LEEP NR NR Conization, loop Excision, ablation║║
excision

Screening for Cervical Cancer 83 Oregon Evidence-based Practice Center

Table 5c. Quality Rating and Limitations of RCTs of HPV Screening Strategies for Cervical
Cancer Screening (KQ3)
117,197,216-
NTCC Phase Finnish NTCC Phase 114,214 115,160,215 ARTISTIC
112,113,209-211 120,133,134,212,213 112,113,210,211 POBASCAM Swedescreen 218
II Trial I
USPSTF Quality Fair Fair Fair Fair Fair Fair
Quality Issues -Participants not -Single screening -Cytology may be -In Round 2, all -Cytology reading not -Colposcopists
blinded round thus far relatively poor if women had HPV with described aware of HPV+/cyto
community cytology; doesn’t really neg results.
-Cytology may be -Cytologist, standards not test repeat HPV -Patient unblinding to
relatively poor if colposcopists, and good, especially screening. HPV at year 3 due to -No biopsies in neg
community pathologists not for LBC (14 labs); high CIN2+/3+ in those colpos.
standards not good blinded to HPV were blind to -Round 2 results for HPV+.
(14 labs) results; community HPV. 2/3 of sample still not -Incomplete Rd 2
colposcopy; no reported. -Round 2 followup is screening and
-Colposcopists, biopsies in normal -Colposcopists, limited to one year— followup.
local histologists colpos histologists not -Blinding not reported doesn’t include
not blind to HPV blind to HPV for participants, but in retesting results. -Round 2 data
results; but blinded -Randomization results. place for cytology and ignored CIN2+
central review. scheme not HPV, not reported for histology following
reported -Community histology. normal cytology to
-Community colpos colpos repeated if make diagnostic
repeated if normal -Eligibility not normal but criteria the same in
but ―clearly clear, except age ―clearly abnormal both arms—reduces
abnormal cytology‖; no impact of retesting
cytology‖; no clear clear biopsies (HPV+/cyto-)
biopsies taken in taken in negative
negative colpos colpos. -Women linked to
NHS registries only
-Non-compliant -Non-compliant for cancer incidence
women in Rd 1 not women in Rd 1 not & mortality, not
invited to Rd 2 invited to Rd 2 intermediate
(2.8% in IG vs (2.7% in IG vs outcomes as was
0.7% in CG) 0.6% in CG). done in the other
trials

*NTCC Phase I and NTCC Phase II, maximum followup after invitation to Round 2 reported
†POBASCAM, followup among a subset of the population
‡Swedescreen, median followup years between enrollment and colposcopy
§ARTISTIC, maximum followup reported
║ASCCP details for reference only: For HSIL, immediate LEEP is an alternative to colposcopy with endocervical assessment. ASCCP guidelines for adolescent
women (20 years and younger), recommendations for AGC, and post-colposcopy management are not summarized here. May use HPV 16/18 genotyping for
women ≥30 years who are cytology negative and HPV+, refer immediately to colposcopy if positive for HPV 16 or 18.
¶ASCCP guidelines: Pregnant women with LSIL may defer colposcopy, post-menopausal women with LSIL may follow ASC-US protocol

Screening for Cervical Cancer 84 Oregon Evidence-based Practice Center

#NTCC Phase I and NTCC Phase II, colposcopy threshold varied by site: ASC-US+ (7 sites) or LSIL+ (2 sites)
**NTCC Phase I, colposcopy threshold varied by age
††Swedescreen, colposcopy threshold varied by site
‡‡NTCC Phase I, repeat testing protocol varied by age, currently reporting women aged < 35, older women had none
§§Finnish, treatment threshold varied by date and age
║║ARTISTIC, treatment method varied by site

ASC-H: atypical squamous cells cannot exclude HSIL; ASC-US: atypical squamous cells of undetermined significance; CC: conventional cytology; CG: control
group; CIN: cervical intraepithelial neoplasia; cyto: cytology; HC2: Hybrid Capture 2; HPV: human papillomavirus; HSIL: high-grade squamous intraepithelial
lesion; IG: intervention group; LBC: liquid based cytology; LEEP: loop electrosurgical excision procedure; LSIL: low-grade squamous intraepithelial lesion; NA: not
applicable, NR: not reported, NTCC: New Technologies for Cervical Cancer Screening; PCR: polymerase chain reaction, Rd: round, y: years

Screening for Cervical Cancer 85 Oregon Evidence-based Practice Center

Table 6. Characteristics of RCTs of Cytology Testing With HPV Triage of Positive Cytology (KQ3)
116,176,219-222 119
ALTS Bjerre
Country United States Sweden
Total randomized and screened 5,060 674
Ages recruited 18-81 22-60
Older women NR IG: 172
CG: 162
Younger women NR IG: 165
CG: 175
Number of Rounds 1 1
Round Interval (y) NA NA
Followup 2 years 7 months
Screening Approach IG: LBC w/ HPV (HC2) triage IG: CC w/ HPV (HC2) triage
CG: LBC CG: CC
Criteria for immediate colposcopy referral IG: HPV+ (or missing), or HSIL+ IG: HPV+
CG: HSIL+ CG: ASC-US+
Repeat testing protocol IG: Followup cytology at 6 month intervals (HPV results None
masked), HSIL  colposcopy

CG: Followup cytology at 6 month intervals (HPV results

masked), HSIL  colposcopy
Treatment threshold CIN2+, in addition to women with persistent lesions (CIN1+ All women with positive triage test
and cytology results from ≥ of the previous two visits
showed LSIL or HPV+ASC-US)
Treatment LEEP LEEP, laser conization
USPSTF Quality Good Good
Quality Issues -Repeat cyolgoy threshold of HSIL for referral colposcopy - Small sample size
versus ASC-US in recent guidelines

ASC-US: atypical squamous cells of undetermined significance; CC: conventional cytology; CG: control group; CIN: cervical intraepithelial neoplasia; HC2: Hybrid
Capture 2; HPV: human papillomavirus; HSIL: high-grade squamous intraepithelial lesion; IG: intervention group; LBC: liquid based cytology; LEEP: loop
electrosurgical excision procedure; LSIL: low-grade squamous intraepithelial lesion; NA: not applicable, NR: not reported

Screening for Cervical Cancer 86 Oregon Evidence-based Practice Center

Table 7. Characteristics of Studies Examining Absolute Test Performance of Primary Screening
With HPV Test Alone and Combination HPV and Cytology Testing (KQ3)
Study ID Primary Prevalence of
Number
Screening Primary Test Positivity Disease (in women USPSTF
Setting Study Design of Patient Age
Years of Test Outcomes Rate with colposcopy/ Quality
Patients
study Evaluated biopsy results)

Bigras Switzerland Consecutive Hybrid HSIL+ 13,842 Mean: 44.4 yr HC2 (HR): CIN2: 1.5% Fair
124
2005 series Capture 2 (range 17-93) 8.2% CIN3: 3.7%
Private practice ≥30 years: AIS: 0.2%
April 2002 to HC2 performed 96.4% LBC (ASC- Invasive carcinoma:
January 2004 Routine screening on residual LBC US+): 3.6% 0
sample
Kulasingam U.S. Consecutive Hybrid CIN2+, 4,075 Mean: 25 yr HC2 (HR): CIN2: 4.9% Good
122
2002 series Capture 2 CIN3+ (SD 5.7) 28.4% CIN3+: 8.6%
3 Planned & <30 yr: 81% CIN3+ (corrected for
December Parenthood clinics Swab of cervix PCR ≥30 yr: 19% PCR (HR): colposcopy
1997 to in Washington collected after 18.3% attendance and
October 2000 State cytology for HC2 verification bias):
or PCR testing LBC (ASC- 3.2%
Routine screening US+): 16.6%
After Jan 2000,
HC2 performed
on residual LBC
sample
121,126
CCCast Canada RCT with 2 arms: Hybrid CIN2+ 5,020 30-39 yr: HC2 (HR): CIN2+: 3.0% Fair
1) Focus on HPV: Capture 2 Focus on 38.5% 6.3% in Focus
September Medical practices HC2 followed by Pap 40-49 yr: on HPV
2002 to in Quebec & CC 35.0% 5.8% in Focus
February Newfoundland 2) Focus on Pap: 4,957 50-59 yr: on Pap
2005 CC followed by Focus on 20.4%
Routine screening HC2 HPV 60-69 yr: 6.1% CC (ASC-US+):
2.7% in Focus
Both screening on HPV
tests included in 3.0% in Focus
each arm, order of on Pap
collection was
randomized

Screening for Cervical Cancer 87 Oregon Evidence-based Practice Center

 Study ID Primary Prevalence of
Number
Screening Primary Test Positivity Disease (in women USPSTF
Setting Study Design of Patient Age
Years of Test Outcomes Rate with colposcopy/ Quality
Patients
study Evaluated biopsy results)
110
Coste 2003 France Consecutive Hybrid CIN2+ 1,323 Mean (SD): HC2 (HR): CIN2 or CIN3: 2.0% Good
series, split Capture 2 HC2 33.3 yr (11.1) 16.02% Invasive cancer:
de Cremoux Two public sample 0.3%
128
2003 university 1,757 CC LBC (ASC-
hospitals and two LBC slide & LBC US+): 12.1%
Cochand- private practices prepared from CC
Priollet sample and HC2 CC (ASC-US+):
127
2001 Routine screening assay performed 10.0%
on residual
September sample from LBC
1999 to May
2000
Cardenas- U.S. and Canada Consecutive Hybrid CIN2+ 1,850 Mean: 46.7 yr HC2: 7.9% CIN 2/3 or cancer: Fair
Turanzas (cancer center & series, split Capture 2 Screening: 1.9%
125
2008 community sample CC (ASC-US+): Diagnosis: 25.9%
hospital) 7.1%
October 1998
to November Women recruited
2005 through
advertising in
local media
123
Petry 2003 Germany Consecutive Hybrid CIN2+, 7,908 Mean: 42.7 yr HC2 (HR): CIN2+: 8.6% Fair
series Capture 2 CIN3+ 30-60 years: 6.4% CIN3+: 6.9%
December 28 urban, 94.6%
1998 to suburban or rural, HC2 sample CC (PapIIw+):
December office-based collected following 3.1%
2000 gynecological CC sample at
practices same visit

Routine screening

AIS: adenocarcinoma in situ; ASC-US: atypical squamous cells of undetermined significance; CC: conventional Papanicolaou test; CIN: cervical intraepithelial
neoplasia; HC2: Hybrid Capture 2; HPV: human papillomavirus; HR: high risk; HSIL: high-grade squamous intraepithelial lesion; LBC: liquid-based cytology; LSIL:
low-grade squamous intraepithelial lesion; PapIIw: Munich cytology classification approximately equivalent to borderline/ASC-US; PCR: polymerase chain
reaction; RCT: randomized controlled trial; SCC: squamous cell carcinoma; SD: standard deviation; U.S.: United States; USPSTF: United States Preventive
Services Task Force

Screening for Cervical Cancer 88 Oregon Evidence-based Practice Center

Table 8a. Results for RCTs of HPV Screening Strategies in Cervical Cancer Screening, Women
≥30 or 35 Years of Age (KQ3)
NTCC Phase Finnish NTCC Phase 114,214 Swedescreen ARTISTIC
Parameter Rd 112,113,209-211 120,133,134,212,213‡‡ 112,113,210,211 POBASCAM 115,160,215 117,197,216-218
II Trial I
N Randomized
and Screened 49,196 71,337 45,174 44,938 12,527 24,510
(All Ages)
Ages Recruited 25-60 25-65 25-60 30-56 32-38 20-64**
Screened
35,471 59,757 33,364 17,155 12,527 19,344
Women aged ≥
(35-60y) (35-65y) (35-60y) (30-56y) (32-38y) (30-64y)
30-35y
IG: 17,724 IG: 29,968 IG: 16,706 IG: 8,575 IG: 6,257 IG: 14,507
R1
CG: 17,747 CG: 29,789 CG: 16,658 CG: 8,580 CG: 6270 CG: 4,837
Sample Size
IG: 17,401 IG: 16,332 IG: 6,887 IG: 6,257 **
R2 NR NR
CG: 17,658 CG: 16,561 CG: 6,838 CG: 6,270
IG: HC2 IG: HC2 w/CC triage IG: HC2+LBC IG: PCR+CC IG: PCR+CC IG: HPV+LBC
R1
Screening CG: CC CG: CC CG: CC CG: CC CG: CC CG: LBC
Approach IG: CC IG: CC IG: PCR+CC IG: PCR+CC IG: HPV+LBC
R2 NA
CG: CC CG: CC CG: PCR+CC CG: CC CG: LBC
IG: 1,029 (5.8%) IG: 1,789 (10.7%)
* *
B CG: 555 (3.1%) NR CG: 594 (3.6%) NR NR NR
† †
CG: 182 (1.0%) CG: 212 (1.3%)
‡
IG: 258 (0.9%) IG: 56 (0.7%) IG: 146 (2.3%) §
R1 NR NR 248 (1.3%)
Test Positivity CG: 293 (1.0%) CG: 54 (0.6%) CG: 150 (2.4%)
#
IG: 38 (0.6%) IG: 47 (0.40%)
R2 NR NA NR NR #
CG: 50 (0.7%) CG: 16 (0.41%)
#
IG: 94 (1.1%) IG: 405 (2.2%)
C NR NA NR NR #
CG: 104 (1.2%) CG: 121 (2.0%)
IG: 1,029 (5.8%) IG: 1,773 (10.6%)
B NR NR NR NR
CG: 435 (2.5%) CG: 498 (3.0%)
IG: 258 (0.9%) IG: 201 (2.3%) IG: 707 (4.9%)
R1 NR NR NR
Colposcopy CG: 293 (1.0%) CG: 115 (1.3%) CG: 197 (4.1%)
║║ **
Referrals IG: 87 (1.3%) IG: 160 (NR)
R2 NR NA NR NR **
CG: 129 (1.9%) CG: 42 (NR)
IG: 288 (3.4%) IG: 867 (6.0%)
C NR NA NR NR
CG: 244 (2.8%) CG: 239 (4.9%)
Positive B 0.80 (0.55-1.18) NR 0.34 (0.21-0.54) NR NR NR
††
Predictive R1 NR See footnote NR NR NR 0.63 (0.44-0.90)
#
Value for R2 NR NR NR NR NR 0.32 (0.18-0.55)
#
CIN3+ C NR NA NR NR NR 0.54 (0.44-0.66)

Screening for Cervical Cancer 89 Oregon Evidence-based Practice Center

 NTCC Phase Finnish NTCC Phase 114,214 Swedescreen ARTISTIC
Parameter Rd 112,113,209-211 120,133,134,212,213‡‡ 112,113,210,211 POBASCAM 115,160,215 117,197,216-218
II Trial I
B NR NR NR NR NR NR
IG: 52 (0.29%) IG: 32 (0.11%) IG: 52 (0.31%) IG: 68 (0.79%) IG: 72 (1.15%) IG: 116 (0.80%)
R1
Absolute CG: 22 (0.12%) CG: 23 (0.08%) CG: 33 (0.20%) CG: 40 (0.47%) CG: 55 (0.88%) CG: 38 (0.79%)
#
Detection for IG: 3 (0.02%) IG: 5 (0.03%) IG: 24 (0.35%) IG: 16 (0.26%) IG: 29 (0.25%)
R2 NR #
CIN3+ CG: 13 (0.07%) CG: 11 (0.07%) CG: 54 (0.79%) CG: 30 (0.48%) CG: 18 (0.47%)
#
IG: 55 (0.31%) IG: 57 (0.34%) IG: 92 (1.07%) IG: 88 (1.41%) IG: 262 (1.51%)
C NR #
CG: 35 (0.20%) CG: 44 (0.26%) CG: 94 (1.10%) CG: 85 (1.36%) CG: 98 (1.77%)
B NR NR NR NR NR NR
Relative
R1 2.37 (1.44-3.89) 1.38 (0.81-2.36) 1.57 (1.02-2.43) 1.70 (1.15-2.51) 1.31 (0.92-1.87) 1.02 (0.71-1.47)
Detection Ratio #
R2 0.23 (0.07-0.82) NR 0.46 (0.16-1.33) 0.45 (0.28-0.72) 0.53 (0.29-0.98) 0.53 (0.30-0.96)
for CIN3+ #
C 1.57 (1.03-2.40) NR 1.30 (0.87-1.91) 0.98 (0.74-1.30) 1.04 (0.77-1.39) 0.85 (0.67-1.08)
B NR NR NR NR NR NR
Relative
R1 2.13 (1.51-3.00) 1.36 (0.98-1.89) 1.78 (1.30-2.44) 1.56 (1.14-2.13) 1.51 (1.13-2.02) 1.21 (0.91-1.60)
Detection Ratio #
R2 0.25 (0.10-0.68) NR 0.59 (0.28-1.24) 0.53 (0.36-0.78) 0.58 (0.36-0.96) 0.63 (0.42-0.96)
for CIN2+ #
C 1.58 (1.16-2.13) NR 1.50 (1.13-1.98) 1.00 (0.79-1.27) 1.17 (0.92-1.49) 0.99 (0.83-1.19)
B NR NR NR NR NR NR
§§ #,,§§ §§
IG: 4 (0.02%) IG: 6 (0.02%) IG: 2 (0.01%) IG: 5 (0.06%)
R1 §§ #,,§§ §§ NR NR
Invasive CG: 2 (0.01%) CG: 4 (0.01%) CG: 6 (0.04%) CG: 2 (0.02%)
§§ §§
Cervical IG: 0 (0%) IG: 0 (0%) IG: 2 (0.03%)
R2 §§ NR §§ NR NR
Cancer CG: 3 (0.02%) CG: 4 (0.02%) CG: 7 (0.10%)
§§ §§ #,§§
IG: 4 (0.02%) IG: 2 (0.01%) IG: 7 (0.08%) IG: 1 (0.02%) IG: 8 (0.04%)
C §§ NR §§ #,§§
CG: 5 (0.03%) CG: 10 (0.06%) CG: 9 (0.10%) CG: 2 (0.03%) CG: 4 (0.07%)
Bold indicates statistical significance
*NTCC Phase I and NTCC Phase II, colposcopy referral threshold varied by site: ASC-US+ (7 sites)
†NTCC Phase I and NTCC Phase II, colposcopy referral threshold varied by site: LSIL+ (2 sites)
‡Swedescreen, colposcopy referral threshold (ASC-US+ or HSIL+): only ASC-US+ reported
§ARTISTIC, colposcopy referral threshold (HSIL+) pooled across both arms
#ARTISTIC, all age data reported (n=15,542), incomplete round 2 followup
**ARTISTIC, sample size for age-specific data not reported as Round 2 is incomplete
†† Finnish Trial, PPV reported across three age-groups in IG: 35-44 [1.81 (0.84-3.89)], 45-54 [1.63 (0.57-4.65)], and ≥ 55 [1.13 (0.36-3.51)]; CG: referent
‡‡Finnish Trial, extended 5-year followup data for a subset of the screened population (n=38,670); PPV for CIN3+, 1.49 (0.98-2.26); absolute detection for CIN3+,
IG: 59 (0.30%), CG: 33 (0.17%); relative detection ratio for CIN3+, 1.77 (1.16-2.74); invasive cervical cancers, IG: 6 (0.03%), CG: 3 (0.02%)
§§Invasive cervical cancers include adenocarcinoma and/or squamous cell carcinoma for NTCC Phase I, NTCC Phase I and ARTISTIC – all others ICC only
║║Colposcopy compliance reported in NTCC Phase I (IG: 1669, CG: 453) and NTCC Phase II (all women, IG: 1813, CG: 615)
ASC-US: atypical squamous cells of undetermined significance; B: baseline; C: cumulative; CC: conventional cytology; CG: control group; CIN: cervical
intraepithelial neoplasia; HC2: Hybrid Capture 2; HPV: human papillomavius; HSIL: high-grade squamous intraepithelial lesion; ;IG: intervention group; LBC: liquid-
based cytology; LSIL: low-grade squamous intraepithelial lesion; NA: not applicable; NR: not reported; NTCC: New Technologies for Cervical Cancer Screening;
PCR: polymerase chain reaction; Rd: Round; R1: Round 1; R2: Round 2

Screening for Cervical Cancer 90 Oregon Evidence-based Practice Center

Table 8b. Results for RCTs of HPV Screening Strategies in Cervical Cancer Screening, Women
<30 or 35 Years of Age (KQ3)
Parameter 112,113,209-211 120,133,134,212,213 112,113,210,211 117,197,216-218
Rd NTCC Phase II Finnish Trial NTCC Phase I ARTISTIC
N Randomized and
Screened 49,196 71,337 45,307 24,510
(All Ages)
Ages Recruited 25-60 25-65 25-60 20-64
Screened Women ≤30- 13,725 11,580 11,810 5,166
35 years of age (25-34y) (25-34y) (25-34y) (20-29y)
IG: 6,937 IG: 5,869 IG: 6,002 IG: 3,879
R1
CG: 6,788 CG: 5711 CG: 5,808 CG: 1,287
Sample Size
IG: 6,577 IG: 5,761 ¶
R2 NA NR
CG: 6,714 CG: 5,769
IG: HC2 IG: HC2 w/CC triage IG: HC2+LBC IG: HPV+LBC
R1
CG: CC CG: CC CG: CC CG: LBC
Screening Approach
IG: CC IG: CC IG: HPV+LBC
R2 NA
CG: CC CG: CC CG: LBC
IG: 907 (13.1%) IG: 530 (8.8%)
* *
B CG: 270 (4.0%) NR CG: 261 (4.5%) NR
† †
CG: 136 (2.0%) CG: 129 (2.2%)
Test Positivity IG: 166 (2.8%) ‡
R1 NR NR 215 (4.2%)
CG: 127 (2.2%)
R2 NR NA NR NR
C NR NA NR NR
IG: 907 (13.1%) IG: 712 (11.9%)
B NR NR
CG: 244 (3.6%) CG: 237 (4.1%)
IG: 166 (2.8%) IG: 540 (13.9%)
R1 NR NR
Colposcopy CG: 127 (2.7%) CG: 123 (9.6%)
║║ ¶
Referral IG: 124 (NR)
R2 NR NR NR ¶
CG: 32 (NR)
IG: 664 (17.1%)
C NR NR NR
CG: 115 (12.0%)
B 0.66 (0.31-1.40) NR 0.80 (0.55-1.18) NR
Positive Predictive R1 NR 0.70 (0.30-1.64) NR 0.50 (0.36-0.69)
Value for CIN3+ R2 NR NA NR NR
C NR NA NR NR
B NR NR NR NR
IG: 45 (0.65%) IG: 10 (0.17%) IG: 23 (0.38%) IG: 117 (3.02%)
Absolute Disease R1
CG: 11 (0.16%) CG: 11 (0.19%) CG: 25 (0.43%) CG: 42 (3.26%)
Detection for CIN3+
IG: 2 (0.03%) IG: 8 (0.14%)
R2 NR NR
CG: 10 (0.15%) CG: 8 (0.14%)

Screening for Cervical Cancer 91 Oregon Evidence-based Practice Center

 Parameter 112,113,209-211 120,133,134,212,213 112,113,210,211 117,197,216-218
Rd NTCC Phase II Finnish Trial NTCC Phase I ARTISTIC
IG: 47 (0.68%) IG: 31 (0.52%)
C NR NR
CG: 21 (0.31%) CG: 33 (0.57%)
B NR NR NR NR
Relative Disease Rate R1 4.00 (2.07-7.73) 0.88 (0.38-2.08) 0.89 (0.51-1.57) 0.93 (0.65-1.31)
for CIN3+ R2 0.20 (0.05-0.93) NR 1.00 (0.38-2.67) NR
C 2.19 (1.31-3.66) NR 0.91 (0.56-1.48) NR
B NR NR NR NR
Relative Disease Rate R1 4.54 (2.95-6.99) 1.29 (0.88-1.89) 1.99 (1.35-2.92) 1.07 (0.83-1.38)
for CIN2+ R2 0.40 (0.17-0.95) NR 0.73 (0.34-1.60) NR
C 2.80 (1.98-3.95) NR 1.63 (1.16-2.28) NR
B NR NR NR NR
§§ §§
IG: 1 (0.01%) IG: 0 (0%)
R1 §§ NR §§ NR
CG: 0 (0%) CG: 1 (0.02%)
Invasive Cervical §§ §§
IG: 0 (0%) IG: 0 (0%)
Cancer R2 §§ NR §§ NR
CG: 0 (0%) CG: 2 (0.03%)
§§ §§
IG: 1 (0.01%) IG: 0 (0%)
C §§ NR §§ NR
CG: 0 (0%) CG: 3 (0.05%)
Bold indicates statistical significance
*NTCC Phase I and NTCC Phase II, colposcopy referral threshold varied by site: ASC-US+ (7 sites)
†NTCC Phase I and NTCC Phase II, colposcopy referral threshold varied by site: LSIL+ (2 sites)
‡ARTISTIC, colposcopy referral threshold (HSIL+) pooled across both arms
¶ ARTISTIC, sample size for age-specific data not reported as Round 2 is incomplete
#All age data reported, majority of participants were older women
§§Invasive cervical cancers include adenocarcinoma and/or squamous cell carcinoma
║║Colposcopy compliance reported in NTCC Phase I (IG: 666, CG: 219) and NTCC Phase II (all women, IG: 1813, CG: 615)

ASC-US: atypical squamous cells of undetermined significance; B: baseline; C: cumulative; CC: conventional cytology; CG: control group; CIN: cervical
intraepithelial neoplasia; HC2: Hybrid Capture 2; HPV: human papillomavirus; HSIL: high-grade squamous intraepithelial lesion; IG: intervention group; LBC: liquid-
based cytology; LSIL: low-grade squamous intraepithelial lesion; NA: not applicable; NR: not reported; NTCC: New Technologies for Cervical Cancer Screening;
PCR: polymerase chain reaction; Rd: Round; R1: Round 1; R2: Round 2

Screening for Cervical Cancer 92 Oregon Evidence-based Practice Center

Table 9a. Absolute Test Performance By Age of Primary Screening With HPV Test Alone and
Combination HPV and Cytology Testing Among Developed Countries Only, Women ≥30 Years of
Age (KQ3)
Sensitivity Specificity Positive Predictive Value Negative Predictive Value
Sample
Study Cytology HC2 Cytology HC2 Cytology HC2 Cytology HC2
Size
Reference HC2 ASC- & HC2 ASC- & HC2 ASC- & HC2 ASC- &
(N)
US+ Cytology US+ Cytology US+ Cytology US+ Cytology
Detection of CIN3+
97.3 46.0 100 95.2 98.0 94.9 8.7 8.4 100 99.7 100
Petry 9.7
123 7,908 (83.2- (30.8- (93.7- (93.4- (96.7- (93.1- (6.3- (6.2- (55.3- (98.8- (99.1-
2003 * * (6.1-15) * *
99.6) 61.9) 100) 96.5) 98.8) 96.2) 11.8) 11.4) 100) 99.9) 100)
86.0 49.7 49.7 83.0 86.4 94.7
Kulasingam † †
122 774 (59.7- (32.9- (32.9- (76.8- (84.8- (92.8- NR NR NR NR NR NR
2002 † †
96.9) 71.5) 71.5) 87.1) 88.1) 96.1)
Detection of CIN2+
97.0 58.7 92.4 96.9 8.8 12.4 99.98 99.75
Bigras
124 13,842 (91.8- (48.6- NR (91.9- (96.6- NR (7.3- (9.6- NR (99.96- (99.67- NR
2005
99.4) 68.2) 92.9) 97.2) 10.6) 15.6) 100) 99.83)
Cardenas- 1,850 17
Turanzas 69 (41- 12 99 99
44 (20- 93 (91- 94 (95%
2008
125 89) NR NR (95% CI NR (95% (95% CI NR
70) 95) (92 - 95) CI
NR) CI NR) NR)
NR)
Coste
110
2003
de
96
Cremoux 65 76 85 98 97 ‡ ‡
128 3,080 (88- ‡ ‡ NR NR NR NR NR NR
2003 (50-80) (59-93) (83-87) (98-99) (97-98)
100)
Cochand-
Priollet
127
2001 ║
62.7 38.3 38.3 83.0 86.4 95.0
Kulasingam † †
122 774 (31.4- (19.3- (19.3- (76.6- (84.7- (93.0- NR NR NR NR NR NR
2002 † †
93.2) 63.3) 63.3) 87.2) 88.3) 96.4)
Mayrand 7.0
121 97.4 56.4 100 94.3 97.3 92.5 8.5 5.5 100 99.8 100
2007 (95%
9,977 (95% CI (95% CI (95% CI (95% (95% CI (95% CI (95% CI (95% CI (95% (95% CI (95% CI
Mayrand § § CI § §
126 NR) NR) NR) CI NR) NR) NR) NR) NR) CI NR) NR) NR)
2006 NR)
97.8 43.5 100 95.3 98.0 93.8 10.9 11.4 8.6 100 99.7
Petry
123 7,908 (86.3- (30.0- (93.7- (93.5- (96.7- (91.8- (8.2- (7.5- (6.5- (55.3- (98.7- NR
2003
99.7) 58.0) 100) 96.6) 98.8) 95.3) 14.2) 16.9) 11.3) 100) 99.9)

Screening for Cervical Cancer 93 Oregon Evidence-based Practice Center

Table 9b. Absolute Test Performance By Age of Primary Screening With HPV Test Alone and
Combination HPV and Cytology Testing Among Developed Countries Only, Women <30 Years of
Age (KQ3)
Sensitivity Specificity Positive Predictive Value Negative Predictive Value
Sample
Study Cytology HC2 Cytology HC2 Cytology HC2 Cytology HC2
Size
Reference HC2 ASC- & HC2 ASC- & HC2 ASC- & HC2 ASC- &
(N)
US+ Cytology US+ Cytology US+ Cytology US+ Cytology
Detection of CIN3+
92.5 65.4 64.0 70.1 81.5 87.6
Kulasingam † †
122 3,301 (83.5- (51.9- (51.1- (66.5- (80.7- (86.7- NR NR NR NR NR NR
2002 † †
97.3) 79.1) 77.6) 73.1) 82.3) 88.4)
Detection of CIN2+
Kulasingam 73.5 50.1 47.9 71.1 82.1 88.3
122 † †
2002 3,301 (53.3- (35.2- (34.1- (67.3- (81.3- (87.4- NR NR NR NR NR NR
† †
87.7) 62.2) 60.0) 74.0) 83.0) 89.2)

*Petry: HC2 and cytology reported as positive on either test with cytology threshold of Pap IIw+ (equivalent to ASC-US+) for CIN2+ and PapIII+ for CIN3+.
†Kulasingam: HC2 and cytology reported as ASC-US+ and hrHPV+
‡Coste: HC2 and cytology reported as HSIL+ or RLU/cut-off value ratio > 1.0 if ASC-US or AGUS.
§Mayrand: HC2 and cytology reported as Pap result of ASC-US+ or HPV ≥ 1 pg HPV DNA/ml
║Coste: Data was not stratified by age, study included women > 18 years of age; average age was 33.3 years

ASC-US: atypical squamous cells of undetermined significance, AGUS: atypical glandular cells of undetermined significance, CC: conventional cytology, CI:
confidence interval, CIN: cervical intraepithelial neoplasia, DNA: deoxyribonucleic acid, HC2: Hybrid Capture 2, HPV: human papillomavirus, hr: high-risk; LBC:
liquid-based cytology, LSIL: low-grade squamous intraepithelial lesion, ml: milliliter, NR: not reported, RLU: relative light units

Screening for Cervical Cancer 94 Oregon Evidence-based Practice Center

Table 10. Characteristics of Studies Examining Absolute Test Performance of Cytology Testing
With HPV Triage of Positive Cytology (KQ3)
Study ID Primary Prevalence of Disease
Number
Screening Primary Patient Test Positivity (in women with USPSTF
Setting Study Design of
Years of Test Outcomes Age Rate colposcopy/biopsy Quality
Patients
Study Evaluated results)

Andersson Sweden Consecutive Hybrid CIN2+, 177 Mean: 34 All All Fair
136
2005 series, split Capture 2 CIN3+ yr (range HC2 (HR): 65.5% CIN2: 15.3%
Gynecologic sample 23-60) CC (ASC-US+): CIN3: 6.2%
Dates NR departments of 47.5%
three university HC2 assay Referred with ASC-US
hospitals of performed on Referred with CIN2: 11.5%
Stockholm CC sample ASC-US CIN3: 7.7%
HC2 (HR): 44.2%
4-6 months after CC (ASC-US+): Referred with LSIL
referral cytology NR CIN2: 16.8%
CIN3: 5.6%
Women with low- Referred with
grade atypia (ASC- LSIL
US or LSIL) HC2 (HR): 74.4%
detected at a CC (ASC-US+):
population-based NR
screening

Bergeron France Consecutive Hybrid CIN2+ 378 Mean: 35 All All Fair
137
2000 series Capture 2 yr (range HC2 (HR): 53.7% CIN2+: 6.9%
41 participating 15-75) CC (ASC-US+):
March gynecologists; HC2 sample 49.7% Referred with ASC-US
1996 to number of clinics collected CIN2+: 10.8%
August NR following CC Referred with
1998 sample at same ASC-US Referred with LSIL
Within two months visit HC2 (HR): 43.2% CIN2+: 5.2%
after referral CC (ASC-US+):
cytology 32.4%

Women referred for Referred with

ASC-US or LSIL LSIL
smears in the HC2 (HR): 58.1%
Laboratoire Pasteur CC (ASC-US+):
Cerba, a private 56.9%
laboratory

Screening for Cervical Cancer 95 Oregon Evidence-based Practice Center

 Study ID Primary Prevalence of Disease
Number
Screening Primary Patient Test Positivity (in women with USPSTF
Setting Study Design of
Years of Test Outcomes Age Rate colposcopy/biopsy Quality
Patients
Study Evaluated results)

DelMistro Italy Comparison of: Hybrid CIN2+ 749 Median HPV+: 24.2% CIN2: 1.9% Fair
138
2010 (1) immediate Capture 2 Age: 42 Pap (ASC-US+): CIN3: 2.0%
Five centers in colposcopy, (2) yr 29.4% ICC: None reported
2005-2007 Veneto region in repeat Pap, and (range:
Northeast Italy (3) HPV test for 25-64)
participating in triage of ASC-
organized cervical US
screening program
All participants
received all
three tests at
baseline and 12
months later

Women with
any positive
screening test
invited for
repeat Pap and
HPV test at 6
months

Manos U.S. Consecutive Hybrid HSIL+ 973 HC2 Median: HC2 (HR): 39.5% HSIL (CIN2-3): 6.6% Good
100
1999 series Capture 2 37 yr Invasive cancer: 0.1%
Participants (prototype) 957 CC (range CC (ASC-US+):
October identified from HC2 sample 15-78) 38.9%
1995 to cohort of 46,009 collected
June 1996 women belonging to following CC
Kaiser Permanente sample at initial
Medical Care visit (referral
Program, Northern cytology)
California Region,
who had routine Repeat CC
cervical screening collected at
at 1 of 12 colposcopy
gynecology clinics examination
at 4 participating and used to
medical centers estimate results
of a repeat

Screening for Cervical Cancer 96 Oregon Evidence-based Practice Center

 Study ID Primary Prevalence of Disease
Number
Screening Primary Patient Test Positivity (in women with USPSTF
Setting Study Design of
Years of Test Outcomes Age Rate colposcopy/biopsy Quality
Patients
Study Evaluated results)

Median of 67 days cytology

(range 12-240 days) conducted
after referral within 6 months
cytology

Women with initial

ASC-US cytology
results

ASC-US: atypical squamous cells of undetermined significance; CC: conventional Papanicolaou test; CIN: cervical intraepithelial neoplasia; HC2: Hybrid Capture
2; HPV: human papillomavirus; HR: high risk; HSIL: high-grade squamous intraepithelial lesion; LBC: liquid-based cytology; LSIL: low-grade squamous
intraepithelial lesion; NR: not reported; U.S.: United States; USPSTF: United States Preventive Services Task Force

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Table 11. Results of RCTs for Cytology Testing With HPV Triage of Positive Cytology (KQ3)
116,176,219-222 119
Parameter ALTS Bjerre
All ages
N Randomized and Screened (All Ages) 5,060 674
Ages Recruited 18-81 22-60
IG: 1161 IG: 337
Sample Size
CG: 1164 CG: 336
IG: LBC w/ HPV (HC2) triage IG: CC w/ HPV (HC2) triage
Screening Approach
CG: LBC CG: CC
HPV+: 1767 (50.7%) IG: 207 (61.4%)
Test Positivity
ASC-US+: 2019(57.9%) CG: 148 (43.9%)
IG: 645 (55.6%) IG: 208 (62%)
Colposcopy Referral
CG: 143 (12.3%) CG: 138 (41%)
Positive Predictive Value for CIN3+ NR 0.80 (0.61-1.04)
IG: 73 (6.3%) IG: 72 (21.4%)
Absolute Disease Detection for CIN3+
CG: 59 (5.1%) CG: 60 (17.8%)
Relative Disease Rate for CIN3+ 1.24 (0.88-1.73) 1.20 (0.88-1.63)
Relative Disease Rate for CIN2+ NR 1.32 (1.04-1.67)
IG: 0 (0%) IG: 0 (0%)
Invasive Cervical Cancer
CG: 1 (0.09%) CG: 1 (0.3%)
Women < 35 years of age
IG: 165
Screened Women < 35 years of age NR
CG: 175
Test Positivity NR IG: 126 (76.4%)
CG: 88 (50.3%)
Colposcopy Referral NR NR
Positive Predictive Value for CIN3+ NR NR
Absolute Disease Detection for CIN3+ NR IG: 40 (24.2%)
CG: 39 (22.3%))
Relative Disease Rate for CIN3+ NR 1.09 (0.38-2.08)
Relative Disease Rate for CIN2+ NR 1.34 (1.00-1.79)
Invasive Cervical Cancer NR IG: 0 (0%)
CG: 0 (0.0%)
Women ≥ 35 years of age
IG: 172
Screened Women ≥ 35 years of age NR
CG: 162
Test Positivity NR IG: 75 (43.6%)
CG: 60 (37.0%)
Colposcopy Referral NR NR
Positive Predictive Value for CIN3+ NR NR
Absolute Disease Detection for CIN3+ NR IG: 32 (18.6%)
CG: 21 (13.0)

Screening for Cervical Cancer 98 Oregon Evidence-based Practice Center

 116,176,219-222 119
Parameter ALTS Bjerre
Relative Disease Rate for CIN3+ NR 1.44 (0.86-2.38)
Relative Disease Rate for CIN2+ NR 1.32 (0.89-1.97)
Invasive Cervical Cancer NR IG: 0 (0%)
CG: 1 (0.62%)

Bold indicates statistical significance

ALTS: ASCUS-LSIL Triage Study; ASC-US, atypical squamous cells of undetermined significance; CC: conventional cytology; CIN: cervical intraepithelial
neoplasia; CG: control group; HC2: Hybrid Capture 2; HPV: human papillomavirus; IG: intervention group; LBC: liquid-based cytology; NR: not reported; R1:
Round 1

Screening for Cervical Cancer 99 Oregon Evidence-based Practice Center

Table 12. Absolute Test Performance of Cytology Testing With HPV Triage of Positive Cytology
(KQ3)
Sensitivity Specificity False Positive Rate
Triage of ASC-US Triage of LSIL Triage of ASC-US Triage of LSIL Triage of ASC-US Triage of LSIL
Study ID
HC2 & HC2 & HC2 & HC2 & HC2 & HC2 &
HC2 CC HC2 CC HC2 CC HC2 CC HC2 CC HC2 CC
CC CC CC CC CC CC
Detection of CIN3+

75.0 75.0 100 71.4 58.3 64.6 27.1 50.0 41.7 35.4 72.9 50.0
Andersson
136 (19.4- (19.4- NR (59.0- (29.0- NR (43.2- (49.5- NR (19.3- (40.7- NR (27.6- (22.2- NR (63.9- (40.7- NR
2005
99.4) 99.4) 100.0) 96.3) 72.4) 77.8) 36.1) 59.3) 56.8) 50.5) 80.7) 59.3)
Detection of CIN2+

60.0 60.0 89.3 60.7 59.5 66.7 29.9 51.5 40.5 33.3 70.1 48.5
Andersson
136 (26.2- (26.2- NR (71.8- (40.6- NR (43.3- (50.5- NR (21.0- (41.2- NR (25.6- (19.6- NR (60.0- (38.2- NR
2005
87.8) 87.8) 97.7) 78.5) 74.4) 80.4) 40.0) 61.8) 56.7) 49.5) 79.0) 58.8)
100 100
83 66 92 93 62 71 46 44 45 32 38 29 54 56 55 68
Bergeron (76.8- (76.8-
137 (51.6- (34.9- (61.5- (66.1- (51.3- (61.8- (36.4- (37.7- (39.2- (25.9- (28.8- (19.7- (43.2- (49.8- (48.2- (62.3-
2000 100.0 100.0
97.9) 90.1) 99.8) 99.8) 71.2) 80.3) 56.8) 50.2) 51.8) 37.7) 48.7) 38.2) 63.6) 62.3) 60.8) 74.1)
) )
89.2 76.2 64.1 63.8 35.9 36.2
Manos
100 (78.4- (63.5- NR NA NA NA (60.9- (60.5- NR NA NA NA (32.8- (33.1- NR NA NA NA
1999
95.2) 85.7) 67.2) 66.9) 39.1) 39.5)
21.4 27.7 37.5
93.1 74.1 100 78.6 72.3 62.5
DelMistro (95% (95% (95%
138 (91.3- (70.9- (100- NA NA NA (75.7- (69.0- (58.9- NA NA NA NA NA NA
2010 CI CI CI
94.9) 77.3) 100) 81.6) 75.6) 66.0)
NR) NR) NR)

Screening for Cervical Cancer 100 Oregon Evidence-based Practice Center

Table 12. Absolute Test Performance of Cytology Testing With HPV Triage of Positive Cytology
(KQ3) (cont.)
Positive Predictive Value (95% CI) Negative Predictive Value (95% CI)
Triage of ASC-US Triage of LSIL Triage of ASC-US Triage of LSIL
Study ID
HC2 HC2 HC2 HC2
HC2 CC HC2 CC HC2 CC HC2 CC
& CC & CC & CC & CC
Detection of CIN3+

7.8 96.6 96.9 100 96.7

136 13.0 15.0 7.5
Andersson 2005 NR (2.6- NR (82.2- (83.8- NR (89.1- (88.7- NR
(2.8-33.6) (3.2-37.9) (3.1-14.9)
17.3) 99.9) 99.9) 100.0) 99.6)
Detection of CIN2+

30.0 26.9 26.6 86.2 87.5 90.6 82.0

136 26.1
Andersson 2005 (11.9- NR (18.2- (16.3- NR (68.3- (71.0- NR (75.0- (70.0- NR
(10.2-48.4)
54.3) 37.1) 39.1) 96.1) 96.5) 98.0) 90.6)
22.2 17.2 7.5 96.8 94.7 97.9 99.1 100 100
137 20.8 8.4 9.2
Bergeron 2000 (10.1- (8.9- (4.2- (89.0- (86.9- (88.7- (95.1- (96.8- (95.5-
(10.5-35.0) (4.5-13.9) (5.1-15.0)
39.2) 28.7) 12.2) 99.6) 98.5) 99.9) 100.0) 100.0) 100.0)
98.8 97.4
100 15.1 12.9
Manos 1999 NR NA NA NA (97.4- (95.7- NR NA NA NA
(11.7-19.2) (9.8-16.8)
99.5) 98.5)
9.4
138 14.9 (12.4- 9.5 (7.3-
DelMistro 2010 (7.3- NA NA NA NR NR NR NA NA NA
17.5) 11.6)
11.6)
ASC-US: atypical squamous cells of undetermined significance; CC: conventional Papanicolaou test; CI: confidence interval; CIN: cervical intraepithelial neoplasia;
HC2: Hybrid Capture 2; LSIL: low-grade squamous intraepithelial lesion; NA: not applicable; NR: not reported

Screening for Cervical Cancer 101 Oregon Evidence-based Practice Center

Table 13. Characteristics of HPV Harms Studies (KQ5)
Study ID USPSTF Setting
Quality Population Details
Study Design

Kitchener Fair Manchester, England N: 2,508

139
2007
General practices in primary care within the National Cervical Screening Program Patient Age: NR

Women with normal or mildly abnormal cytology who had been recruited into the ARTISTIC
trial were mailed a booklet of questionnaires approximately two weeks after they had
received the results of their baseline cytology

Two study groups:

HPV-revealed
HPV-concealed
140
Maissi 2004 Fair England N: 1,376 Baseline
1,011 Followup
143
Maissi 2005 Two of the three centers taking part in the English HPV/LBC pilot study
Patient Age:
Cross sectional questionnaire sent within one week of research team being informed that Baseline:
smear test results had been sent. Second questionnaire sent six months after receipt of test Mean (SD)
results Normal: 40.2 yr (12.2)
HPV-: 40.5 yr (11.3)
HPV+: 31.6 yr (9.7)
No HPV test: 35.4 yr (10.4)

Followup:
Mean (SD)
Normal: 40.5 yr (12.1)
HPV-: 41.6 yr (11.1)
HPV+: 32.7 yr (9.8)
No HPV test: 36.6 yr (11.1)

McCaffery Fair London, UK N: 271

141
2004
National Health Service well-woman clinic Patient Age:
Mean: 32 yr (SD 8.0, range 20-61)
Cross sectional survey using postal questionnaire sent one week after receipt of HPV and <30 yr: 55%
cytology screening results 30-34 yr: 18%
35-39 yr: 10%
≥40 yr: 17%

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Table 13. Characteristics of HPV Harms Studies (KQ5) (cont.)
Setting
Study ID USPSTF
Population Details
Quality
Study Design

McCaffery Fair Australia N: 314 women randomized

142
2010 HPV: 104
18 urban and rural family planning clinics across the country IC: 104
RS: 106
Multi-center RCT of triage testing
235 (75%) included in primary
Randomized to three arms: analysis, 305 (97%) in sensitivity
analysis
HPV: HPV testing (HC2) arranged as soon as possible
IC: Choice of HPV or repeat smear, informed by decision aid Patient Age:
RS: Repeat smear 6 months after randomization 30 yr and over: 66%
Under 30 yr : 34%
Baseline questionnaire assessing psychosocial wellbeing was conducted immediately after
consent, close to receipt of first abnormal smear result

Followup questionnaires conducted at regular intervals during the 12 months after triage
testing Baseline questionnaire assessing psychosocial wellbeing was conducted
immediately after consent, close to receipt of first abnormal smear result

HC2: Hybrid Capture 2, HPV: human papillomavirus, IC: informed choice, LBC: liquid-based cytology, NS: not significant, RS: repeat smear; SD: standard
deviation, USPSTF: United States Preventive Services Task Force, UK: United Kingdom, Wks: weeks, Yr: year

Screening for Cervical Cancer 103 Oregon Evidence-based Practice Center

Table 14. Outcomes of HPV Harms Studies (KQ5)
Timing of
Quality of
assessment after Distress Sexual health or
Anxiety life
Study ID screening results (CSQ or Concern relationships
(STAI) (EuroQOL
given & comparison GHQ) (SRS or PEAPS)
or SF-36)
groups
McCaffery et al, 1 week
141
2004 Normal cytology: Worse feelings
HPV+ vs HPV- about past,
Higher Higher NA NA
present, future
sexual partners*
Abnormal or Worse feelings
No
unsatisfactory cyto: Higher NA about past/future NA
difference
HPV+ vs HPV- sexual partners*
Kitchener et al, 2 weeks
139
2007 Normal cytology: Lower sexual
No No
known HPV+ vs NA satisfaction with NA
difference difference
unknown HPV+ current partner
Mildly abnormal No difference
No No
cytology: known HPV+ NA NA
difference difference
vs unknown HPV+
Normal cytology: No difference
Higher
Known HPV+ vs Higher NA NA
known HPV-
Mild abnormal Higher sexual
No No
cytology: Known NA satisfaction with NA
difference difference
HPV+ vs. known HPV- current partner
Maissi et al, 1 week
140
2004, 2005 Normal cytology: Greater
no HPV test Higher for Higher for concern &
Borderline cytology: No
HPV+ HPV+ higher Not evaluated
no HPV test, HPV-, difference
group group perceived
HPV+ risk HPV+†
6 months
Normal cytology: Greater
no HPV test concern Higher level
Borderline cytology: and higher sexual health
no HPV test, HPV-, No No perceived worries among No
HPV+ difference difference risk women with difference
abnormal abnormal pap
pap no HPV who were HPV+
test†
McCaffery et al, 2 weeks
142
2010 HPV test (immediate) More
Repeat Cytology (6 intrusive
No No No
mo.) thoughts No difference
difference difference difference
Informed choice among HPV
test group
Over 1 year (average daily score)
HPV test (immediate) Greater
Repeat Cytology (6 Lower for satisfaction
No No
mo.) HPV test with care in No difference
difference difference
Informed choice group HPV test
group
*Study specific assessment tool
†Scale not reported
CSQ: Cervical Screening Questionnaire, EuroQOL: European Quality of Life, GHQ: General Health Questionnaire,
HPV: human papillomavirus; Mo: months; NA: not available; SF-36: Short Form 36; STAI: State-Trait Anxiety
Inventory

Screening for Cervical Cancer 104 Oregon Evidence-based Practice Center

Table 15. Summary of Evidence By Key Question
Validity of
Number and Design of Studies Major Limitations Summary of Findings
Evidence

KQ1. When should cervical cancer screening begin, and does this vary by screening technology or by age, sexual history, or other patient
characteristics?

5 studies Lack of RCT level Overall fair quality Cervical cancer in teens is rare, whereas HPV infections and
3 population-based cohort studies evidence, lack of cytologic abnormalities are common and are usually transient.
1 prospective cohort study information regarding the Good consistency False positive cytology results are more common in women
1 case-control study influence of risk factors across studies under age 25 (3.1 to 3.5%) than in women aged 26 to 39 (2.1
on cervical cancer to 2.6%). Results from a large, case-control study (n=11, 901
screening in young Applicable to U.S. women aged 20 to 69 years) found screening women under
women age 25 was not associated with a decreased incidence of
cervical cancer diagnosed prior to the age of 30, although an
impact on stage IB+ cervical cancer could not be ruled out. In
this study, an overall protective effect of screening on invasive
cervical cancer (ICC) incidence was not demonstrated until
age 32.

KQ2. To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic yield and reduce indeterminate results and inadequate
samples compared to conventional cytology?

4 studies RCTs provide relative test Overall good quality In two RCTs (n=134,162 women aged 25 to 60 years), liquid-
1 RCT of LBC + HPV vs. CC performance data based cytology (LBC) and conventional cytology (CC) did not
1 RCT of LBC vs. CC comparing LBC and CC. Good consistency differ significantly at any cytologic threshold in measures of
1 consecutive series, split-sample study One RCT was not directly across studies relative sensitivity or of absolute sensitivity or specificity for
1 prospective cohort study (derived from designed to answer the detection of CIN2+ or CIN3+. LBC yields a lower proportion of
RCT) KQ, but is supplemented Mostly applicable to unsatisfactory slides than CC. Absolute test performance
by another larger RCT U.S. (especially studies (n=7,404) largely confirm trial findings.
that was. Studies RCTs)
performed in nonU.S.
primary care settings.
KQ3. What are the benefits of using HPV testing as a screening test, either alone or in combination with cytology, compared with not testing for HPV?
(See also Tables 16a and 16b for age-specific round specific screening program detection for each HPV-enhanced primary screening trial)

Primary screening with HPV test alone

12 studies (7 in countries similar to U.S. in Only about half (7/12) of One large fair- After a single screening round in NTCC Phase II among
cervical cancer screening) studies were conducted in quality RCT (NTCC 35,471 Italian women aged 35 to 60 years, about twice as
2 RCTs of HC2 vs. CC (1 relevant to U.S.) countries with population Phase II) of HC2 vs. many CIN3+ and CIN2+ were detected in the HC2 arm
1 RCT and 9 cross-sectional studies of cervical cancer screening CC in women aged compared with CC. During the second screening round using
absolute test performance of HC2 or HPV similar to U.S. (1 RCT; 6 25 to 60 years (28% CC in both arms, CIN3+ was relatively decreased in women
observational/RCT of aged 25 to 34 initially screened with HC2 compared with cytology (0.23, 95%

Screening for Cervical Cancer 105 Oregon Evidence-based Practice Center

 Validity of
Number and Design of Studies Major Limitations Summary of Findings
Evidence

PCR (6 relevant to U.S.) absolute test years), with a CI 0.07 to 0.82). Relative cumulative detection of both CIN2+
performance). second round of CCand CIN3+ were increased about 57% in the HC2 screened
only ; 6 fair- or good-
arm. In 13,725 women aged 25 to 34 years, about four times
RCT didn’t report quality cross- as many CIN3+ and CIN2+ were detected after initial HC2
outcomes as CIN2+ or sectional studies.screening compared with cytology. During Round 2, CIN3+
CIN3+, but author was relatively decreased in the HC2 arm (0.20, 95% CI 0.05 to
provided data on request. Consistently 0.93). Relative cumulative detection of CIN2+ and CIN3+ was
RCT does not report improved sensitivity about doubled. Experts suggest excess relative CIN2+ may
cumulative data on false or detection of reflect over-diagnosis.
positives, relative PPVs, CIN2+/CIN3+ with Cumulative colposcopies are not reported, however baseline
colposcopies or related HPV testing vs. CC; referrals were more than doubled in HC2-screened women
harms, only cumulative consistently reduced aged 35 to 60 years (5.8%) compared with CC only (2.5%). In
disease detection. test specificity. younger women, baseline colposcopies were markedly
increased with HC2 screening (13.1%) compared with CC
RCT tests one round of Uncertain screening (3.6%).
HPV screening only as program impact on
second screening round is possible harms, but Trial investigators pooled invasive cancers from these primary
conventional cytology likely worse in HC2 results (NTCC Phase II) with HC2-CC co-testing results
(CC) in both arms. younger women. (NTCC Phase I) due to insignificant statistical heterogeneity
113
between trials. Pooled results suggested decreased
Very limited evidence Fair applicability, invasive cancers in women aged 35 years and older screened
available on HC2 HPV primarily for women with HPV (6 total invasive cervical cancers in the HPV
primary screening in > 30 to 35 years. screening arms compared to 15 in the CC only arms
women under 30 years of Small number of [p=0.052]). However, cancer outcomes would ideally come
age. younger women in from comparable screening strategies and reflect clearly
test performance similar opportunities for diagnosis through comparable delivery
studies and less of colposcopies and/or long enough followup with registry
than 1/3 of trial linkages to allow disease ascertainment outside the screening
under 35 years. program.
For women over 30, one-time HC2 HPV test is relatively much
more sensitive (40% or more) but less specific (3 to 5%) than
cytology for the detection of CIN2+ and CIN3+. Much less
evidence in women under 30, suggests HC2 is 23 to 27%
more sensitive, but much less specific (11%) compared with
cytology for the detection of CIN2+/3+.
HPV testing with cytology triage of positive HPV (reflex cytology)

1 study Only one RCT with a Fair quality A very large trial (n=71,337) of screened Finnish women aged
1 RCT of HC2 with CC triage vs. CC triage single round of screening 25 to 64 years compared a single round of cytology triage of a
alone (Finnish Trial) reported as of yet, One large RCT with positive HPV test with cytology alone for the detection of
although a second round a single round of CIN2+. After 2 to 4 years, the use of cytology to triage positive

Screening for Cervical Cancer 106 Oregon Evidence-based Practice Center

 Validity of
Number and Design of Studies Major Limitations Summary of Findings
Evidence

is planned. screening reported, HC2 HPV tests resulted in identification of more CIN2+ lesions
and 5 year followup (RR 1.34, CI 1.04 to 1.72), with a trend towards more CIN3+
Cumulative Impact on recently reported in lesions (RR 1.22, 95% CI 0.78 to 1.92), than cytology alone at
colposcopy referrals or a subset of women a threshold of LSIL. After 5 years of followup, CIN3+ was
PPV not reported. (aged 30 to 64 significantly increased in intention-to-screen analyses (1.44,
years). 95% CI 1.01 to 2.05) as well as among women screened
(1.77, 95% CI 1.16 to 2.74, including 11 ICC/ACIS in HPV arm
Fair applicability to and 6 ICC/ACIS in CC only arm). Time until detection of
the U.S. (tests benefit is about one year for those referred to colposcopy
used); Finnish immediately, but approximately 3 years for those undergoing
population is not repeat screening and surveillance. Almost half of cases of
multi-racial and has CIN3+ detected during extended followup came from women
lower cervical undergoing repeat screening and surveillance. In women 35
cancer incidence and older, baseline colposcopies were similarly small (1%)
and mortality between arms, with higher repeat testing in HPV-cytology
triage arm (7.2%) than CC (6.0%). Authors report simulated
relative PPV, but need full Round 1 results and further rounds.
In younger women, overall colposcopies were higher in both
arms that in older women (2.8%), with twice the retesting in
HPV (15.8%) than in CC.
Evidence is somewhat supplemented by co-testing trial
results since 3 of 4 RCTs retested for HPV+ results if cytology
was below colposcopy threshold. However, these trials used
different, higher cytology thresholds, and theoretically have a
cytology testing safety net in place since cytology was done in
all women.
Combination HPV and cytology testing (co-testing)

4 RCTs (all in countries similar to U.S., within Data apply primarily to Overall fair quality European trials evaluated HPV-cytology co-testing versus
national cervical cancer screening) women aged 30 and cytology in 127,149 screened women aged 20 to 64 (16,976
2 RCTs of HPV PCR + CC vs. CC alone older. About 2/3 of data All report after two younger than 30 to 35 years) through two rounds of screening
(POBASCAM, Swedescreen) reflect HC2 usage, and screening rounds, within national screening programs. In women older than 30
2 RCTs of HC2 + LBC vs. LBC or CC 1/3 PCR. All trials use but three are years, no trials showed an impact on relative CIN3+ for HPV-
alone (NTCC Phase I, ARTISTIC) CC co-testing and for incomplete for cytology co-testing compared with cytology. Only one trial
control group screening Round 2. (NTCC Phase I) that referred co-tested women for ASC-US+
(except ARTISTIC). or HPV+ showed an impact on cumulative CIN2+ detection
Some unexplained (1.55, 95% CI 1.25 to 1.93), which some believe may indicate
Trials used different inconsistency in over-diagnosis of regressive disease. All but NTCC Phase I
screening/rescreening, results (see showed a significant decrease in relative CIN3+ detection in
retesting, and referral limitations) – may Round 2 of screening among co-tested women compared with

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 Validity of
Number and Design of Studies Major Limitations Summary of Findings
Evidence

protocols, including reflect incomplete cytology. Experts propose this as one surrogate for enhanced
variable colposcopy reporting true disease impact in programs of ongoing cervical cancer
referral thresholds from screening. Impact on ICC was limited due to few cases and
ASC-US+ to HSIL+ that Protocols for relatively short time frames. Two trials included women under
differ from U.S. colposcopy referrals, 35 years, but only one (NTCC Phase I) reported complete
recommended practice possible differences age-specific results. HPV-cytology co-testing did not impact
and from one another. in compliance with CIN3+ detection, but increased cumulative CIN2+ in younger
referrals or retesting, women to about the same degree as in older women (RR
Only 1 RCT referred or other differences. 1.63, 95% CI 1.16 to 2.28). Indirect comparisons between
women immediately for NTCC Phase I and II in women 35 to 64 years suggest no
HPV+ results when Conducted in additional benefit to co-testing above HPV screening alone,
cytology was below countries applicable although immediate colposcopies were higher in co-testing
threshold. Thus, trials to the U.S. using (10.6%) than in cytology (3.0%) or indirectly compared to HPV
primarily test HPV HPV and cytology primary screening (5.8%) in these trials all using the same
screening with cytology technologies cytology and HPV tests and thresholds.
triage. available in the U.S. In the single trial that reported cumulative PPV/colposcopies
Only two trials used same (ARTISTIC) reflecting repeat co-testing, cumulative relative
testing strategy in Round PPV was significantly reduced for CIN2+ or CIN3+ (1.86 false
2 as in Round 1. positive results with HC2-LBC co-testing for every one with
LBC alone). Women in the co-testing arm under 35 years of
Trials did not consistently age had twice (17.1%) the cumulative colposcopy referral rate
report cumulative false as women 35 to 60 years (6.0%).
positives, relative PPVs, Three of four co-testing trials (ARTISTIC, POBASCAM,
or colposcopies. Swedescreen) have not completely reported Round 2 (and
therefore cumulative) screening results (i.e., relative detection,
About two-thirds of data relative colposcopies, relative treatment rates, relative harms),
reflect HC2 use, one-third thus limiting current interpretation.
reflect HPV PCR use.
In cross-sectional studies of 17,885 women over 30 years, a
single HC2 test with CC (co-testing) was more sensitive for
CIN2+ or CIN3+, but less specific than CC alone. These
studies varied in their definitions of a positive co-test. In two
studies defining a positive cotest as HPV+ or ASC-US+, co-
test was 44 to 56 percent more sensitive but 4 to 5 percent
less specific than ASC-US+ cytology alone.

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 Validity of
Number and Design of Studies Major Limitations Summary of Findings
Evidence

The 5-year cumulative risk of CIN3+ lesions per woman

screened was lower (0.1 percent) after a combined negative
high-risk HPV test result and negative cytology or a negative
HPV test alone (0.2 percent) than after negative cytology
alone (0.8 percent). Large cohort studies suggest very low
cumulative risk of CIN3+ in women HC2 negative with
cytology less than ASC-US+: 0.16% after 4 years and 0.28%
after six years—with similar 6-year results in HC2 negative
women, but higher 6-year CIN3+ in cytology negative women
(0.97%). After 10 years in 20,810 U.S. women (mean age
35.9 years), cumulative incidence of CIN3+ among HPV
negative women was 0.87 (95% CI, 0.62 to 1.12) compared
with cytology<ASC-US+ women (1.38, 95% CI 1.10 to 1.67).
Cytology testing with HPV triage of positive cytology (reflex HPV)

6 studies RCTs do not address the Overall fair quality A single HPV test is more sensitive than a single repeat
2 RCTs of repeat cytology and HPV versus most important clinical cytology test for the detection of CIN2+ among women with
cytology question regarding the Protocol and ASC-US referral cytology and appears to have equal
alone value of a one time high- colposcopy referral specificity. Testing strategies involving either 1) HPV testing
1 prospective cohort and 3 cross-sectional risk HPV test versus threshold inconsist- plus cytology versus cytology alone or 2) HPV testing plus
studies of absolute test performance repeat cytology. Obser- ency, particularly cytology once versus repeat cytology every 6 months for 2
vational studies had small with U.S. practice years demonstrated a non-significant increase in CIN3+
numbers but overall across studies detection among women with ASC-US referral cytology but
findings were consistent resulted in more colposcopies.
with other systematic Fair to poor
reviews on this topic. No applicability of trials, HPV testing is not useful for the triage of LSIL cytology due to
data available to assess good applicability of the high proportion of positive HPV tests among women with
impact of age on value of observational LSIL cytologic diagnoses and referral of the majority of women
HPV triage of ASC-US or studies to colposcopy.
LSIL cytology.
KQ4. What are the harms of liquid-based cytology?

No evidence other than that provided in studies included for Key Question 2, which show no difference in false positive rates between LBC and conventional
cytology.
KQ 5. What are the harms of using HPV testing as a screening test, either alone or in combination with cytology?

4 studies Small studies and only Overall fair quality A positive result for HPV is associated with transient increases
1 RCT two evaluating symptoms in anxiety and distress as well as increased concern about
1 prospective cohort study both in short term and Good consistency sexual health, but these symptoms do not persist at 6 month
2 cross-sectional studies long term. High across studies followup. No short-term differences in anxiety or distress were

Screening for Cervical Cancer 109 Oregon Evidence-based Practice Center

 Validity of
Number and Design of Studies Major Limitations Summary of Findings
Evidence

proportions of shown among women randomized to triage of ASC-US Pap

nonresponders on Applicable to U.S. with HPV test versus repeat cytology versus choice of either
surveys. HPV test or repeat cytology; however, women who underwent
HPV testing had less distress at one-year followup.
ASC-US: atypical squamous cells of undetermined significance; CIN: cervical intraepithelial neoplasia; HPV: human papillomavirus; KQ: key question; LSIL: low-
grade squamous intraepithelial lesion; No: number; RCT: randomized controlled trial

Screening for Cervical Cancer 110 Oregon Evidence-based Practice Center

Table 16a. Relative Detection Ratio By Screening Round for RCTs of HPV Screening Strategies in
Cervical Cancer Screening (Women ≥30 or 35 Years)
Study ID
Screening Approach Round CIN3+ CIN2+ Invasive Cervical Cancer
N Total & by Age
Primary screening with HPV test alone
112,113,209-211
NTCC Phase II ICC-AD
Round 1  2.37 (1.44-3.89)  2.13 (1.51-3.00)
Round 1: Primary HC2 vs. CC IG: 4, CG: 2
Round 2: CC vs. CC ICC-AD
Round 2  0.23 (0.07-0.82)  0.25 (0.10-0.68)
Total: 49,196 IG: 0, CG: 3
<35: 13,725 ICC-AD
Cumulative  1.57 (1.03-2.40)  1.58 (1.16-2.13)
>35: 35,471 IG: 4, CG: 5
HPV testing with cytology triage of positive HPV (reflex cytology)
120,133,134,212,213
Finnish Trial ICC-AD†
Round 1 1.38 (0.81-2.36) 1.36 (0.98-1.89)
Round 1: HPV with cytology triage vs. CC IG: 6, CG: 4
Total: 71,337 Extended Round 1 IG: 6 ICC/ 5 ACIS/ 11 total
<30: 11,580 Followup  1.77 (1.16-2.74) CG: 3 ICC/ 3 ACIS/ 6 total
>30: 59,757 (up to 5-years)
Extended Round 1 Followup:
Total: 38,670
Cumulative
30-39: 9,201
40-64: 29,469
Combination HPV and cytology testing (co-testing)
112,113,210,211
NTCC Phase I ICC-AD
Round 1  1.57 (1.02-2.43)  1.78 (1.30-2.44)
Round 1: Co-testing: HC2 + LBC vs. CC IG: 2, CG: 6
Round 2: CC vs. CC ICC-AD
Round 2 0.46 (0.16-1.33) 0.59 (0.28-1.24)
Total: 45,174 IG: 0, CG: 4
<35: 11,810 ICC-AD
Cumulative 1.30 (0.87-1.91)  1.50 (1.13-1.98)
>35: 33,364 IG: 2, CG: 10
115 160,215
Swedescreen Round 1 1.31 (0.93-1.86)  1.51(1.13-2.01)
Rounds 1 & 2: Co-testing: PCR + CC vs. CC Pooled data only
Total: 12,527 Round 2  0.53 (0.29-0.98)  0.58 (0.36-0.95) IG: 1 ICC/ 4 ACIS-AD/ 5 total
<30: None CG: 5 ICC/ 4 ACIS-AD/ 9 total
Cumulative 1.04 (0.77-1.39) 1.17 (0.92-1.49)
>30: 12,527
114,214
POBASCAM IG: 5 ICC/ 3 ACIS / 8 total
Round 1  1.70 (1.15-2.51)  1.56 (1.14-2.13)
Round 1: Co-testing: PCR + CC vs. CC CG: 2 ICC / 1 ACIS / 3 total
Round 2: PCR + CC vs. PCR + CC IG: 2 ICC/ 0 ACIS/ 2 total
Round 2  0.44 (0.27-0.71)  0.52 (0.36-0.77)
Total: 17,155 CG: 7 ICC/ 3 ACIS/ 10 total
<30: None IG: 7 ICC/ 3 ACIS/ 10 total
Cumulative 0.98 (0.74-1.30) 1.00 (0.79-1.27)
>30: 17,155 CG: 9 ICC/ 4 ACIS/ 13 total

Screening for Cervical Cancer 111 Oregon Evidence-based Practice Center

 Study ID
Screening Approach Round CIN3+ CIN2+ Invasive Cervical Cancer
N Total & by Age
117,197,216-218
ARTISTIC Round 1 1.02 (0.71-1.47) 1.21 (0.91-1.60)
Rounds 1 & 2: Co-testing: HC2 + LBC vs. LBC ICC-AD†
Total: 24,510 Round 2  0.53 (0.30-0.96)*  0.63 (0.42-0.96)* IG: 8, CG: 4
<30: 5,166
>30: 19,344 Cumulative 0.85 (0.67-1.08)* 0.99 (0.83-1.19)*

Bold: Statistically Significant

*ARTISTIC CIN3+ and CIN2+ pooled across all ages at Round 2 and Cumulative, majority of participants (79%) were women aged > 30 years
†Invasive cervical cancer cases pooled across all ages and rounds; majority of participants were women aged > 30 years

ACIS: Adenocarcinoma in situ; AD: adenocarcinoma; CC: Conventional cytology; CG: control group; HC2: Hybrid capture 2; ICC: invasive cervical cancer; IG:
intervention group; LBC: liquid based cytology

Screening for Cervical Cancer 112 Oregon Evidence-based Practice Center

Table 16b. Relative Detection Ratio By Screening Round for RCTs of HPV Screening Strategies in
Cervical Cancer Screening (Women <30 or 35 Years)
Study ID
Screening Approach Round CIN3+ CIN2+ Invasive Cervical Cancer
N Total & by Age
Primary screening with HPV test alone
112,113,209-211
NTCC Phase II ICC-AD
Round 1  4.00 (2.07-7.73)  4.54 (2.95-6.99)
Round 1: Primary HC2 vs. CC IG: 1, CG: 0
Round 2: CC vs. CC ICC-AD
Round 2  0.20 (0.05-0.93)  0.40 (0.17-0.95)
Total: 49,196 IG: 0, CG: 0
<35: 13,725 ICC-AD
Cumulative  2.19 (1.31-3.66)  2.80 (1.98-3.95)
>35: 35,471 IG: 1, CG: 0
HPV testing with cytology triage of positive HPV (reflex cytology)
120,133,134,212,213
Finnish Trial Round 1 0.88 (0.38-2.08) 1.29 (0.88-1.89) NR†
Round 1: HPV with cytology triage vs. CC
Total: 71,337 Round 2
<30: 11,580
>30: 59,757
‡
Extended Round 1 Followup : Cumulative
Total: 38,670 (> 30 years)
Combination HPV and cytology testing (co-testing)
112,113,210,211
NTCC Phase I ICC-AD
Round 1 0.89 (0.51-1.57)  1.99 (1.35-2.92)
Round 1: Co-testing: HC2 + LBC vs. CC IG: 0, CG: 1
Round 2: CC vs. CC ICC-AD
Round 2 1.00 (0.38-2.67) 0.73 (0.34-1.60)
Total: 45,174 IG: 0, CG: 2
<35: 11,810 ICC-AD
Cumulative 0.91 (0.56-1.48)  1.63 (1.16-2.28)
>35: 33,364 IG: 0, CG: 3
117,197,216-218
ARTISTIC
Rounds 1 & 2: Co-testing: HC2 + LBC vs. LBC Round 1 0.92 (0.65-1.31) 1.07 (0.83-1.38)
Total: 24,510 NR†
Round 2 NR* NR*
<30: 5,166
>30: 19,344 Cumulative NR* NR*
Bold: Statistically Significant
*ARTISTIC CIN3+ and CIN2+ pooled across all ages at Round 2 and Cumulative, majority of participants (79%) were women aged > 30 years, see Table 18a
†Invasive cervical cancer cases pooled across all ages and rounds; majority of participants were women aged > 30 years, see Table 18a
‡
Finnish Trial, extended 5-year followup data for a subset of the screened population (n=38,670); relative detection ratio for CIN3+, 1.77 (1.16-2.74); invasive
cervical cancers, IG: 6 (0.03%), CG: 3 (0.02%)
ACIS: adenocarcinoma in situ; AD: adenocarcinoma; CC: conventional cytology; CG: control group; HC2: hybrid capture 2; ICC: invasive cervical cancer; IG:
intervention group; LBC: liquid based cytology

Screening for Cervical Cancer 113 Oregon Evidence-based Practice Center

Table 17. European Perspective in Interpreting Comparative HPV Screening Trials162

Suggested hierarchy of outcomes for new cervical cancer screening methods

Rank Outcome
1 Cervical cancer mortality (QALY gained)
2 Cervical cancer morbidity / Stage IB+ incidence
3 Cervical cancer incidence (including microinvasive)
4 Reduced CIN3+ incidence*
5 Increased detection of CIN3+ (or CIN2+)*
More CIN3+ detection overall (cumulative CIN3+)
More CIN2+ followed by less CIN3+ at subsequent screening
CIN2+ may exaggerate benefit through including overdiagnosis
6 Increased test positivity with increase, similar, or hardly reduced PPV*
*Surrogates may need to suffice for purposes of health policy, followed by modeling.

CIN: cervical intraepithelial neoplasia; PPV: positive predictive value; QALY: quality-adjusted life years

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Table 18. What Data Are Reported in RCTs of HPV Screening Strategies in Cervical Cancer
Screening
Primary HPV HPV with Cytology
Combined HPV/Cytology Co-testing
Screening Triage
NTCC Phase II Finnish Trial NTCC Phase I ARTISTIC Swedescreen POBASCAM
B X X
positives

R1 X X X X
Test

R2 X X
C X X
B X X
referrals

R1 X X X
Colpo

R2 X X
C X X
B X X
R1 X X
PPV

R2 X
C X
B
CIN 2+/3+
Detection

R1 X X X X X X
R2 X X X X X

C X X X X X

B
R1 X X X X
ICC

R2 X X X
C X X X X X

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Table 18. What Data Are Reported in RCTs of HPV Screening Strategies in Cervical Cancer
Screening (cont.)
115,160,21
NTCC Phase II Finnish NTCC Phase I 117,197,216-218 Swedescreen 114,214
112,113,209-211 120,133,134,212,213 112,113,210,211 ARTISTIC 5 POBASCAM
Trial
Different tests in Only one screening Different tests in R1 Interval between R1 Mean FU 4.1 years, 5-year interval
R1 and R2: HC2 round reported to and R2: HC2 & and R2 ranged from incomplete for R2 between rounds
vs CC in R1, CC date, second LBC vs CC in R1, 26 to 54 months (only immediate (3 in most trials)
vs CC in R2 planned at 5 years CC vs CC in R2 Incomplete R2 FU, colposcopy 59% of
Does not exclude Study includes few Does not exclude with 34% not yet referrals complete) participants had
women with participants age women with CIN2+ attending R2 at time Number of women not completed
CIN2+ in R1 from <30 (5% each arm) in R1 from R2 of analysis with incomplete FU 6.5 years’ FU at
R2 Cytology referral For those attending not quantified time of analysis
Additional Cytology referral threshold differed R2, histology FU R2 occurs outside For both R1 and
Limitations / threshold differed by site (2 sites after screening study with registry R2, data reported
Considerations by site (2 sites LSIL+, 7 sites ASC- shortened (<30 FU only only for those
LSIL+, 7 sites US+) months) for 29% Referral threshold completing all 6.5
ASC-US+) Younger women Maximum FU from differed by site years’ FU
had different baseline of 7 years, (about half ASC- In R2 all women
referral protocol but mean FU NR US+, half HSIL+) received both
and larger and Study includes HPV and
differential attrition ages ≥ 30 years cytology tests
only (range just 32- Study includes
38) ages ≥ 30 years
only
§Data reported in age-specific strata

ASC-US: atypical squamous cells of undetermined significance; B: Baseline; C: Cumulative; CC: conventional cytology; CIN: cervical intraepithelial neoplasia;
colpo: colposcopy; FU: followup; ICC: invasive cervical cancer; HC2: Hybrid Capture 2; HSIL: high-grade squamous intraepithelial lesion; HPV: human
papillomavirus; LSIL: low-grade squamous intraepithelial lesion; NR: not reported; NTCC: New Technologies in Cervical Cancer, R1: Round 1; R2: Round 2; PPV:
positive predictive value

Screening for Cervical Cancer 116 Oregon Evidence-based Practice Center

Table 19. Cumulative Incidence of CIN3+ By Baseline Testing Status of RCTs and Cohort Studies
With Long-Term Followup Data
European 117,135,197,216-218 Kaiser Finnish
Baseline 114,214 ARTISTIC 115,160,215 134 169
Cohort POBASCAM Swedescreen Permanente NW Trial Danish Study
Testing 167 All ages and age- 168
Study † Aged 30+ years Aged 30+ years Cohort Study Aged 30+ Aged 30+ years
Status specific
(all ages) (all ages) years
HPV- 27/1000 2/1000 All Ages 48/1000
/Cyto+ (95% CI 6 to (5 yrs) 8.3/1000 (2 yrs)
(FU yrs) 60) (95% CI 4.0 to 15.2)
(6 yrs) (6 yrs)
HPV- 2.7/1000 All Ages 8.7/1000 0.1/1000
(FU yrs) (95% CI 1.2 to 1.5/1000 (95% CI 6.2 to (5 yr extended
4.5) (6 yrs) 11.2) FU)
(6 yrs) (10 yrs)
< 30 yrs
3.5/1000
(6 yrs)
≥ 30 yrs
1.1/1000
(6 yrs)
HPV- 2.8/1000 1/1000 All Ages 0/1000 1.6/1000 0.8/1000
/Cyto- (95% CI 1.0 to (5 yrs) 0.7/1000 (2 yrs) (95% CI 0.8 to 2.4) (3 yrs)
(FU yrs) 4.7) (3 yrs)* (4 yrs)
4/1000
(6 yrs)
2.3/1000 (5 yrs)
(95% CI 1.4 to 3.6)
17/1000
(6 yrs)
(10 yrs)
Cyto- 9.7/1000 All Ages 13.8/1000 0.4/1000
(FU yrs) (95% CI 5.3 to 2.9/1000 (95% CI 11.0 to (5 yr extended
13.4) (6 yrs) 16.7) followup)
(6 yrs) (10 yrs)
Cyto- 100/1000 6/1000 All Ages 39/1000 43/1000
/HPV+ (95% CI 62 to (5 yrs) 40.5/1000 (2 yrs) (3 yrs)
(FU yrs) 151) (95% CI 29.8 to 53.6)
93/1000
(6 yrs) (6 yrs)
(5 yrs)
212/1000
(10 yrs)
*A lower proportion of baseline HPV negative/cytology negative women completed Round 2 screening (60%) than among groups with some test positivity at
baseline. Therefore, results are not completely representative.
† Limited by verification bias (only test positives according to initial and rescreening protocols were uniformly assessed for disease outcomes)
CI: confidence interval; Cyto: cytology; FU: followup; HPV: human papillomavirus; NW: northwest; Yrs: years

Screening for Cervical Cancer 117 Oregon Evidence-based Practice Center

Appendix A. Terminology and Abbreviations
223
Adenocarcinoma : Cancer that begins in cells that line certain internal organs and that have gland-like (secretory)
properties.

Baseline screening: Initial cross-sectional results from a screening episode, with associated histologic results from
immediate colposcopy referrals. Does not include complete retesting results (repeat screens after an initial equivocal
result) or associated histology. For example, in Phase 1 of the NTCC trial, baseline results included histologic lesions
detected up to one year after initial colposcopy referral, but not lesions detected over the full three-year interval
between screening rounds.
223
Cervical cancer : Cancer that forms in tissues of the cervix (the organ connecting the uterus and vagina). It is
usually a slow-growing cancer that may not have symptoms but can be found with regular Pap tests.
223
Cervix : The lower, narrow end of the uterus that forms a canal between the uterus and vagina.
223
Colposcopy : Examination of the vagina and cervix using a lighted magnifying instrument called a colposcope.
223
Cone biopsy : Surgery to remove a cone-shaped piece of tissue from the cervix and cervical canal. Cone biopsy
may be used to diagnose or treat a cervical condition. Also called conization.
223
Cryotherapy : Any method that uses cold temperature to treat disease.
223
Cytology : The study of cells using a microscope.

False positive: A patient with an abnormal screening test but a normal gold standard test for disease. Depending on
the outcome of interest, the definition of a normal disease outcome will vary. For example, in analyzing the
performance of a cytology screening test result of LSIL+ to predict CIN3+ detected by colposcopically-directed
biopsy, false positives would be women with LSIL+ cytology and either normal colposcopy (no biopsy), normal
biopsy, or biopsy showing CIN1 or CIN2.
223
Histology : The study of tissues and cells under a microscope.
224
HPV testing : Detects presence of HPV genetic material (DNA) high-risk for cervical cancer.
223
HPV vaccine : A vaccine being studied in the prevention of human papillomavirus infection and cervical cancer.
Infection with certain types of HPV increases the risk of developing cervical cancer. Also called human papillomavirus
vaccine.
223
Liquid-based cytology : A method for screening for cancerous or precancerous changes of the cervix performed
by scraping cells from the cervix and rinsing the sampling device into a vial containing a liquid preservative.
223
Loop electrosurgical excision procedure : A technique that uses electric current passed through a thin wire loop
to remove abnormal tissue. Also called loop excision and LEEP.
223
Pap smear : A method developed by Dr. George Papanicolaou for screening for cancerous or precancerous
changes of the cervix performed by scraping cells from the cervix and fixing them on a glass slide. Also known as
conventional cytology.
163
Primary cervical cancer screening test(s) : A first test (historically cervical cytology) that, if abnormal and meets
a pre-established threshold (such as LSIL+), leads to referral for a diagnostic procedure (usually colposcopy and
biopsy).

Rescreening: The next routine screening episode after a negative screening test result.
163
Retesting : After a primary cervical cancer screening test, those with abnormal results who do not reach the
threshold for diagnostic referral go through a repeated protocol of follow-up screening with later colposcopy referral
based on persistent or advancing abnormalities.

Round 1 screening: Screening test results (both initial Round 1 results and retesting results) and associated
histology for the full duration of Round 1.

Round 2 screening: Screening test results (both initial Round 2 results and restesting results) and associated
histology for the full duration of Round 2.

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Appendix A. Terminology and Abbreviations

Screening: Testing asymptomatic individuals in order to detect disease at an earlier, more treatable stage and
minimize adverse outcomes.

Screening interval (or rescreening interval): Time between routine screening episodes (e.g. three years).

Screening program: A comprehensive screening plan including routine screening intervals and protocols for
retesting after equivocal tests and for referral to colposcopy, represented by the designs of national screening
programs or of randomized controlled trials.
223
Squamous cell carcinoma : Cancer that begins in squamous cells, which are thin, flat cells that look like fish
scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the
body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma.
163
Triage test : A test applied to those with a positive primary test to further select women before referral for a
diagnostic procedure (colposcopy and biopsy).

List of acronyms and abbreviations

Abbreviation/Acronym Phrase, term, name of instrument
AGC Atypical glandular cells (specify endocervical or not otherwise specified [NOS])
AGUS Atypical glandular cells of undetermined significance
ACIS Endocervical adenocarcinoma in situ
ASC-H Atypical squamous cells – cannot exclude HSIL
ASC-US Atypical squamous cells of undetermined significance
CC Conventional cytology
CI Confidence interval
CIN Cervical intraepithelial neoplasia
CIS Carcinoma in situ
CKC Cold knife conization
CSQ Cervical Screening Questionnaire
DR Detection rate
ECC Endocervical curettage
GHQW-12 General Health Questionnaire
HC2 Digene Hybrid Capture 2 high-risk HPV DNA test
HIV Human immunodeficiency virus
HPV Human papillomavirus
HR Hazard ratio
hrHPV High-risk human papillomavirus
High-grade squamous intraepithelial lesion encompassing: moderate and severe
HSIL
dysplasia, CIN2, CIN3, and carcinoma in situ
ICC Invasive cervical cancer
IQR Interquartile range
LBC Liquid-based cytology
LEEP Loop electrosurgical excision procedure
Low-grade squamous intraepithelial lesion encompassing: human papillomavirus/
LSIL
mild dysplasia/CIN1
OR Odds ratio
PCR Polymerase chain reaction
PEAPS-Q Psychosocial Effects of Abnormal Pap Smear Questionnaire
PPV Positive predictive value
RCT Randomized controlled trial
RFPP Relative false positive proportion
RLU Relative light unit
RR Relative risk
SCC Squamous cell carcinoma
SD Standard deviation
SE Standard error
SONE Strips of neoplastic endocervix
S-STAI-6 Short form of Spielberger State-Trait Anxiety Inventory
STI Sexually transmitted infection
VIA Visual inspection with acetic acid

Screening for Cervical Cancer 119 Oregon Evidence-based Practice Center

Appendix B. Detailed Methods

Literature Search Strategy

For all key questions (KQs), we used existing systematic evidence reviews and meta-analyses to the extent possible
and supplemented with primary systematic literature searches bridging the time period covered by the prior review.
Results are presented in a cumulative fashion, incorporating the relevant studies from the prior review. We evaluated
the studies included in the previous review by Hartmann and colleagues against the inclusion and exclusion criteria
for the current review, and found only one study was eligible for inclusion.100 For all key questions, we initially
searched for systematic reviews, meta-analyses, and evidence-based guidelines on cervical cancer screening in the
Database of Abstracts of Reviews of Effects (DARE), the Cochrane Database of Systematic Reviews (CDSR),
PubMed, and the Health Technology Assessment database (HTA) from 2000 through 2007. Subsequent searches
specific to each key question supplemented evidence found in the search of reviews and meta-analyses. Two
reviewers independently examined abstracts from all searches for relevance to all key questions.

For KQs 1, 3, 4, and 5 (addressing age to begin screening, benefits of HPV testing, and harms of liquid-based
cytology and HPV testing), we found no systematic reviews or meta-analyses that met our inclusion criteria.
Therefore, we conducted primary literature searches to cover the time period since the previous USPSTF review
(2000 through September 2010) in MEDLINE and the Cochrane Collaboration Registry of Clinical Trials (CCRCT)
without restrictions on study designs. For KQ5, we also searched PsycINFO to capture adverse psychological effects
of HPV testing. Search terms are listed in Appendix B, Table 1.

For KQ2, we found two systematic reviews of liquid-based cytology providing coverage through July 2003.97,98 We
used these reviews as source documents and bridged their searches for liquid-based cytology. Therefore, for KQ2,
we searched MEDLINE and CCRCT, without restrictions on study designs, from the beginning of 2003 through
September 2010.

We also obtained articles from outside experts and through reviewing bibliographies of other relevant articles and
systematic reviews. In addition to these searches for published trials, we searched the following sources for
unpublished trials: Computer Retrieval of Information on Scientific Projects (CRISP), ClinicalStudyResults.org,
Current Controlled Trials, ClinicalTrials.gov.

Inclusion and Exclusion Criteria

We developed the following set of inclusion/exclusion criteria that were applied to the key questions. Differences in
inclusion, exclusion, and quality criteria precluded us from incorporating any of the existing systematic reviews or
meta-analyses that were identified; however, the high-quality reviews and meta-analyses were used to check the
completeness of our searches for primary studies.

Populations: This review addresses all females at risk for cervical cancer. Studies focusing only on high-risk
populations (e.g., HIV-infected women) or women who have had a hysterectomy were excluded.

Settings: This review includes studies conducted in primary care or other settings generalizable to primary care (e.g.,
family planning clinics, STI clinics, school-based health clinics). No studies were excluded based on geographic
location.

Screening interventions: This report addresses the following screening interventions:

1. Liquid-based cytology (obtained as a screening test or adjunct to screening rather than followup of documented
disease)
2. Conventional cytology
3. Primary screening with HPV test alone
4. HPV testing with cytology triage of positive HPV (reflex cytology)
5. Combination HPV and cytology testing (co-testing)
6. Cytology testing with HPV triage of positive cytology (reflex HPV)

For KQ3, we focused on the high-risk HPV types as identified by Hybrid Capture 2 (16, 18, 31, 33, 35, 39, 45, 51, 52,
56, 58, 59, and 68). We included studies that used HC2 or PCR (including Linear Array and Amplicor) to identify
these 13 HPV types. We excluded studies that focused exclusively on HPV types not listed above. We also
excluded studies of in-situ hybridization, p16 immunostaining, and viral load.

Outcomes: For KQ1, we included studies reporting age-specific incidence and prevalence of CIN2, CIN3, invasive
carcinoma, or death. For KQs 2 and 3, we included studies reporting detection of histologically-confirmed CIN2,

Screening for Cervical Cancer 120 Oregon Evidence-based Practice Center

Appendix B. Detailed Methods

CIN3, and invasive cervical cancer. For KQ4, we included studies of psychological distress and the consequences
of false positive results (e.g., colposcopy/biopsy, unnecessary treatment). For KQ5, we included studies reporting the
following harms of HPV testing: stigma and under-screening due to association with sexually-transmitted disease,
partner discord, unnecessarily labeling some women as high risk, anxiety from and consequences of high-risk
labeling, and undermined importance of cytologic screening. We did not systematically review the harms of treatment
procedures such as LEEP, cryotherapy, and laser cone biopsy. Instead, we report the results of two systematic
reviews on the harms of cervical cancer treatment procedures.

Study designs: For KQ1, addressing when to begin screening, we included RCTs, CCTs, population-based
prospective and retrospective cohort studies, case-control studies, ecological-level reports correlating population-
based rates of CIN and cancer detection with screening, systematic reviews, and meta-analyses. We only included
studies in routine screening populations that present age-specific outcomes, report screening-related denominators,
and use age intervals that allow for evaluation of young women separately.

For KQs 2 and 3, evaluating liquid-based cytology and HPV testing, we included studies that provided evidence
regarding absolute and relative test performance. Our specific criteria are as follows:

1) To determine absolute test performance, we required that the reference standard of colposcopy and/or biopsy was
systematically applied to all those screening positive and at least a random sample of screen negatives, with valid
adjustment for verification bias when necessary. The reference standard must have been independent of the
screening test (i.e., the screening test results were not used to establish the final diagnosis).
2) If a study did not test negatives appropriately with the gold standard, we could not use their absolute test
performance estimates. However, if the study was a randomized controlled trial, compared test performance within
the randomization scheme, and was of appropriate quality, then we included relative test performance measures.
3) Many studies reported theoretical test performance by estimating results for different screening and management
programs than what was actually done in the trials. We determined these calculations could not be included if the
assumptions required to estimate performance introduced potential threats to validity. We usually could not
determine how to fairly assess whether these assumptions affected the validity of the calculated test performance,
and if they did, what direction or degree of bias was introduced.

For HPV testing in primary screening, we included studies conducted in routine screening populations that compared
HC2 or PCR to cytology (conventional or liquid based). For HPV triage of women with ASC-US or LSIL cytology, we
included studies in women referred with a single ASC-US or LSIL cytology result that compared HPV triage to repeat
cytology.

For KQs 4 and 5, addressing the harms of liquid-based cytology and HPV testing, we included RCTs, CCTs, case-
control studies, systematic reviews, and high-quality observational studies.

Quality: We excluded studies that met criteria for “Poor” quality using the USPSTF design-specific criteria (Appendix
B, Table 3).

Language: We excluded non-English language abstracts and articles.

Article Review and Data Abstraction

We reviewed a total of 4,262 abstracts and 641 complete articles for all KQs (Appendix B, Figure 1). While we
conducted three searches to cover age to begin screening, liquid-based cytology, HPV testing, and harms of liquid-
based cytology and HPV testing, we reviewed all abstracts for potential inclusion for any of the KQs. Two
investigators independently reviewed all abstracts.

Two investigators independently reviewed articles against inclusion/exclusion criteria specific for each key question
and marked articles for exclusion as soon as an exclusion criterion was met. Included studies that met all criteria
95
were then independently rated for quality by two investigators, using the USPSTF’s study design-specific criteria
101
supplemented by National Institute for Health and Clinical Excellence (NICE) criteria for quality assessment and
102
the QUADAS tool for quality assessment of diagnostic accuracy studies (Appendix B, Table 3). The Methods Work
Group of the USPSTF has defined a three-category rating of “good,” “fair,” and “poor” based on these criteria. In
general, a good study meets all criteria well. A fair study does not meet, or it is not clear that it meets, at least one
criterion, but has no known important limitation that could invalidate its results. A poor study has important
limitations. Articles were rated as good, fair, or poor by each rater, and disagreements were settled by consensus.
Studies receiving a poor final quality rating were excluded from the review. Listings of excluded articles for each key
question, along with the reason for exclusion, are in Appendix D Tables 1-5. A list of all exclusion criteria is in
Appendix B Table 2.

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Appendix B. Detailed Methods

There are 35 studies (reported in 66 articles) included in this review. For KQ1, we found 5 studies reported in 6
articles, none of which were included in the previous USPSTF report. For KQ2, we found 4 studies reported in 7
articles, none of which were included in the previous USPSTF report. For KQ3, we found 22 studies reported in 48
articles, 1 of which was included in the previous USPSTF report. For KQ4, we found no studies. For KQ5, we found
4 studies reported in 5 articles, none of which were included in the previous USPSTF report. One primary reviewer
abstracted relevant information such as study setting, population, screening method, and outcomes into standardized
evidence tables for each included article (Appendix C Tables 1-4). A second reviewer checked the abstracted data
for accuracy and completeness.

Data Synthesis

We found no data for KQ4. Except for cytology testing with HPV triage of positive cytology (KQ3), data synthesis for
all questions was qualitative because heterogeneity in the samples, settings, study designs, and instruments did not
allow for quantitative synthesis. In the results text, studies are summarized qualitatively within the key questions. For
KQ3 addressing HPV testing, studies are categorized by the four different uses of HPV testing in cervical cancer
screening. In addition, randomized controlled trials providing primarily relative test performance measures within
screening programs are described first, followed by studies reporting absolute test performance data. Studies from
countries with less developed cervical cancer screening programs are discussed separately due to their lower
applicability to the US population. Where possible, the data is provided stratified by age for two primary reasons: 1)
the FDA has approved the use of HC2 in women 30 years and older as an adjunct to cytology to assess the absence
70,71
or presence of high-risk HPV types, and 2) the prevalence of high-risk HPV is much lower in women aged 30 and
older than in women under age 30, dropping sharply with age from a prevalence of 35 percent for women aged 15-19
to <15 percent for women aged 30-39 (Figure 3). For evidence on the benefits of using HPV testing to triage women
with ASC-US cytology, we estimated the combined difference in sensitivity and specificity between HPV and repeat
conventional cytology. A random effects model was used to incorporate variation among studies. For the difference
in sensitivity and specificity between HC2 and cytology, we used risk difference as the effect measure. Statistical
2 103
heterogeneity was assessed by Cochran’s Q test and the I statistic. All analyses were performed using Stata 10.0
(StataCorp, College Station, TX, 2007).

Many of the results reported in the evidence and summary tables are calculated from data provided in the articles.
Such calculations are indicated in the evidence tables by ‘(calc)’ following the results. In the randomized controlled
trials, results were generally reported using women screened (instead of women randomized as in an “intention-to-
screen” analysis) within each arm and each round. To be consistent, we abstracted from the articles or calculated
results using the number of women screened within each randomized arm as the denominator unless noted as
otherwise in the evidence tables. Consideration of program results only among women screened may be less
appropriate to determine overall population impact, but acceptable when primarily evaluating the relative merits
(including false positives and other adverse effects) of efficacious screening alternatives.

The trials reviewed generally applied the histology reference standard to screen-positive but not systematically to
screen-negative participants. The numbers of true positive versus false positive screening test results are thus
known (if not always fully reported), represented in the tables below as “a” and “b” respectively. However, the
numbers of true versus false negative results (“d” and “c”) and the total numbers of participants with (a+c) and without
(b+d) disease are unknown (collectively, all the shaded cells below).

Intervention arm Disease

+ ─
+ a1 b1 a1+b1
Test 1
─ c1 d1 c1+d1
a1+c1 b1+d1 n1 =a1+b1+c1+d1

Absolute test performance in the intervention group:

Sensitivity1 = a1/a1+c1
Specificity1 = d1/b1+d1

Control arm Disease

+ ─
+ a2 b2 a2+b2
Test 2
─ c2 d2 c2+d2
a2+c2 b2+d2 n2 =a2+b2+c2+d2

Screening for Cervical Cancer 122 Oregon Evidence-based Practice Center

Appendix B. Detailed Methods

Absolute test performance in the control group:

Sensitivity2 = a2/a2+c2
Specificity2 = d2/b2+d2

As a result, absolute sensitivity and specificity as defined above cannot be derived. However, clinically relevant
relative test performance measures can be calculated. In a randomized trial where disease prevalence is expected to
be the same between study arms, if the number of participants in each arm of the trial are the same then the number
of participants with disease (a+c) should be the same in the intervention and control groups, i.e., (a1+c1) = (a2+c2).
The relative detection rate (RDR, which could also be called relative sensitivity) can then be calculated:

Relative detection rate (RDR) = [a1/(a1+c1)]/a2/(a2+c2)] = a1/a2

Where the number of participants in each arm of the trial differs, the RDR can be calculated instead as:

Relative detection rate (RDR) = [(a1/n1)/(a2/n2)]

Where
a1 = cases of disease detected (or true positives) in the intervention arm
n1 = number of participants in the intervention arm
a2 = cases of disease detected (or true positives) in the control arm
n2 = number of participants in the control arm

We used the latter formula, correcting for differences in number of participants between arms, in all our RDR
calculations. Inclusion of CIN outcomes from opportunistic screening varied between trials, and was not always
clearly reported. For example, detection rates (a/n) and relative detection rates reported for the POBASCAM trial
used the numerator of all CIN or cancer cases detected in each study arm, regardless of screening test result,
including cases detected by opportunistic screening in screen-negative women. ARTISTIC publications included only
screen-detected CIN in reported detection rates, and we did the same in calculating age-specific RDRs. For the
Finnish trial, initial publications appeared to include only screen-detected CIN in detection rates, though CIN
outcomes were not reported by screening test result. Extended followup published in 2010 reported RDRs in both
screen-positive women and all attendees, and we reported the results in all attendees as better representing the real-
world effectiveness of the screening program. Swedescreen appeared to report screen-detected CIN in Round 1
RDRs, while including opportunistic screening from both rounds with Round 2.

Less often reported, but analogous to the RDR, is another relative test performance measure, which we have called
the relative false positive proportion (RFPP). The RFPP is an estimate of the relative harms of screening tests,
specifically the relative proportion of women referred unnecessarily to colposcopy.

Relative False Positive Proportion (RFPP) = [(b1/n1)/(b2/n2)]

Where
b1 = false positives in the intervention arm (i.e., those with a positive screening test not found by histology to have
true disease)
n1 = number of participants in the intervention arm
b2 = false positives in the control arm
n2 = number of participants in the control arm

A similar calculation of “relative specificity” is not possible, as it would require information on true versus false
negatives which these trials do not obtain (specifically, d1 and d2 or the true negatives in the tables above). We
therefore neither abstracted nor calculated any specificity measure from the trials. Both absolute and relative positive
predictive value (PPV) should be calculable for all trials since this measure describes screen-positive women only, for
whom full histology data were obtained. Wherever reported data allowed, we abstracted or calculated both PPV
measures as well.

Absolute PPV in the intervention group = PPV1 = a1/(a1+b1)

Where
a1 = cases of disease detected (in screen-positive participants, i.e., true positives) in the intervention arm

Screening for Cervical Cancer 123 Oregon Evidence-based Practice Center

Appendix B. Detailed Methods

a1+b1 = all participants in the intervention arm with a positive screening test

Absolute PPV in the control group = PPV2 = a2/(a2+b2)

Where
a2 = cases of disease detected (in screen-positive participants, i.e., true positives) in the control arm
a2+b2= all participants in the control arm with a positive screening test

Relative PPV (intervention vs. control arm) = PPV1/PPV2

The randomized controlled trials of HPV testing include complicated, different protocols for followup retesting and
referral to colposcopy among those with positive results not meeting the threshold for immediate colposcopy referral.
In some cases, studies used different colposcopy referral thresholds; therefore, we performed PPV and RFPP
calculations using the lowest referral criterion for cytology, HPV+ and/or ASC-US+, to define a positive screening test.
This is a conservative strategy that may overestimate false positives for trials with higher initial referral criteria such
as POBASCAM, ARTISTIC (both HSIL+), and the Finnish trial (LSIL+), though the relative test performance
measures available from these trials may be less affected than would absolute test performance measures. A
conservative definition of a positive screening test is consistent with the cumulative CIN outcomes reported in the
trials and used in test performance calculations, including results from intensified followup as well as from immediate
colposcopy. It is also consistent with clinical practice, in which an ASC-US+ cytology result or positive HPV test
triggers additional followup, even if not immediate referral to colposcopy.

External Review Process

The USPSTF appointed eight liaisons to guide the scope and reporting of this review. The work plan for the review
was sent to four experts on cervical cancer screening, whom we asked to comment on the general proposed
approach, scope of the review, and adequacy of the identified questions. In addition, ten outside experts provided
feedback on a draft version of this evidence synthesis.

Screening for Cervical Cancer 124 Oregon Evidence-based Practice Center

 Appendix B Figure 1. Search Results and Article Flow

Abstracts reviewed

N=4,262

Articles reviewed from

outside sources

N=211 Total articles reviewed

N=641

Articles reviewed Articles reviewed Articles reviewed Articles reviewed Articles reviewed
for key question 1 for key question 2 for key question 3 for key question 4 for key question 5
N=95 N=149 N=337 N=11 N=49

Articles excluded Articles excluded Articles excluded Articles excluded Articles excluded
for key question 1 for key question 2 for key question 3 for key question 4 for key question 5
N=89 N=142 N=289 N=11 N=44

Articles included Articles included Articles included Articles included Articles included
for key question 1 for key question 2 for key question 3 for key question 4 for key question 5
N=6 N=7 N=48 N=0 N=5
(5 studies) (4 studies) (22 studies) (4 studies)

Screening for Cervical Cancer 125 Oregon Evidence-based Practice Center

Appendix B Table 1. Search Strategies

Systematic Reviews
Databases: CDSR, DARE, HTA, Pubmed
2000 to January 2007

1. "Uterine Cervical Neoplasms"[MeSH] OR "Uterine Cervical Dysplasia"[MeSH] OR "Cervical Intraepithelial

Neoplasia"[MeSH] OR "Papillomavirus Infections"[MeSH] OR "Papillomaviridae"[MeSH]
2. "Mass Screening"[MeSH:NoExp] OR "Vaginal Smears"[MeSH]
3. screen*[tiab] OR "vaginal smear"[tiab] OR "vaginal smears"[tiab] OR Papanicolaou[tiab] OR
Papanicolau[tiab] OR pap[tiab]
4. "cervical smear"[tiab] OR "cervical smears"[tiab]
5. 2 OR 3 OR 4
6. 1 AND 5
7. "cervical cancer screening"[tiab]
8. "hpv testing"[tiab]
9. "cervical screening"[tiab]
10. "Vaginal Smears"[MeSH]
11. "liquid based cytology"[tiab]
12. "human papillomavirus testing"[tiab]
13. 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12
14. 13 AND systematic[sb] Limits: English, Publication Date from 2000 to 2007

When to Begin Screening (KQ1)

Databases: Medline, CCRCT
2000 to September 2010

1. uterine cervical diseases/ or uterine cervical dysplasia/ or uterine cervical neoplasms/

2. Cervical Intraepithelial Neoplasia/
3. Vaginal Smears/
4. 1 or 2 or 3
5. mass screening/
6. screen$.ti,ab.
7. 5 or 6
8. 4 and 7
9. cervical cancer screening.ti,ab.
10. cervical neoplas$ screening.ti,ab.
11. cervical screening.ti,ab.
12. 8 or 9 or 10 or 11
13. Coitus/
14. (first adj4 intercourse).ti,ab.
15. (first adj4 coitus).ti,ab.
16. (initi$ adj4 intercourse).ti,ab.
17. (sexual$ adj4 activ$).ti,ab.
18. chronologic$ age.ti,ab.
19. different age$.ti,ab.
20. (young$ adj2 wom#n).ti,ab.
21. (age adj2 specific).ti,ab.
22. (beg#n$ adj4 screen$).ti,ab.
23. (start$ adj4 screen$).ti,ab.
24. (age adj4 beg#n$).ti,ab.
25. (age adj4 start$).ti,ab.
26. (age adj4 first).ti,ab.
27. age factors/
28. age distribution/
29. (old$ adj2 wom#n).ti,ab.
30. (stop$ adj4 screen$).ti,ab.
31. (age adj4 stop$).ti,ab.
32. age restrict$.ti,ab.
33. (withdraw$ adj4 screen$).ti,ab.
34. 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31
or 32 or 33
35. 12 and 34
36. limit 35 to english language

Screening for Cervical Cancer 126 Oregon Evidence-based Practice Center

Appendix B Table 1. Search Strategies

37. limit 36 to yr="2000 - 2010"

Liquid-based Cytology Benefits (KQ2) & Harms (KQ4)

Databases: Medline, CCRCT
2003 to September 2010 (KQ2), 2000 to September 2010 (KQ4)

1. Cervix Uteri/cy [Cytology]

2. Uterine Cervical Diseases/pa, di [Pathology, Diagnosis]
3. Uterine Cervical Neoplasms/pa, di [Pathology, Diagnosis]
4. Cervical Intraepithelial Neoplasia/pa, di [Pathology, Diagnosis]
5. Uterine Cervical Dysplasia/pa, di [Pathology, Diagnosis]
6. Vaginal Diseases/pa, di [Pathology, Diagnosis]
7. Vaginal Smears/
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. Cytological Techniques/
10. Histocytological Preparation Techniques/
11. Cytodiagnosis/
12. 9 or 10 or 11
13. cervix.ti,ab,hw.
14. cervical.ti,ab,hw.
15. vaginal.ti,ab,hw.
16. 13 or 14 or 15
17. 12 and 16
18. ((cervical or cervix or vaginal) adj3 cytolog$).ti,ab.
19. 8 or 17 or 18
20. liquid$.ti,ab.
21. fluid based.ti,ab.
22. thinprep.ti,ab.
23. thin prep.ti,ab.
24. surepath.ti,ab.
25. autocyte.ti,ab.
26. cytorich.ti,ab.
27. monolayer.ti,ab.
28. mono layer.ti,ab.
29. thin layer.ti,ab.
30. 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29
31. 19 and 30
32. "Sensitivity and Specificity"/
33. "Predictive Value of Tests"/
34. ROC Curve/
35. False Negative Reactions/
36. False Positive Reactions/
37. Diagnostic Errors/
38. "Reproducibility of Results"/
39. Reference Values/
40. Reference Standards/
41. Observer Variation/
42. Quality Control/
43. Quality Assurance, Health Care/
44. standards.fs.
45. specificit$.ti,ab.
46. sensitiv$.ti,ab.
47. predictive value.ti,ab.
48. accurac$.ti,ab.
49. false positive$.ti,ab.
50. false negative$.ti,ab.
51. miss rate$.ti,ab.
52. error rate$.ti,ab.
53. comparison$.ti.
54. compare$.ti.
55. comparing.ti.
56. comparative study.pt.

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Appendix B Table 1. Search Strategies

57. detection rate$.ti,ab.

58. diagnostic yield$.ti,ab.
59. 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50
or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58
60. 31 and 59
61. limit 60 to english language
62. limit 61 to humans
63. limit 61 to animals
64. 63 not 62
65. 61 not 64
66. limit 65 to yr="2003 - 2010"
67. harm$.ti,ab.
68. adverse$.ti,ab.
69. adverse effects.fs.
70. inadequate$.ti,ab.
71. 67 or 68 or 69 or 70
72. 31 and 71
73. limit 72 to english language
74. limit 73 to humans
75. limit 73 to animals
76. 75 not 74
77. 73 not 76
78. limit 77 to yr="2000 - 2010"
79. 66 or 78

HPV DNA Testing Benefits (KQ3) & Harms (KQ5)

Databases: Medline, CCRCT, PsycINFO
2000 to September 2010

1. Papillomavirus Infections/di [Diagnosis]

2. Papillomaviridae/ip [Isolation & Purification]
3. Alphapapillomavirus/ip [Isolation & Purification]
4. Human papillomavirus 16/ip [Isolation & Purification]
5. Human papillomavirus 18/ip [Isolation & Purification]
6. (hpv$ adj3 test$).ti,ab.
7. (hpv$ adj3 detect$).ti,ab.
8. (papillomavirus$ adj3 test$).ti,ab.
9. (papillomavirus$ adj3 detect$).ti,ab.
10. (papilloma virus$ adj3 test$).ti,ab.
11. (papilloma virus$ adj3 detect$).ti,ab.
12. DNA Probes, HPV/
13. hybrid capture.ti,ab.
14. hc2.ti,ab.
15. hc 2.ti,ab.
16. hcII.ti,ab.
17. hc II.ti,ab.
18. digene.ti,ab.
19. pcr.ti.
20. polymerase chain reaction$.ti.
21. polymerase chain reaction/
22. Reverse Transcriptase Polymerase Chain Reaction/
23. linear array.ti,ab.
24. amplicor.ti,ab.
25. 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24
26. papillomavirus$.ti,ab,hw.
27. papillomaviridae$.ti,ab,hw.
28. papilloma virus$.ti,ab,hw.
29. hpv$.ti,ab,hw.
30. 26 or 27 or 28 or 29
31. 25 and 30
32. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 31
33. cervix.ti,ab,hw.

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Appendix B Table 1. Search Strategies

34. cervical.ti,ab,hw.
35. vaginal.ti,ab,hw.
36. (pap or Papanicolaou).ti,ab.
37. "Diagnostic Techniques, Obstetrical and Gynecological"/
38. female.sh.
39. 33 or 34 or 35 or 36 or 37 or 38
40. 32 and 39
41. "Sensitivity and Specificity"/
42. "Predictive Value of Tests"/
43. ROC Curve/
44. False Negative Reactions/
45. False Positive Reactions/
46. Diagnostic Errors/
47. "Reproducibility of Results"/
48. Reference Values/
49. Reference Standards/
50. Quality Control/
51. Quality Assurance, Health Care/
52. specificit$.ti,ab.
53. sensitiv$.ti,ab.
54. predictive value.ti,ab.
55. accurac$.ti,ab.
56. false positive$.ti,ab.
57. false negative$.ti,ab.
58. miss rate$.ti,ab.
59. error rate$.ti,ab.
60. comparison$.ti.
61. compare$.ti.
62. comparing.ti.
63. comparative study.pt.
64. detection rate$.ti,ab.
65. diagnostic yield$.ti,ab.
66. performance.ti,ab.
67. triage/
68. 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59
or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67
69. 40 and 68
70. limit 69 to english language
71. limit 70 to yr="2000 - 2010"
72. limit 71 to humans
73. limit 71 to animals
74. 73 not 72
75. 71 not 74

Screening for Cervical Cancer 129 Oregon Evidence-based Practice Center

Appendix B Table 2. Exclusion Criteria for Key Questions

Exclusion Criteria Applied to All Key Questions

Population:
 Studies focusing only on high-risk populations (e.g., HIV-infected women) or women who have had a
hysterectomy
Setting:
 Screening not conducted in primary care or other setting with primary care-comparable population
Design:
 Editorials; Letters; Non-systematic reviews; Opinions
Quality:
 Does not meet quality criteria
No relevant outcomes
Precedes search period
Article covered by an included systematic review
Systematic review used as source document only
Non-English

Additional Exclusion Criteria Specific to Each Key Question

Key Question 1 - When should cervical cancer screening begin, and does this vary by screening technology or by
age, sexual history, or other patient characteristics?

Population:
 Conducted solely in referred population
Design:
 Data not stratified by age
 Denominators for outcomes unknown
 Age intervals presented don’t allow evaluation of young women separately
 Modeling study
 Ecological study reporting incidence/mortality in total population without link to screening
 Provides prevalence data only

Key Question 2 - To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic yield
and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?

Relevance:
 Does not focus on cervical cancer screening
 Focused on treatment of CIN, carcinoma in situ, or invasive cervical cancer
 Focused on methods to promote uptake and continuance of appropriate screening
 Focused on methods to improve follow up of abnormal screening findings
 Focused on comparison of tools for collection of cytologic samples (e.g., type of spatula, brush, or swab)
 Focused on patient education, satisfaction, or test acceptability
Population:
 Conducted solely in referred population or doesn’t report outcomes in routine screening population
separately
Design:
 Case-control study
 Does not systematically apply reference standard of colposcopy and/or biopsy
 Reference standard applied to screening test positives only (for studies of absolute test performance)
 Physician choice of cytology
 No comparison to conventional cytology
Screening intervention:
 Obtained as follow up of documented disease
 Home self-test
 See and treat
 Automated screening technologies

Key Question 3 - What are the benefits of using HPV testing as a screening test, either alone or in combination
with cytology, compared with not testing for HPV?

Relevance:
 Does not focus on cervical cancer screening

Screening for Cervical Cancer 130 Oregon Evidence-based Practice Center

Appendix B Table 2. Exclusion Criteria for Key Questions

 Focused on treatment of CIN, carcinoma in situ, or invasive cervical cancer

 Focused on methods to promote uptake and continuance of appropriate screening
 Focused on methods to improve follow up of abnormal screening findings
 Focused on patient education, satisfaction, or test acceptability
Population:
 For primary screening, conducted solely in referred population or doesn’t report outcomes in routine
screening population separately
 For triage studies, includes women with repeated abnormal smears or abnormal smear other than ASC-
US or LSIL
Design:
 Case-control study
 Does not systematically apply reference standard of colposcopy and/or biopsy
 Reference standard applied to screening test positives only (for studies of absolute test performance)
 Physician choice of cytology
 No comparison to cytology
Screening intervention:
 Home self-test
 See and treat
 HPV testing conducted to follow up on treatment
 In-situ hybridization
 p16 immunostaining
 Tests of viral load
 Focus on HPV types other than: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
 Hybrid Capture I

Key Question 4 - What are the harms of liquid-based cytology?

Relevance:
 Focus on harms of treatment procedures (e.g., LEEP, cryotherapy, laser cone biopsy)
Screening intervention:
 Obtained as follow up of documented disease
 Home self-test
 See and treat
 Automated screening technologies

Key Question 5 - What are the harms of using HPV testing as a screening test, either alone or in combination with
cytology?

Relevance:
 Focus on harms of treatment procedures (e.g., LEEP, cryotherapy, laser cone biopsy)
Screening intervention:
 Home self-test
 See and treat
 HPV testing conducted to follow up on treatment
 In-situ hybridization
 p16 immunostaining
 Tests of viral load
 Focus on HPV types other than: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
 Hybrid Capture I

Screening for Cervical Cancer 131 Oregon Evidence-based Practice Center

Appendix B Table 3. Quality Rating Criteria

United States Preventive Services Task National Institute for Health and Clinical 102
Design 95 101 The QUADAS Tool
Force quality rating criteria Excellence methodology checklists
• Comprehensiveness of sources • The study addresses an appropriate and Not applicable
Systematic reviews and considered/search strategy used clearly focused question
meta-analyses • Standard appraisal of included studies • A description of the methodology used is
• Validity of conclusions included
• Recency and relevance are especially • The literature search is sufficiently rigorous to
important for systematic reviews identify all the relevant studies
• Study quality is assessed and taken into
account
• There are enough similarities between the
studies selected to make combining them
reasonable
• Accurate ascertainment of cases • The study addresses an appropriate and Not applicable
Case-control studies • Nonbiased selection of cases/controls with clearly focused question
exclusion criteria applied equally to both • The cases and controls are taken from
• Response rate comparable populations
• Diagnostic testing procedures applied equally • The same exclusion criteria are used for both
to each group cases and controls
• Measurement of exposure accurate and • What percentage of each group (cases and
applied equally to each group controls) participated in the study?
• Appropriate attention to potential • Comparison is made between participants
confounding variables and non-participants to establish their
similarities or differences
• Cases are clearly defined and differentiated
from controls
• Is it clearly established that controls are non-
cases?
• Measures have been taken to prevent
knowledge of primary exposure influencing
case ascertainment
• Exposure status is measured in a standard,
valid and reliable way
• The main potential confounders are identified
and taken into account in the design and
analysis
• Have confidence intervals been provided?

Screening for Cervical Cancer 132 Oregon Evidence-based Practice Center

Appendix B Table 3. Quality Rating Criteria

United States Preventive Services Task National Institute for Health and Clinical 102
Design 95 101 The QUADAS Tool
Force quality rating criteria Excellence methodology checklists
• Initial assembly of comparable groups • The study addresses an appropriate and Not applicable
Randomized controlled employs adequate randomization, including clearly focused question
trials (RCTs) first concealment and whether potential • The assignment of subjects to treatment
confounders were distributed equally among groups is randomized
groups • An adequate concealment method is used
• Maintenance of comparable groups (includes • Subjects and investigators are kept ‘blind’
attrition, crossovers, adherence, about treatment allocation
contamination) • The treatment and control groups are similar
• Important differential loss to follow-up or at the start of the trial
overall high loss to follow-up • The only difference between groups is the
• Measurements: equal, reliable, and valid treatment under investigation
(includes masking of outcome assessment) • All relevant outcomes are measured in a
• Clear definition of the interventions standard, valid and reliable way
• All important outcomes considered • What percentage of the individuals or
clusters recruited into each treatment arm of
the study dropped out before the study was
completed?
• All the subjects are analyzed in the groups to
which they were randomly allocated (often
referred to as intention-to-treat analysis)
• Where the study is carried out at more than
one site, results are comparable for all sites

Screening for Cervical Cancer 133 Oregon Evidence-based Practice Center

Appendix B Table 3. Quality Rating Criteria

United States Preventive Services Task National Institute for Health and Clinical 102
Design 95 101 The QUADAS Tool
Force quality rating criteria Excellence methodology checklists
• Initial assembly of comparable groups • The study addresses an appropriate and Not applicable
Cohort studies employs consideration of potential clearly focused question
confounders with either restriction or • The two groups being studied are selected
measurement for adjustment in the analysis; from source populations that are comparable
consideration of inception cohorts in all respects other than the factor under
• Maintenance of comparable groups (includes investigation
attrition, crossovers, adherence, • The study indicates how many of the people
contamination) asked to take part did so, in each of the
• Important differential loss to follow-up or groups being studied
overall high loss to follow-up • The likelihood that some eligible subjects
• Measurements: equal, reliable, and valid might have the outcome at the time of
(includes masking of outcome assessment) enrollment is assessed and taken into
• Clear definition of the interventions account in the analysis
• All important outcomes considered • What percentage of individuals or clusters
recruited into each arm of the study dropped
out before the study was completed?
• Comparison is made between full
participants and those lost to follow-up, by
exposure status
• The outcomes are clearly defined
• The assessment of outcome is made blind to
exposure status
• Where blinding was not possible, there is
some recognition that knowledge of exposure
status could have influenced the assessment
of outcome
• The measure of assessment of exposure is
reliable
• Evidence from other sources is used to
demonstrate that the method of outcome
assessment is valid and reliable
• Exposure level or prognostic factor is
assessed more than once
• The main potential confounders are identified
and taken into account in the design and
analysis
• Have confidence intervals been provided?

Screening for Cervical Cancer 134 Oregon Evidence-based Practice Center

Appendix B Table 3. Quality Rating Criteria

United States Preventive Services Task National Institute for Health and Clinical 102
Design 95 101 The QUADAS Tool
Force quality rating criteria Excellence methodology checklists
• Screening test relevant, available for primary • The nature of the test being studied is clearly • The spectrum of patients are representative
Diagnostic accuracy care, adequately described specified of the patients who will receive the test in
studies • Study uses a credible reference standard, • The test is compared with an appropriate practice
performed regardless of test results gold standard • Selection criteria are clearly described
• Reference standard interpreted • Where no gold standard exists, a validated • The reference standard is likely to correctly
independently of screening test reference standard is used as a comparator classify the target condition
• Handles indeterminate result in a reasonable • Patients for testing are selected either as a • The time period between the reference
manner consecutive series or randomly, from a standard and the index test is short enough
• Spectrum of patients included in study clearly defined study population to be reasonably sure that the target
• Sample size • The test and gold standard are measured condition did not change between the two
• Administration of reliable screening test independently (blind) of each other tests
• The test and gold standard are applied as • The whole sample or a random selection of
close together in time as possible the sample receives verification using a
• Results are reported for all patients that are reference standard of diagnosis
entered into the study • Patients receive the same reference
• A pre-diagnosis is made and reported standard regardless of the index test result
• The reference standard is independent of the
index test
• The execution of the index test is described
in sufficient detail to permit replication of the
test
• The execution of the reference standard is
described in sufficient detail to permit its
replication
• The index test results are interpreted without
knowledge of the results of the reference
standard
• The reference standard results are
interpreted without knowledge of the results
of the index test
• The same clinical data is available when test
results are interpreted as would be available
when the test is used in practice
• Uninterpretable/ intermediate test results are
reported
• Withdrawals from the study are explained

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Appendix C Table 1. Evidence Table for Age at Which to Begin Screening (KQ1)

Number of patients
Patient
Study ID Objective Study design Setting Prevalence Inclusion & exclusion
characteristics
criteria
Insinga To examine routine Observational cohort study US NA - see outcomes 227,915 total 1998 (Total KPNW
104
2004 cervical cancer KPNW female population enrolled population)
screening diagnoses 1997-2002 health plan inpatient and KPNW histology files -- 150,052 eligible sample Ethnicity
and outcomes on an outpatient administrative and HMO serving greater with 2 years continuous White: approx. 90%
age-specific basis in laboratory data for women enrolled Portland, OR region health insurance Asian: 2.6%
a US population at Kaiser Permanente Northwest enrollment over 1997- Hispanic: 2.3%
(KPNW) in 1998 Women attending 1998 African American:
routine screening 103,476 outcome 1.6%
Incident episode of care associated analysis sample with Native American:
with particular routine smear continuous health plan 0.8%
defined to begin with initial smear enrollment over 1997- Other minority: 1.1%
and end when at least nine months 2002
had passed without receipt of
follow-up smear or other related
cervical service
Sigurdsson To evaluate the value Correlational study Iceland NA - see outcomes NA - see outcomes NR
225
2010 of screening in the
age group 20-34 by Data from Cancer Detection Clinic Nationwide screening
Sigurdsson analyzing trends in registry (preinvasive disease) and program registry
105
2007 preinvasive and Cancer Registry of the Icelandic
invasive disease Cancer Society (invasive disease) Women attending
routine screening
Includes both organized and
spontaneous screening results

Screening program characteristics:

1964 organized screening began
1969 became nationwide, with
screening at 2-3 year intervals in
25- to 69-year-olds
1979 intensified with improved call-
recall system and improved quality
assurance
1988 lower age limit decreased to
20 years

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Appendix C Table 1. Evidence Table for Age at Which to Begin Screening (KQ1)

Funding Quality
Study ID Outcomes Other outcomes Applicability
source rating
Insinga Merck Outcomes of 1998 abnormal routine smears as % of routine smears Screening attendance in 1998 Fair Good
104
2004 Research Age Routine Smears (N) CIN2 CIN3 False positive smear Age Screening per 1,000 female
Laborator 15-19 1,046 0.5 0.2 3.1 enrollees
-ies 20-24 852 0.6 0.2 3.5 15-19 217.0
25-29 1,952 0.6 0.6 2.1 20-24 468.0
30-39 5,992 0.3 0.4 2.6 25-29 649.9
40-49 8,405 0.1 0.1 2.4 30-39 508.7
50-59 7,162 0.1 0.0 2.3 40-49 403.4
60-69 3,543 0.0 0.0 1.6 50-59 360.8
70-79 1,657 0.0 0.1 1.8 60-69 280.7
80+ 288 0.0 0.0 2.1 70-79 164.1
Overall 30,936 0.3 0.2 2.4 80+ 53.3
Overall 294.7
Only 15 cases of invasive cancer so age-specific rates not reported
Sigurdsson NR Incidence of invasive cancer per 100,000 women in population Screening attendance Fair Good
225
2010 Time Period Age Incidence 1979-1988
1964-1988 20-24 2.1 Age 20-24: 23%
Sigurdsson 25-29 11.8 Age 25-29: 62%
105
2007 30-34 21.4 Age 30-34: 72%
35-39 38.5
1989-2008 20-24 2.8 1989-2003
25-29 16.6 Age 20-24: 62%
30-34 20.3 Age 25-29: 78%
35-39 22.5* Age 30-34: 82%
Time Period Age Stage IA Stage IB Stage IIA+
1964-1988 20-29 2.7 2.7 1.1 2008
20-34 4.7 3.6 2.4 Age 20-24: 51%
1989-2008 20-29 6.6* 2.8 0.2 Age 25-39: 63%
20-34 8.9* 4.0 0.2* Age 30-34: NR
*Significant rate difference between time periods
Detection rate of CIN2 and CIN3 per 1,000 women screened
Women CIN2 CIN3
Age Time Period Screened (N) N Rate N Rate
20-24 1979-1988 11,658 30 2.6 94 8.1
1989-2003 36,224 253 7.0 522 14.4
25-29 1979-1988 22,123 66 2.9 430 19.4
1989-2003 38,921 179 4.6 928 23.8
30-34 1979-1988 21,077 35 1.7 403 19.1
1989-2003 40,062 108 2.7 690 17.2
Data not reported for 2004-2008

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Appendix C Table 1. Evidence Table for Age at Which to Begin Screening (KQ1)

Number of patients
Study ID Objective Study design Setting Prevalence Inclusion & Patient characteristics
exclusion criteria
Peto To describe Prospective cohort study UK High-risk HPV 54,060 women NR
32
2004 the prevalence provided samples
relationship Recruitment between 1988 and 1993 Over 100 (in random cohort of 6,462 49,655 met inclusion
between HPV general HPV-typed women) criteria
detection at Smear and histology results in study database practitioners
entry and updated from laboratory records at 6-monthly and screening Age N % Inclusion: Women
cytologic and intervals during recruitment and through 1998 clinics in 15-19 69 20.4 of any age attending
histologic for histology results Greater 20-24 92 18.2 for routine screening
followup Manchester 25-29 93 14.4
Date of diagnosis defined as date of first area who used 30-34 86 6.8 Exclusion:
abnormal smear in 2 years preceding Christie Hospital 35-39 47 4.9 Inadequate entry
histological confirmation of CIN2, CIN3, or cytology 40-44 28 2.9 smear (3,391),
cancer laboratory 45-49 15 2.9 previous CIN3 (505),
50-54 29 2.6 abnormal smear in
HPV at entry assayed in age- and period- Women 55-69 1 0.9 preceding year (509)
stratified random sample attending Overall 460 7.1
routine
screening

Funding Quality
Study ID Outcomes Other outcomes Applicability
source rating
32
Peto 2004 Cancer Prevalence of CIN2 and CIN3+ as % of total smears Annual incidence of new cases of CIN3+ Fair Good
Research in women with a screening interval of
UK Age at CIN2 CIN3 less than 5 years following a normal
smear Prevalence (n) OR (95% CI) Prevalence (n) OR (95% CI) smear
20-24 0.59% (56) 1.15 (0.79-1.68) 0.69% (65) 0.84 (0.61-1.15) (estimated by dividing number of cases by
25-29 0.57% (63) 1.00 0.96% (107) 1.00 woman-years of followup since last smear)
30-34 0.48% (42) 0.81 (0.54-1.20) 1.23% (107) 1.18 (0.90-1.55)
35-39 0.42% (31) 0.68 (0.44-1.05) 0.78% (57) 0.71 (0.51-0.98) Age Incidence per 1,000 per year
40-44 0.31% (21) 0.48 (0.29-0.80) 0.67% (45) 0.58 (0.40-0.82) 15-19 1.56
45-49 0.08% (4) 0.17 (0.04-0.32) 0.37% (19) 0.30 (0.19-0.50) 20-24 2.22
50-54 0.24% (10) 0.35 (0.18-0.68) 0.28% (12) 0.23 (0.13-0.42) 25-29 4.07
55+ 0.04% (3) 0.05 (0.02-0.16) 0.20% (16) 0.15 (0.09-0.26) 30-34 3.67
Overall 0.38% (230) 0.70% (428) 35-39 2.44
40-44 1.53
45-49 0.85
50-54 0.76
55-59 0.58
60-64 0.19
65-69 1.39

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Appendix C Table 1. Evidence Table for Age at Which to Begin Screening (KQ1)

Number of patients
Study ID Objective Study design Setting Prevalence Inclusion & Patient characteristics
exclusion criteria
Woodman To describe Prospective cohort study UK (during followup) 2,011 enrolled Mean Age (SD): 17.5 (1.2)
106
2001 the natural HPV+ (any): 407/1,075 1,075 in final sample Ethnicity
history of Recruitment between 1988 and 1992 One Birmingham (37.9%) White: 94%
incident HPV Brook Advisory HPV+ (HR): 276/1,075 Inclusion: Aged 15- Afro-Caribbean: 3%
infection and At study entry, obtained risk factor Centre (25.7%) 19 years South Asian: 2%
its temporal profile and cervical smear; women CIN2: 14/1,075 (1.3%) Other: 0.2%
relation to the asked to reattend at six month Women who had CIN3: 14/1,075 (1.3%) Exclusion: Abnormal Education: NR
occurrence of intervals for updated risk factor recently become smear at entry (148), Socioeconomic Class (Father's
cytologic profiles and further cervical and sexually active HPV+ at entry (244), Occupation)
abnormality serum samples; median number of HPV+ and abnormal Professional: 6%
and visits = 4; median duration of smear at entry (138), Intermediate: 23%
development followup = 29 months provided only 1 Skilled, Non-manual: 7%
of high-grade sample evaluable for Skilled, Manual: 37%
CIN Women with cytologic abnormalities cytology & HPV Partly Skilled: 8%
referred for colposcopy and biopsy; testing (406) Unskilled: 2%
colposcopic and cytologic Armed Services: 0.1%
surveillance maintained in these Unoccupied: 5%
patients; treatment postponed until Inadequately Described: 11%
histological evidence of CIN2+, at HIV+: NR
which point women left study Attended STD Clinic: 2%
Smoking
All stored cervical samples tested for Non-smoker: 59%
HPV using PCR after clinical followup Ex-smoker: 9%
had ended; tested for 2 low-risk types Smoker: 33%
(6 or 11) and 6 high-risk types (16, Median duration of sexual
18, 31, 33, 52, and 58); additional activity before study entry: 1
tests assigned numerical types not year (range 0-7)
identified by type-specific PCR

Funding Quality
Study ID Outcomes Other outcomes Applicability
source rating
Woodman Cancer Cumulative risk at three years (95% CI) Median duration of detectability (IQR) Good Good
106
2001 Research Any HPV type: 43.8 (40.1-47.5) Any HPV type: 13.7 months (8.0-25.4)
Campaign HPV 16: 10.5 (8.3-12.7) HPV 16: 10.3 months (6.8-17.3)
HPV 18: 6.6 (4.8-8.4) HPV 18: 7.8 months (6.0-12.6)
Any cytologic abnormality: 28 (25-32)
Incident cytologic abnormality after first detection of HPV: 33 (26-40) Median duration of first episode of
CIN2+ (after any type of HPV infection): 7.8 (2.7-22.0) cytologic abnormality (IQR):
CIN2+ (after HPV 16 infection): 8.5 (3.7-19.2)* 8.7 months (5.8-13.8)
CIN2+ (after HPV 18 infection): 3.3 (1.4-8.1)*
Median time to diagnosis of CIN2+ from

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Appendix C Table 1. Evidence Table for Age at Which to Begin Screening (KQ1)

Cumulative risk at five years study entry:

Any HPV type: 60% 36.1 months (range 6.6-104.0)

Risk of CIN2+ by time since first exposure to HPV 16 Median time to diagnosis of CIN2+ from
Relative hazards ratio (95% CI) first detection of HPV:
Unexposed: 1.00 26 months (range 0-69)
≤6 months: 5.98 (1.33-26.85)
6-12 months: 18.02 (5.50-59.03) Timing of progression to CIN2+:
12-18 months: 14.22 (3.76-53.86) During 1st HPV+ episode: 13/28 (46.4%)
>18 months: 2.60 (0.75-8.99) During 2nd HPV+ episode: 8/28 (28.6%)
During 3rd HPV+ episode: 1/28 (3.6%)
*Controlling for any other HPV exposure During 4th HPV+ episode: 1/28 (3.6%)
Remained HPV-: 5/28 (17.9%)

Number of patients
Study ID Objective Study design Setting Prevalence Inclusion & Patient characteristics
exclusion criteria
Sasieni To study the Case-control study UK NR 4,012 cases NR
23
2009 effect of 7,889 controls
cervical Cases with invasive cervical cancer Population based
screening on (including micro-invasive) diagnosed Inclusion: Age 20-69
incidence of between 1990 and 2008 Women
cervical diagnosed with Exclusion: Cases
cancer as a Controls were women ever registered ICC identified not in the cervical
function of with an NHS GP; in most cases from histology cancer call/recall
age selected randomly records at system
various centers
Controls matched to cases on age and in the UK over
area of residence, and half of controls differing time
matched by GP periods, a year at
a time
Data on screening history abstracted
from cervical cytology records in the UK Controls
national cervical screening call/recall identified from
system (NHS and many private NHS records
providers)

Smears taken between 1988 and 2008

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Appendix C Table 1. Evidence Table for Age at Which to Begin Screening (KQ1)

Funding Quality
Study ID Outcomes Other outcomes Applicability
source rating
Sasieni Cancer Fair Good
23
2009 Research Protective effect of screening in past Screening history for women aged 20-24 at
UK and against developing cancer in future diagnosis (73 participants)
NHS
cervical Age at Age at OR* Most cases (93%) younger than 25 were diagnosed
screening diagnosis screening (95% CI) with cancer despite screening:
programme with ICC
Screen-detected: 32 (44%) (calc)
25-29 20-21 1.51 Interval (last result normal): 15 (21%)
(0.95-2.38) History of abnormal cytology: 21 (29%)
22-24 1.11 Never screened or lapsed: 5 (7%)
(0.83-1.50)
35-39 30-31 0.79
(0.57-1.1) Benefit associated with being screened twice
32-34 0.55** by age 26
(0.44-0.69)
45-49 40-41 0.40 Age at Age at OR for OR for all
(0.27-0.58) diagnosis screening stage IB+ stages
42-44 0.37 with ICC (95% CI) (95% CI)
(0.29-0.48)
55-59 50-51 0.27 26.5-29 20-22 0.90 1.1
(0.17-0.43) and (0.38-2.2) (0.62-2.0)
52-54 0.26 23-25
(0.19-0.36)
23-25 1.00 1.00
only (Ref.) (Ref.)
*Odds ratio estimating risk of cervical cancer
in those with screening (in one of two time
periods before diagnosis) vs. risk in those
without screening in either time period

**Bold indicates statistically significant

risk reduction associated with screening

CI-confidence interval; CIN-cervical intraepithelial neoplasia; GP- general practitioner; HMO-health maintenance organization; HPV-human papillomavirus; ICC- invasive cervical
cancer; IQR-inter-quartile range; KPNW-Kaiser Permanente Northwest; NHS- National Health Service; NR-not reported; OR-odds ratio; NA-not applicable; PCR- Polymerase chain
reaction; UK-United Kingdom, US-United States

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Primary
Number of Application of
screening test
patients gold standard
Study ID evaluated Study design Setting Prevalence of disease Patient characteristics
Inclusion and (histological
Collection
exclusion criteria verification)
method
109
Taylor 2006 ThinPrep Samples South Africa CIN2: 57/5,558 = 1.0% 5,647 total Age Colposcopy with
collected at clinic CIN3+: 66/5,558 = 1.2% LBC: 3,184 35-39: LBC 39.4%, CC endocervical
Ayre's type visit six months Three primary (CIN3+ includes 14 SONE (56.4%) 37.5% curettage and
spatula and after enrollment care clinical sites cases) CC: 2,463 40-49: LBC 41.4%, CC biopsy of all
cytobrush in screen and in Khayelitsha (43.6%) 43.7% colposcopic
treat RCT (periurban, 50-65: LBC 19.3%, CC abnormalities in
informal Inclusion: Ages 18.8% all women
Cytology method settlement 35-65, previously
(LBC vs. CC) outside Cape unscreened Ethnicity: NR
rotated on six Town)
month basis Exclusion: Employed: LBC 24.8%,
High-risk, Pregnant, history CC 26.5%
previously of hysterectomy
unscreened or prior treatment Education
women enrolled for CIN No school:
in cervical LBC 9.3%, CC 9.0%
cancer Some primary school:
prevention trial LBC 38.1%, CC 36.6%
Some high school:
LBC 44.2%, CC 46.8%
High school graduate:
LBC 8.4%, CC 7.6%

Treated with cryotherapy

in prior 6 mos:
LBC 14.1%, CC 14.7%

HIV+: LBC 12.8%, CC

12.4%

Trichomonas vaginalis:
LBC 10.7%, CC 10.6%
Current smoker:
LBC 7.1%, CC 8.4%

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Study ID Funding source Quality rating Applicability Yield Insufficient samples Sensitivity (95% CI)
109
Taylor 2006 NR Fair Poor for absolute test ASC-US Unsatisfactory Detection of CIN2+:
performance, but not LBC: 9.3% LBC: 2.2% ASC-US+
for relative test CC: 9.5% CC: 0.8%, p<.01 LBC: 70.6 (58.3-81.0)
performance CC: 83.6 (71.2-92.2)
LSIL Satisfactory but limited
High-risk population, LBC: 4.3% LBC: 6.5% LSIL+
HIV prevalent, includes CC: 3.3% CC: 27.9%, p<.01 LBC: 60.3 (47.7-71.9)
only women never CC: 69.1 (55.2-80.9)
screened for cervical ≥HSIL
cancer, 14.5% with LBC: 2.7% HSIL+ (calc)
previous treatment CC: 3.7% LBC: 30/68 = 44.1
(32.1-56.7)
Test Positivity Rate CC: 32/55 = 58.2 (44.1-
(ASC-US+): 71.3)
LBC = 16.4%
CC = 16.4% Detection of CIN3+
(calc):
ASC-US+
LBC: 25/33 = 75.8
(57.7-88.9)
CC: 29/33 = 87.9 (71.8-
96.6)

LSIL+
LBC: 22/33 = 66.7
(48.2-82.0)
CC: 24/33 = 72.7 (54.5-
86.7)

HSIL+
LBC: 18/33 = 54.5
(36.4-71.9)
CC: 21/33 = 63.6 (45.1-
79.6)

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Positive predictive value Negative predictive False positive rate Other performance
Study ID Specificity (95% CI) Comments
(95% CI) value (95% CI) (95% CI) characteristics
109
Taylor 2006 Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+ No significant CIN2+ and CIN3+
ASC-US+ ASC-US+ ASC-US+ (calc): differences in include SONE =
LBC: 2583/3046 = 84.8 LBC: 9.4 (7.0-12.3) LBC: 99.2 (98.8-99.5) ASC-US+ sensitivity or women diagnosed
(83.5-86.1) CC: 11.4 (8.5-15.0) CC: 99.6 (99.2-99.8) LBC: 15.2 (13.9- specificity when with strips of
CC: 2033/2389 = 85.1 16.5) stratified by HIV neoplastic
(83.6-86.5) LSIL+ LSIL+ CC: 14.9 (13.5-16.4) status or age group endocervix on
LBC: 18.6 (13.7-24.4) LBC: 99.1 (98.7-99.4) (<40 years vs. ≥40 their endocervical
LSIL+ CC: 22.4 (16.3-29.4) CC: 99.3 (98.8-99.6) LSIL+ years) curettage who
LBC: 2867/3046 = 94.1 LBC: 5.9 (5.1-6.8) either were not
(93.2-94.9) HSIL+ (calc) HSIL+ (calc) CC: 5.5 (4.6-6.5) Sensitivity and diagnosed with
CC: 2257/2389 = 94.5 LBC: 30/85 = 35.3 (25.2- LBC: 2991/3029 = 98.7 specificity results CIN2 or CIN3 on
(93.5-95.4) 46.4) (98.3-99.1) HSIL+ similar when subset their biopsy or had
CC: 32/90 = 35.6 (25.7- CC: 2331/2354 = 99.0 LBC: 1.8 (1.4-2.3) of women no biopsy
HSIL+ (calc) 46.3) (98.5-99.4) CC: 2.4 (1.8-3.1) randomized to no
LBC: 2991/3046 = 98.2 cryotherapy arm
(97.7-98.6) Detection of CIN3+ Detection of CIN3+ Detection of CIN3+ analyzed separately
CC: 2331/2389 = 97.6 (calc): (calc): (calc):
(96.9-98.2) ASC-US+ ASC-US+ ASC-US+
LBC: 25/511 = 4.9 (3.2- LBC: 2595/2603 = 99.7 LBC: 15.8 (14.5-
Detection of CIN3+ (calc): 7.1) (99.4-99.9) 17.1)
ASC-US+ CC: 29/402 = 7.2 (4.9- CC: 2038/2042 = 99.8 CC: 15.5 (14.0-17.0)
LBC: 2595/3081 = 84.2 10.2) (99.5-99.9)
(82.9-85.5) LSIL+
CC: 2038/2411 = 84.5 LSIL+ LSIL+ LBC: 6.4 (5.6-7.4)
(83.0-86.0) LBC: 22/220 = 10.0 (6.4- LBC: 2883/2894 = 99.6 CC: 6.1 (5.1-7.1)
14.7) (99.3-99.8)
LSIL+ CC: 24/170 = 14.1 (9.3- CC: 2265/2274 = 99.6 HSIL+
LBC: 2883/3081 = 93.6 20.3) (99.3-99.8) LBC: 2.2 (1.7-2.8)
(92.6-94.4) CC: 2.9 (2.2-3.6)
CC: 2265/2411 = 93.9 HSIL+ HSIL+
(92.9-94.9) LBC: 18/85 = 21.2 (13.1- LBC: 3014/3029 = 99.5
31.4) (99.2-99.7)
HSIL+ CC: 21/90 = 23.3 (15.1- CC: 2342/2354 = 99.5
LBC: 3014/3081 = 97.8 33.4) (99.1-99.7)
(97.2-98.3)
CC: 2342/2411 = 97.1
(96.4-97.8)

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Primary
Number of
screening test Application of
patients
evaluated gold standard
Study ID Study design Setting Prevalence of disease Patient characteristics
(histological
Inclusion and
Collection verification)
exclusion criteria
method
110
Coste 2003 ThinPrep Consecutive France CIN 2-3: 35/1,754 = 2.0% 2,585 Total Mean age (SD): 33.3 (11.1) Colposcopy and
series, split 1,757 women directed biopsy of
de Cremoux Cervexbrush or sample Two public Invasive cancer: 6/1,754 attending for Ethnicity: NR abnormalities in
128
2003 appropriate university = 0.3% routine all women
brushes and hospitals and screening Education
Cochand-Priollet spatulas two private 828 women No schooling or primary only:
127
2001 practices referred for 4%
colposcopy Secondary: 53%
Women Higher: 43%
attending for Inclusion:
routine Women ≥18 HIV+: 0%
screening and years old
women referred undergoing Previous documented
for colposcopy spontaneous Chlamydia trachomatis
due to screening for infection: 1%
abnormalities cervical cancer
detected on prior Exclusion: Current smoker: 31%
screening Pregnant, no
smears* cervix, recent (<1
year) history of
*We report surgery or laser
results for treatment of the
routine cervix, cervix not
screening visible by
sample only physician,
mentally
retarded, clinical
or psychological
status not
allowing
collection of
required samples

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Funding Quality Insufficient

Study ID Applicability Yield Sensitivity (95% CI)
source rating samples

110
Coste 2003 French Fair Probably fairly CLINICAL OPTIMIZED Satisfactory for CLINICAL READING OPTIMIZED
Ministry of comparable to READING INTERPRETATION evaluation INTERPRETATION
de Cremoux Health and a US LBC: 87% Detection of CIN2+:
128
2003 the population, ASC- ASC-US/AGUS CC: 91%, p<.0001 ASC-US+ (calc) Detection of CIN2+:
Association although lack US/AGUS LBC: 4.8% LBC: 32/41 = 78.0 ASC-US+ (calc)
Cochand-Priollet de Recherche of experience LBC: 5.6% CC: 5.4% Unsatisfactory for (62.4-89.4) LBC: 35/40 = 87.5
127
2001 contre le with ThinPrep CC: 4.1% evaluation CC: 35/41 = 85.4 (73.2-95.8)
Cancer may mean LSIL LBC: 0.4% (70.8-94.4) CC: 36/41 = 87.8 (73.8-
results aren't LSIL LBC: 5.5% CC: 0.1% 95.9)
comparable LBC: 4.2% CC: 4.7% LSIL+ (calc)
CC: 4.0% Satisfactory for LBC: 28/41 = 68.3 LSIL+ (calc)
HSIL evaluation but (51.9-81.9) LBC: 32/40 = 80.0
HSIL LBC: 3.0% limited by CC: 30/41 = 73.2 (64.4-90.9)
LBC: 2.3% CC: 2.3% LBC: 12.7% (57.1-85.8) CC: 30/41 =30/41 = 73.2
CC: 1.8% CC: 9.1% (57.1-85.8)
Invasive Cancer HSIL+
Invasive LBC: 0% LBC: 51 (36-67) HSIL+
Cancer CC: 0.1% CC: 51 (36-67) LBC: 65 (50-80)
LBC: 0% CC: 60 (45-75)
CC: 0.1% Test Positivity
Rate (ASC-US+):
Test LBC: 13.4%
Positivity CC: 12.4%
Rate (ASC-
US+):
LBC: 12.1%
CC: 10.0%

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Other
Positive predictive value Negative predictive value False positive rate
Study ID Specificity (95% CI) performance Comments
(95% CI) (95% CI) (95% CI)
characteristics

Coste CLINICAL OPTIMIZED CLINICAL OPTIMIZED CLINICAL OPTIMIZED CLINICAL OPTIMIZED Interobserver *Optimized
110
2003 READING INTERPRE READING INTERPRE READING INTERPRE READING INTERPRE Reliability interpretation:
-TATION -TATION -TATION -TATION (assessed in if CC and LBC
de 30% random readings
Cremoux Detection Detection of Detection Detection of Detection of Detection of Detection of Detection of sample) disagree,
128
2003 of CIN2+: CIN2+: of CIN2+ CIN2+ (calc): CIN2+ CIN2+ (calc): CIN2+ CIN2+ (calc): LBC: κ = 0.57 reread to reach
(calc): (calc): (calc): (0.52,0.63) consensus
Cochand- ASC-US+ ASC-US+ ASC-US+ ASC-US+ ASC-US+ Moderate diagnosis, or
Priollet (calc) (calc) ASC-US+ LBC: 35/235 ASC-US+ LBC: ASC-US+ LBC: 11.7 read by
127
2001 LBC: LBC: LBC: 32/212 = 14.9 (10.6- LBC: 1515/1520 = LBC: 10.5 (10.2-13.3) CC: κ = 0.69 independent
1529/1709 = 1515/1715 = = 15.1 (10.6- 20.1) 1529/1538 = 99.7 (99.2- (9.1-12.1) CC: 10.6 (9.1- (0.64,0.74) expert if
89.5 (87.9- 88.3 (86.7- 20.6) CC: 36/217 = 99.4 (98.9- 99.9) CC: 8.2 (7.0- 12.1) Good disagreement
90.9) 89.8) CC: 35/176 16.6 (11.9- 99.7) CC: 9.6) not resolved
CC: CC: = 19.9 (14.3- 22.2) CC: 1532/1537 = LSIL+
1573/1714 = 1532/1713 = 26.6) 1573/1579 = 99.7 (99.2- LSIL+ LBC: 6.9 (5.7-
91.8 (90.4- 89.4 (87.9- LSIL+ 99.6 (99.2- 99.9) LBC: 5.0 8.2)
93.0) 90.9) LSIL+ LBC: 32/150 99.9) (4.0-6.2) CC: 5.4 (4.4-
LBC: 28/114 = 21.3 (15.1- LSIL+ CC: 4.3 (3.4- 6.6)
LSIL+ (calc) LSIL+ (calc) = 24.6 (17.0- 28.8) LSIL+ LBC: 5.4)
LBC: LBC: 33.5) CC: 30/123 = LBC: 1597/1605 = HSIL+
1623/1709 = 1597/1715 = CC: 30/104 24.4 (17.1- 1623/1636 = 99.5 (99.0- HSIL+ LBC: 1.6 (1.0-
95.0 (93.8- 93.1 (91.8- = 28.8 (20.4- 33.0) 99.2 (98.6- 99.8) LBC: 1.2 2.3)
96.0) 94.3) 38.6) 99.6) CC: (0.7-1.8) CC: 1.0 (0.6-
CC: CC: HSIL+ CC: 1620/1631 = CC: 0.8 (0.4- 1.6)
1640/1714 = 1620/1713 = HSIL+ LBC: 26/53 = 1640/1651 = 99.3 (98.8- 1.3)
95.7 (94.6- 94.6 (93.4- LBC: 21/41 49.1 (35.1- 99.3 (98.8- 99.7)
96.6) 95.6) = 51.2 (35.1- 63.2) 99.7)
67.1) CC: 24/41 = HSIL+
HSIL+ HSIL+ CC: 21/34 = 58.5 (42.1- HSIL+ LBC:
LBC: 99 (98 LBC: 98 (98 61.8 (43.6- 73.7) LBC: 1688/1702 =
to 99) to 99) 77.8) 1689/1709 = 99.2 (98.6-
CC: 99 (99 CC: 99 (99 to 98.8 (98.2- 99.5)
to 100) 99) 99.3) CC:
CC: 1696/1713 =
1701/1721 = 99.0 (98.4-
98.8 (98.2- 99.4)
99.3)

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Number of
Primary screening patients Application of gold
Patient Funding
Study ID test evaluated Study design Setting Prevalence of disease Inclusion and standard (histological
characteristics source
Collection method exclusion verification)
criteria
107,112
NTCC ThinPrep Randomized Italy CIN2+ 45,307 Median age: 41 Serious areas identified European
screening ASC-US+ randomized Ethnicity: NR by colposcopy were Union,
Plastic Ayre’s program with Nine LBC: 99/22,708 = 0.44% 22,760 IG Education: NR biopsied Italian
spatula and two arms organized CC: 84/22,466 = 0.37% 22,547 CG HIV+: NR Ministry of
cytobrush IG: cervical 45,174 eligible Other STIs: NR Referral to colposcopy: Health,
HPV (HC2) & screening LSIL+ 22,708 IG Smoking: NR Special
LBC at baseline programs LBC: 73/22,708 = 0.32% 22,466 CG IG: ASC-US+ Project
CC: 70/22,466 = 0.31% “Oncology,”
CG: Women Inclusion: Aged CG: ASC-US+ at seven Compagnia
CC at baseline presenting CIN3+ 25-64 centers (72%), LSIL+ at di S. Paolo
for routine ASC-US+ two centers (28%) FIRMS, and
HC2 assay screening LBC: 45/22,708 = 0.20% Exclusion: participating
performed on CC: 53/22,466 = 0.24% Pregnant, % of women who had Italian
residual hysterectomy, or colposcopy: regions
cytology sample LSIL+ treated for CIN
LBC: 32/22,708 = 0.14% within five years IG: 5.9%
CC: 44/22,466 = 0.20% CG: 2.9%

Quality Insufficient Relative detection ratio Relative false positive Relative positive predictive
Study ID Applicability Yield
rating samples (95% CI) proportion (95% CI) value (95% CI)
107,112
NTCC Fair Fair ASC-US/AGUS Unsatisfactory LBC vs. CC LBC vs. CC LBC vs. CC
LBC: 3.59% results (any
CC: 2.29% reason): Detection of CIN2+ ASC-US+ CIN2+
Relative frequency (95% ASC-US+: 1.17 (0.87- Detection of CIN2+ (calc): ASC-US+: 0.58 (0.44-0.77)
CI): 1.57 (1.41-1.75) LBC: 2.57% 1.56) (783/16,706)/(397/16,658) ASC-US+ (restricted to
LSIL CC: 4.11% ASC-US+ (restricted to = 1.97 (1.75-2.21) centers with ASC-US+
LBC: 2.32% centers with ASC-US+ Detection of CIN3+ (calc): referral criteria): 0.65 (0.49-
CC: 1.26% referral criteria): 1.11 (806/16,706)/(417/16,658) 0.88)
Relative frequency (95% (0.81-1.52) = 1.93 (1.72-2.21) LSIL+: 0.58 (0.43-0.78)
CI): 1.84 (1.60-2.13) LSIL+: 1.03 (0.74-1.43)
HSIL LSIL+ CIN3+
LBC: 0.41% Detection of CIN3+ Detection of CIN2+ (calc): ASC-US+: 0.42 (0.29-0.62)
CC: 0.26% ASC-US+: 0.84 (0.56- (278/16,706)/(154/16,658) LSIL+: 0.40 (0.26-0.62)
Relative frequency (95% 1.25) = 1.80 (1.48-2.19)
CI): 1.57 (1.13-2.18) LSIL+: 0.72 (0.46-1.13) Detection of CIN3+ (calc):
(293/16,706)/(170/16,658)
= 1.72 (1.42-2.07)

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Primary
screening
Number of patients
test
Prevalence Patient Application of gold standard
Study ID evaluated Study design Setting Funding source
of disease Inclusion and characteristics (histological verification)
exclusion criteria
Collection
method
108
NETHCON ThinPrep Cluster RCT, The CIN2+: 89,784 women had Age (calc): Screen-positive women followed European
randomized Netherlands LBC: baseline cytology <30: LBC 0.7%, CC for 18 months according to Commission, Dutch
Rovers by family 346/48,941= LBC: 49,222 0.6% guidelines of the Dutch Society Ministry of Health,
Cervex- practice Women 0.71% CC: 40,562 30-34: LBC 21.1%, CC of Pathologists and Dutch and Belgian
Brush (clinical site) participating CC: 20.3% Society of Obstetrics and Foundation Against
to LBC vs. in Dutch 280/40,047= 88,988 included in 35-39: LBC 14.7%, CC Gynecology Cancer
CC cervical 0.70% primary analysis 14.0%
screening LBC: 48,941 40-44: LBC 18.2%, CC Women with equivocal or low-
Screen- program at CIN3+: CC: 40,047 17.7% grade cytologic abnormalities on
positive 246 family LBC: 45-49: LBC 12.1%, CC initial test offered repeat
women practices 253/48,941= Inclusion: All women 12.1% cytology at 6 and 18 months
followed 0.52% screened at one of 50-54: LBC 12.6%, CC
prospectively All women CC: the participating 13.4% Those whose initial abnormality
for 18 mo. screened at 190/40,047= family practices 55-59: LBC 17.7%, CC persists or progresses at
one of the 0.47% 18.7% followup referred for colposcopy
participating Exclusion: NR >59: LBC 3.1%, CC
practices Carcinoma: 3.1% Women with high-grade
were LBC: Ethnicity: NR abnormalities at baseline or
included in 30/48,941= Education: NR followup referred for colposcopy
study 0.06% Monthly income: NR
CC: HIV+: NR 898 women had histology
14/40,047= Other STIs: NR (36.3% of those with abnormal
0.03% Smoking: NR cytology, in each arm and
overall); 6 additional women had
colposcopy only

Relative test performance

measures comparing LBC to CC
use histology outcomes alone
(“primary final outcome”)

PPVs reported use a combined

histology/follow-up cytology
outcome (“secondary final
outcome”)

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Appendix C Table 2. Evidence Table for Liquid-Based Cytology (KQ2)

Detection of Relative detection Relative positive

Quality Insufficient Relative false positive
Study ID Applicability Yield CIN2+/CIN3+ ratio predictive value
rating samples proportion (95% CI)
(95% CI) (95% CI) (95% CI)

108
NETHCON Good Good ASC-US/AGUS Inadequate Detection of CIN2+: LBC vs. CC (both LBC vs. CC (both ASC- LBC vs. CC
and LSIL baseline cytology: ASC-US+) US+) (unadjusted)
(calc): LBC (ASC-US+):
LBC: LBC: 0.37% 0.71 (0.63-0.78) Detection of CIN2+: Detection of CIN2+ CIN2+ (calc)
1,019/49,222= CC: 1.09% CC (ASC-US+): 0.70 (calc): ASC-US+:
2.07% (0.62-0.78) 1.01 (0.86-1.18) 28.3%/25.9% = 1.09
CC: Excluded from (crude) (878/48,941)/(799/40,047) (0.95-1.25)
899/40,562= analysis Detection of CIN3+: 1.00 (0.84-1.20) = 0.90 (0.82-0.99) LSIL+: 62.8%/60.7%
2.22% (adjusted)* = 1.04 (0.93-1.15)
LBC (ASC-US+): Detection of CIN3+
HSIL (calc): 0.52 (0.45-0.58) Detection of CIN3+: (calc): CIN3+ (calc)
LBC: CC (ASC-US+): 0.47 ASC-US+:
302/49,222= (0.41-0.54) 1.09 (0.90-1.31) (971/48,941)/(889/40,047) 20.7%/17.6% = 1.17
0.61% (crude) = 0.89 (0.82-0.98) (0.99-1.39)
CC: 1.05 (0.86-1.29) LSIL+: 48.9%/41.9%
254/40,562= (adjusted)* = 1.17 (1.01-1.36)
0.63%
Intention to treat
analysis

*Adjusted for age,

study site,
urbanization, and
study period and
taking cluster design
into account
AGUS-Atypical Glandular Cells of Undetermined Significance; ASC-US-atypical squamous cells of undetermined significance; calc-calculated; CC-conventional cytology; CG-control
group; CI-confidence interval; CIN-cervical intraepithelial neoplasia; FU-follow-up; HIV-human immunodeficiency virus; HSIL-high-grade squamous intraepithelial lesion; IG-
intervention group; LBC-liquid-based cytology; LSIL-low-grade squamous intraepithelial lesion; mos-months; NR-not reported; PPV-positive predictive value; RCT-randomized
controlled trial; SD-standard deviation; SONE-strips of neoplastic endocervix; US-United States

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated Number of patients
Patient
Study ID Study design Setting Prevalence of disease
Screening cutoff Inclusion & characteristics
exclusion criteria
Collection method
Primary Screening with HPV Test Alone: Studies reporting absolute test performance measures
124
Bigras 2005 Hybrid Capture 2 Consecutive series, Switzerland All women (calc): 13,842 included in Mean Age: 44.4 (17-
split sample analysis 93)
Positive for high Recruited by 113 CIN2: 23/13,842 = 0.2% Age ≥ 30 years:
oncogenic risk viruses gynecologists from six CIN3: 56/13,842 = 0.4% Inclusion: Women 96.4%
(HPV types 16, 18, 31, Swiss cantons AIS: 3/13,842 = 0.02% attending for routine Ethnicity: NR
33, 35, 39, 45, 51, 52, (Genève, Vaud, Invasive carcinoma: 0 screening at the Education: NR
56, 58, 59, and 68) at Neuchâtel, Fribourg, practice of 1 of 113 Income: NR
≥1 pg/mL Valais, and Tessin), Women with participating HIV+: NR
most of whom are in colposcopy/biopsy gynecologists Other STIs: NR
HC2: Cervex brush private practice; results: Smoking: NR
LBC (Surepath): recruitment was not Exclusion: NR
Cervex brush from sexually CIN2: 23/1,533 = 1.5%
transmitted disease CIN3: 56/1,533 = 3.7%
clinics AIS: 3/1,533 = 0.2%
Invasive carcinoma: 0
Women at low risk --
most had been
screened yearly at
least 5 years before
the study

Application of reference standard Funding Quality Insufficient

Study ID Applicability Yield
(histologic verification) source rating samples

124
Bigras 2005 Colposcopy and biopsy in 77% Unclear Fair Good - low risk Test Positivity Rate NR
(1,031/1,334) of women positive for at population and most HC2: 8.2%
least one test and 4% (502/12,508) screened yearly prior LBC (ASC-US+): 3.6%
random sample of women negative for to study
both tests Concordance (calc)
26.4% of HPV+ samples were
Biopsy was requested on all patients ASC-US+
undergoing colposcopy; the biopsy was 61.3% of ASC-US+ samples
directed if a lesion was noted or random were HPV+
by strongly brushing the proximal

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

endocervical canal if no lesion was % HPV+ by LBC diagnosis:

visualized HSIL: 96.4%
LSIL: 89.9%
All women positive for at least one test ASC-US: 37.7%
(1,334) were referred for ASC-H: 83.3%
colposcopy/biopsy, but 248 (18.5%) AGC: 50.0%
refused, missed appointments, or Negative: 57.1%
underwent follow up in other labs and
55/1,086 (5%) biopsies were HPV/LBC categories:
unsatisfactory for evaluation HPV-LBC-: 90.4%
HPV-LBC+: 1.4%
HPV+LBC+: 2.2%
HPV+LBC-: 6.1%

Positive predictive Negative predictive

Sensitivity Specificity False positive rate Other performance
Study ID value value
(95% CI) (95% CI) (95% CI) characteristics
(95% CI) (95% CI)
124
Bigras 2005 Detection of HSIL+: Detection of HSIL+: Detection of HSIL+ Detection of HSIL+: Detection of HSIL+ % of HSIL+ biopsies
HC2 (HR HPV+): HC2 (HR HPV+): (calc): HC2 (HR HPV+): 99.98 (calc): by HPV/LBC
100.8/103.9 = 97.0 12,695.9/13,738.1 = HC2 (HR HPV+): (99.96-100) HC2 (HR HPV+): 7.6 category:
(91.8-99.4) 92.4 (91.9-92.9) 100.8/1,143 = 8.8 (7.3- LBC (ASC-US+): 99.75 (7.1-8.1) HPV-LBC-: 0%
LBC (ASC-US+): LBC (ASC-US+): 10.6) (99.67-99.83) LBC (ASC-US+): 3.1 HPV-LBC+: 3.0%
61.0/103.9 = 58.7 13,306.1/13,738.1 = LBC (ASC-US+): (2.8-3.4) HPV+LBC+: 55.7%
(48.6-68.2) 96.9 (96.6-97.2) 61/493 = 12.4 (9.6- All estimates corrected HPV+LBC-: 41.3%
15.6) for verification bias All estimates corrected
All estimates corrected All estimates corrected for verification bias All estimates corrected
for verification bias for verification bias All estimates corrected for verification bias
for verification bias

Primary screening test

evaluated Number of patients
Study ID Study design Setting Prevalence of disease Patient characteristics
Screening cutoff Inclusion &
exclusion criteria
Collection method
122
Kulasingam 2002 PCR (NR) Consecutive series US All women (calc): 4,358 eligible Age:
4,075 consented to Mean: 25 (SD 5.7)
Hybrid Capture 2 Separate samples Three Planned CIN2: 50/4,075 = 1.2% participate <30: 81%
for LBC followed by Parenthood CIN3+: 87/4,075 = 2.1% ≥30: 19%
PCR: Positive for high-risk PCR clinics in (includes 1 case of AIS; Inclusion: Age 18- Ethnicity
HPV types (16, 18, 26, 31, Washington 3 of these 87 women 50 African American: 10%
33, 35, 39, 45, 51, 52, 55, Prior to January State found to have American Indian: 1%

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

56, 58, 59, 68, 73, 82, and 2000, HC2 assay microinvasive cancer in Exclusion: History of Asian: 3%
84) performed on Women LEEP specimen) hysterectomy, chronic Hispanic: 4%
HC2: Positive for high-risk residual STM presenting for immune suppression, White: 72%
HPV types (16, 18, 31, 33, samples after annual Women with or treatment for Other: 10%
35, 39, 45, 51, 52, 56, 58, aliquot for PCR examinations colposcopy/biopsy cervical neoplasia Education
59, and 68) at ≥1 RLU removed results: ≤ high school: 40%
> high school: 60%
PCR: Dacron-tipped swab Starting in January CIN2: 50/1,015 = 4.9% Monthly Income
HC2: Dacron-tipped swab 2000, HC2 assay CIN3+: 87/1,015 = 8.6% ≤$400: 25%
(prior to Jan. 2000); Ayres performed on CIN3+ (corrected for $401-$800: 27%
spatula and cytobrush residual LBC liquid colposcopy attendance $801-$1,300: 24%
(starting in Jan. 2000) and verification bias): >$1,300: 24%
LBC (ThinPrep): Ayres 3.2% HIV+: NR
spatula for transformation Other STIs: NR
zone and cytobrush for Smoking: NR
endocervical cells

Application of
reference standard Quality
Study ID Funding source Applicability Yield Insufficient samples
(histologic rating
verification)
122
Kulasingam 2002 Colposcopy and biopsy National Cancer Good Good Test Positivity Rate Insufficient
in women screening Institute PCR: 18.3% PCR: 3.9%
positive on cytology, HC2: 28.4% HC2: 2.1%
PCR, or HC2 and in a LBC (ASC-US+): 16.6%
random sample of 202 Unsatisfactory
(7.7%) women with Concordance* (calc) LBC: 1.9%
negative cytology and (based on 3,996 with satisfactory LBC
PCR test results tests)
PCR
Ectocervical biopsies of 45.9% of HPV+ samples were ASC-US+
visible lesions or the 12 49.9% of ASC-US+ samples were HPV+
o'clock location if no HC2
lesion was visible 38.2% of HPV+ samples were ASC-US+
62.1% of ASC-US+ samples were HPV+

% HPV+ by LBC diagnosis:

HSIL: PCR 82.0%, HC2 85.6%
LSIL: PCR 62.7%**, HC2 81.9%
ASC-US: PCR 35.7%, HC2 47.4%
Negative: PCR 12.0%, HC2 20.5%

HPV/LBC categories:
HPV-LBC-: PCR 73.1%, HC2 66.0%

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

HPV-LBC+: PCR 8.5%, HC2 6.4%

HPV+LBC+: PCR 8.5%, HC2 10.5%
HPV+LBC-: PCR 10.0%, HC2 17.0%

*All estimates corrected for verification

bias and bias due to loss to follow up

**Reported as 64.4% (104/166) in text

Positive
Sensitivity Specificity predictive Negative predictive Other performance
Study ID False positive rate
(95% CI) (95% CI) value value characteristics
(95% CI)
Kulasingam All Ages All Ages NR All Ages All Ages All Ages
122
2002 Detection of CIN3+: Detection of CIN3+: Detection of CIN3+: Detection of CIN3+ % Referred for
PCR (HR HPV+): 88.2 (78.9- PCR (HR HPV+): 78.8 (95% CI NR) (calc): Colposcopy:
93.8) (77.9-79.7) PCR (HR HPV+): 99.5 PCR (HR HPV+): 21.2 PCR (HR HPV+):
HC2 (HR HPV+): 90.8 (83.1- HC2 (HR HPV+): 72.6 HC2 (HR HPV+): 99.6 HC2 (HR HPV+): 27.4 23.4%
95.8) (69.4-75.0) LBC (ASC-US+): 98.5 LBC (ASC-US+): 17.6 HC2 (HR HPV+):
LBC (ASC-US+): 61.3 (48.5- LBC (ASC-US+): 82.4 HC2&LBC: 29.4%
70.9) (81.8-83.1) 98.5 Age <30 years LBC (ASC-US+):
HC2&LBC: 60.3 (47.4-69.6) HC2&LBC: 88.9 (88.1-89.6) All estimates corrected Detection of CIN2+ 19.0%
Age <30 years Age <30 years for verification bias (calc): HC2&LBC: 12.7%
Detection of CIN2+: Detection of CIN2+: and bias due to loss to PCR: 22.2
PCR: 69.9 (49.4-85.2) PCR: 77.8 (76.7-78.9) follow up HC2: 28.9
HC2: 73.5 (53.3-87.7) HC2: 71.1 (67.3-74.0) LBC: 17.9
LBC: 50.1 (35.2-62.2) LBC: 82.1 (81.3-83.0)
HC2&LBC: 47.9 (34.1-60) HC2&LBC: 88.3 (87.4-89.2) Detection of CIN3+
Detection of CIN3+: Detection of CIN3+: (calc):
PCR: 91.1 (81.0-97.2) PCR: 76.8 (75.7-77.8) PCR: 23.2
HC2: 92.5 (83.5-97.3) HC2: 70.1 (66.5-73.1) HC2: 29.9
LBC: 65.4 (51.9-79.1) LBC: 81.5 (80.7-82.3) LBC: 18.5
HC2&LBC: 64.0 (51.1-77.6) HC2&LBC: 87.6 (86.7-88.4)
Age ≥30 years Age ≥30 years Age ≥30 years
Detection of CIN2+: Detection of CIN2+: Detection of CIN2+
PCR: 56.5 (30.3-85.5) PCR: 87.3 (85.5-89.5) (calc):
HC2: 62.7 (34.1-93.2) HC2: 83.0 (76.6-87.2) PCR: 12.7
LBC: 38.3 (19.3-63.3) LBC: 86.4 (84.7-88.3) HC2: 17.0
HC2&LBC: 38.3 (19.3-63.3) HC2&LBC: 95.0 (93.0-96.4) LBC: 13.6
Detection of CIN3+: Detection of CIN3+:
PCR: 80.0 (58.8-92.2) PCR: 87.4 (85.7-89.6) Detection of CIN3+
HC2: 86.0 (59.7-96.9) HC2: 83.0 (76.8-87.1) (calc):
LBC: 49.7 (32.9-71.5) LBC: 86.4 (84.8-88.1) PCR: 12.6

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

HC2&LBC: 49.7 (32.9-71.5) HC2&LBC: 94.7 (92.8-96.1) HC2: 17.0

All estimates corrected for All estimates corrected for LBC: 13.6
verification bias and bias due verification bias & loss to
to loss to follow up followup bias All estimates corrected for
verification bias and bias
due to loss to follow up

Primary screening
test evaluated Number of patients
Study ID Study design Setting Prevalence of disease Patient characteristics
Screening cutoff Inclusion & exclusion
criteria
Collection method
CCCaST Hybrid Capture 2 RCT with 2 arms: Canada All women (calc): 14,953 assessed for Age
Focus on HPV: HC2 eligibility 30-39: 38.5%
121
Mayrand 2007 Positive for high followed by CC 30 selected medical CIN2+ 40-49: 35.0%
oncogenic risk viruses practices in Montreal Conservative Case 10,154 randomly 50-59: 20.4%
126
Mayrand 2006 (HPV types 16, 18, 31, Focus on Pap: CC and surrounding Definition*: 41/10,154 = assigned to screening 60-69: 6.1%
33, 35, 39, 45, 51, 52, followed by HC2 municipalities (province 0.4% 5,059 assigned to Ethnicity (10,019
56, 58, 59, and 68) at of Quebec) and St. Focus on Pap group participants)
≥1 pg/mL Both screening tests John's (province of Liberal Case Definition*: 5,095 assigned to French Canadian:
included in each arm, Newfoundland) 54/10,154 = 0.5% Focus on HPV group 36.7%
HC2: Digene cervical but order of collection English Canadian:
sampler kit was randomized. Tests Physicians recruited Women with 9,977 received 56.9%
CC: Per protocol at performed sequentially from medical practices colposcopy/biopsy assigned intervention Other: 6.4%
each medical practice at same visit identified by cytology results: 5,020 in Focus on Pap Education (10,064)
laboratories as active in group Elementary school:
cervical cancer CIN2+ 4,957 in Focus on 10.3%
screeningWomen Conservative Case HPV group High school: 22.7%
attending routine Definition*: 41/1,365 = Junior college: 29.0%
cervical cancer 3.0% Inclusion: Age 30-69 University: 38.0%
screening Exclusion: Attending Income: NR
Liberal Case Definition*: colposcopy clinic for HIV+: NR
54/1,365 = 4.0% evaluation, treatment Other STIs: NR
or follow up of a Smoking: NR
cervical lesion, without
a cervix, pregnant,
previous history of
invasive cervical
cancer, received
cytology test within 12
months

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID Application of
reference
Insufficient Sensitivity Specificity
Quality rating standard Funding source Yield
samples (95% CI) (95% CI)
(histologic
Applicability verification)
CCCaST Colposcopy and Canadian Test Positivity HC2: NR Group-Specific Comparison of Group-Specific Comparison of
biopsy in 90.9% Institutes of Rate CC: 1.4% in Comparison Screening Comparison Screening
121
Mayrand 2007 (723/795) of Health Research, HC2: both arms Detection of Approaches Using Detection of Approaches
women positive Merck Frosst 6.3% in Focus on CIN2+: Combined Groups CIN2+: Using
126
Mayrand 2006 for at least one Canada, National HPV Conservative Case (n = 9,959 women Conservative Combined
test and 7.1% Cancer Institute 5.8% in Focus on Definition* in two groups who Case Definition* Groups (n =
(665/9,359) of Canada, Fonds Pap HC2: 94.6 (84.2- had available HC2 HC2: 94.1 9,959 women in
Fair random sample of de la Recherche 100.0) and CC results) (93.4-94.8) two groups who
women negative en Santé due CC: CC: 55.4 (33.6- Detection of CC: 96.8 (96.3- had available
Good for both tests Québec 2.7% in Focus on 77.2) CIN2+: 97.3) HC2 and CC
HPV Conservative results)
3.0% in Focus on Liberal Case Case Definition* Liberal Case Detection of
Pap Definition* (95% CI NR) Definition* CIN2+:
HC2: 45.9 (18.9- HC2: 97.4 HC2: 94.2 Conservative
Concordance: 72.9) CC (ASC-US+): (93.5-94.9) Case Definition*
NR CC: 43.4 (13.2- 56.4 CC: 96.9 (96.4- (95% CI NR)
73.6) CC (LSIL+): 42.2 97.4) HC2: 94.3
CC (ASC-US+):
All estimates All estimates 97.3
corrected for All estimates corrected for CC (LSIL+):
verification bias corrected for verification bias 99.1
verification bias
All estimates
corrected for
verification bias

Positive predictive value Negative predictive value Other performance

Study ID False positive rate Comments
(95% CI) (95% CI) characteristics

CCCaST Detection of Comparison of Detection of Comparison of Detection of Comparison of Test Performance *According to the
CIN2+: Screening CIN2+: Screening CIN2+ (calc): Screening by Sampling Order conservative
Mayrand Conservative Approaches Conservative Approaches Conservative Approaches Performance of HC2 definition, cases
121
2007 Case Definition* Using Combined Case Definition* Using Combined Case Definition* Using Combined and CC not were considered
HC2: 6.4 (5.0- Groups (n = HC2: 100.0 (98.6- Groups (n = HC2: 5.9 Groups (n = influenced by order only if confirmed
Mayrand 8.0) 9,959 women in 100.0) 9,959 women in CC: 3.2 9,959 women in of specimen on the LEEP
126
2006 CC: 7.1 (4.8- two groups who CC: 99.8 (99.7- two groups who two groups who collection (i.e., first or specimen or in the

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

10.3) had available 99.9) had available Liberal Case had available second), as judged confirmatory
HC2 and CC HC2 and CC Definition* HC2 and CC by test positivity, biopsy when
Liberal Case results) Liberal Case results) HC2: 5.8 results) unsatisfactory ablative treatment
Definition* Definition* CC: 3.1 smears or those was used. The
HC2: 8.0 (5.6- Detection of HC2: 99.4 (99.1- Detection of Detection of showing ASC-US, liberal definition
11.3) CIN2+: 99.5) CIN2+: All estimates CIN2+: viral load, and includes all cases
CC: 9.1 (4.7- Conservative CC: 99.6 (99.3- Conservative corrected for Conservative sensitivity or of CIN2-3,
16.7) Case Definition* 99.8) Case Definition* verification bias Case Definition* specificity adenocarcinoma
(95% CI NR) (95% CI NR) HC2: 5.7 in situ, or cervical
All estimates HC2: 7.0 All estimates HC2: 100.0 CC (ASC-US+): Referrals for cancers confirmed
corrected for CC (ASC-US+): corrected for CC (ASC-US+): 2.7 Colposcopy(using by histologic
verification bias 8.5 verification bias 99.8 CC (LSIL+): 0.9 combined groups) examination of
CC (LSIL+): 17.5 CC (LSIL+): 99.7 any of the
Conservative Case ectocervical or
All estimates All estimates Definition* endocervical
All estimates corrected for corrected for HC2: 6.1 biopsy specimens.
corrected for verification bias verification bias CC (ASC-US+): 2.9
verification bias CC (LSIL+): 1.0

All estimates
corrected for
verification bias

Primary screening
test evaluated
Number of patients
Study Patient
Study ID Setting Prevalence of disease
Screening cutoff design characteristics
Inclusion & exclusion criteria
Collection method
123
Petry 2003 Hybrid Capture 2 Consecutive Germany All women (calc): 8,466 recruited Mean Age: 42.7
series 8,101 met inclusion criteria Age 30-60 years:
Positive for high 28 urban, suburban CIN2+: 46/7,908 = 0.6% 8,083 with cytology and HC2 94.6%
oncogenic risk viruses HC2 sample or rural, office-based CIN3+: 37/7,908 = 0.5% results Ethnicity: NR
(HPV types 16, 18, 31, collected gynacological (includes 1 case of 7,908 included in test Education: NR
33, 35, 39, 45, 51, 52, following CC practices from invasive cervical performance analysis (excludes Income: NR
56, 58, 59, and 68) at sample at Hannover and carcinoma) 175 with positive test who HIV+: NR
≥1 pg/mL same visit Tuebingen and the refused colposcopy) Other STIs: NR
surrounding areas Women with Smoking: NR
HC2: Digene cervical colposcopy/biopsy Inclusion: Attending for routine
sample device Women attending results: annual screening
CC: Followed routine routine cervical
procedure in each cancer screening CIN2+: 46/536 = 8.6% Exclusion: Genital warts (43),
gynacologocal practice CIN3+: 37/536 = 6.9% history of conization or
(most, but not all, used hysterectomy (13), pregnant

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

cotton-tipped swab) (11), abnormal cytology within 1

year of study entry (8), under
age 30 (167), no written consent
(123)
130
Pan 2003 Hybrid Capture 2 Consecutive China CIN2: 43/1,993 = 2.2% 2,047 recruited Characteristics of
series, split CIN3: 31/1,993 = 1.6% 50 excluded (44 had cytology 1,997 in study sample
226
Belinson 2001 Positive for high sample Recruited from SCC: 12/1,993 = 0.6% and colposcopy only, 2 <35
oncogenic risk viruses villages in 4 years old, 2 having menses, 1 Mean age (SD): 39.1
(HPV types 16, 18, 31, communes in pregnant, 1 screened in pilot (3.16)
33, 35, 39, 45, 51, 52, Xiangyuan County in study) Ethnicity: NR
56, 58, 59, and 68) at Shanxi Province 1,997 in study sample Education: NR
1.0 pg/mL 1,993 included in LBC analyses HIV+: NR
Previously (4 with insufficient epithelial History of
HC2 and LBC unscreened women cells) condyloma: 0.3%
(ThinPrep): Plastic from rural, low- 1,836 included in HPV analyses Trichomoniasis on
spatula and resource setting (4 with insufficient epithelial cells, cytology: 20.6%
endocervical brush 157 without HPV data) Never smoked: 93.3%
Inclusion: Age 35-45
Exclusion: Pregnant, history of
cervical screening, pelvic
radiation, or hysterectomy

Application of
Quality Insufficient
Study ID reference standard Funding source Applicability Yield
rating samples
(histologic verification)
123
Petry 2003 Colposcopy and punch Cancer Society of Fair Good Test Positivity Rate NR
biopsy of any regions Lower Saxony, HC2: 6.4%
suspicious for CIN in Hannover, CC (PapIIw+): 3.1%
women with any degree Germany, the Ria- Concordance (calc)
of cytologic abnormality Freifrau von Fritsch 11.7% of HPV+ samples were PapIIw+
and/or positive for HPV Stiftung, and an 24.3% of PapIIw+ samples were HPV+
test and a random unconditional % HPV+ by CC diagnosis:
sample of 3.4% of formal grant from PapIV+V: 100%
women who were DIGENE PapIIId: 50.8%
negative on both corporation to the PapIII: 21.4%
screening tests University of PapIIw: 10.8%
Hannover and Negative: 5.9%
Tuebingen HPV/CC categories (calc):
HPV-CC-: 91.2%
HPV-CC+: 2.4%
HPV+CC+: 0.8%
HPV+CC-: 5.7%
130
Pan 2003 Colposcopy and biopsy Taussig Cancer Good Fair to Poor Test Positivity Rate Insufficient
in all women Center Cleveland HC2: 17.8% HC2: NR

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)
226
Belinson 2001 Clinic Foundation, Reports high LBC (ASC-US+): 25.7% LBC: 0.2%
If the colposcopic Cancer incidence of
examination was normal, Institute/Hospital, cervical cancer Concordance Unsatisfactory
four 2-mm biopsies were Chinese Academy in Shanxi 60.2% of HPV+ samples were ASC-US+ HC2: NR
taken from positions of Medical Province and 40.8% of ASC-US+ samples were HPV+ LBC: 7.9%*
2,4,8, and 10 o'clock on Sciences, Terry high age-
the exocervix at the Fox Foundation, adjusted % HPV+ by LBC diagnosis (p<.01): *These samples
squamocolumnar Transamerica mortality rate SCC: 100% were reprocessed
junction; endocervical Corporation, from cervical HSIL: 91.3% for LBC without
curettage was also Digene Corp., cancer LSIL: 58.9% HPV testing
performed on all Cytyc Corp., (52/100,000); ASC-US/AGUS: 16.6%
subjects; any Optical Biopsy low resource Negative: 9.6%
abnormalities revealed Tech, LLC, and setting
on colposcopy were also Carl Zeiss, Inc. HPV/LBC categories:
biopsied, and it was HPV-LBC-: 66.6%
acceptable to take more HPV-LBC+: 15.6%
than one biopsy per HPV+LBC+: 10.7%
quadrant HPV+LBC-: 7.1%

Positive predictive
Sensitivity Specificity Negative predictive value False positive rate Other performance
Study ID value
(95% CI) (95% CI) (95% CI) (95% CI) characteristics
(95% CI)
Petry Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of % referred to
123
2003 HC2 (HR HPV+): 45/46 HC2 (HR HPV+): HC2 (HR HPV+): 10.9 HC2 (HR HPV+): 100.0 CIN2+ (calc): colposcopy:
= 97.8 (86.3-99.7) 7,493/7,862 = 95.3 (93.5- (8.2-14.2) (55.3-100) HC2 (HR HPV+): HC2: CIN2+ 5.2, CIN3+
CC (PapIIw+): 20/46 = 96.6) CC (PapIIw+): 11.4 CC (PapIIw+): 99.7 (98.7- 4.7 (3.4-6.5) 5.2
43.5 (30.0-58.0) CC (PapIIw+): 7,706/7,862 (7.5-16.9) 99.9) CC (PapIIw+): 2.0 CC: CIN2+ 2.2, CIN3+
HC2 and CC: 100.0 = 98.0 (96.7-98.8) HC2 and CC: 8.6 (6.5- HC2 and CC: 100.0 (98.8- (1.2-3.3) 2.2
(93.7-100) HC2 and CC: 93.8 (91.8- 11.3) 100) HC2 and CC: 6.2 HC2 and CC: CIN2+ 6.8,
95.3) (4.7-9.2) CIN3+ 5.6
Detection of CIN3+: Detection of CIN3+: Detection of CIN3+:
HC2: 36/37 = 97.3 (83.2- Detection of CIN3+: HC2: 8.7 (6.3-11.8) HC2: 100.0 (55.3-100) Detection of Quality control:
99.6) HC2: 7,493/7,871 = 95.2 CC: 9.7 (6.1-15) CC: 99.7 (98.8-99.9) CIN3+ (calc): 719/925 (77.7%) of CC
CC: 17/37 = 46.0 (30.8- (93.4-96.5) HC2 and CC (PapIII+): HC2 and CC (PapIII+): HC2: 4.8 (3.5-6.6) samples reviewed by an
61.9) CC: 7,712/7,871 = 98.0 8.4 (6.2-11.4) 100.0 (99.1-100) CC: 2.0 (1.2-3.3) independent expert were
HC2 and CC (PapIII+): (96.7-98.8) HC2 and CC in agreement
100.0 (93.7-100) HC2 and CC: 94.9 (93.1- (PapIII+): 5.1(3.8- 96.6% of 600 HC2
96.2) 6.9) samples retested were
in agreement (κ 0.75)

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Positive predictive
Sensitivity Specificity Negative predictive value False positive rate Other performance
Study ID value
(95% CI) (95% CI) (95% CI) (95% CI) characteristics
(95% CI)
130
Pan 2003 Detection of CIN2+ Detection of CIN2+ (calc): Detection of CIN2+ Detection of CIN2+ (calc): Detection of ASC-US/AGUS to SIL
(calc): HC2 (HR): 1505/1753 = (calc): HC2 (HR): 1505/1509 = CIN2+ (calc): ratio: 1.47
Belinson HC2 (HR): 79/83 = 95.2 85.9 (84.1-87.5) HC2 (HR): 79/327 = 99.7 (99.3-99.9) HC2 (HR): 14.1
226
2001 (88.1-98.7) LBC (ASC-US+): 24.2 (19.6-29.2) LBC (ASC-US+): 1475/1480 (12.5-15.9)
LBC (ASC-US+): 81/86 = 1475/1907 = 77.3 (75.4- LBC (ASC-US+): = 99.7 (99.2-99.9) LBC (ASC-US+):
94.2 (87.0-98.1) 79.2) 81/513 = 15.8 (12.7- LBC (LSIL+): 1783/1794 = 22.7 (20.8-24.6)
LBC (LSIL+): 75/86 = LBC (LSIL+): 1783/1907 = 19.2) 99.4 (98.9-99.7) LBC (LSIL+): 6.5
87.2 (78.3-93.4) 93.5 (92.3-94.6) LBC (LSIL+): 75/199 = LBC (HSIL+): 1865/1885 = (5.4-7.7)
LBC (HSIL+): 66/86 = LBC (HSIL+): 1865/1907 = 37.7 (30.9-44.8) 98.9 (98.4-99.4) LBC (HSIL+): 2.2
76.7 (66.4-85.2) 97.8 (97.0-98.4) LBC (HSIL+): 66/108 = (1.6-3.0)
61.1 (51.3-70.3) Detection of CIN3+ (calc):
Detection of CIN3+ Detection of CIN3+ (calc): HC2 (HR): 1508/1509 = Detection of
(calc): HC2 (HR): 1508/1795 = Detection of CIN3+ 99.9 (99.6-100.0) CIN3+ (calc):
HC2 (HR): 40/41 = 97.6 84.0 (82.2-85.7) (calc): LBC (ASC-US+): 1479/1480 HC2 (HR): 16.0
(87.1-99.9) LBC (ASC-US+): HC2 (HR): 40/327 = = 99.9 (99.6-100.0) (14.3-17.8)
LBC (ASC-US+): 42/43 = 1479/1950 = 75.8 (73.9- 12.2 (8.9-16.3) LBC (LSIL+): 1791/1794 = LBC (ASC-US+):
97.7 (87.7-99.9) 77.7) LBC (ASC-US+): 99.8 (99.5-100.0) 24.2 (22.3-26.1)
LBC (LSIL+): 40/43 = LBC (LSIL+): 1791/1950 = 42/513 = 8.2 (6.0-10.9) LBC (HSIL+): 1881/1885 = LBC (LSIL+): 8.2
93.0 (80.9-98.5) 91.8 (90.5-93.0) LBC (LSIL+): 40/199 = 99.8 (99.5-99.9) (7.0-9.5)
LBC (HSIL+): 39/43 = LBC (HSIL+): 1881/1950 = 20.1 (14.8-26.3) LBC (HSIL+): 3.5
90.7 (77.9-97.4) 96.5 (95.5-97.2) LBC (HSIL+): 39/108 = (2.8-4.5)
36.1 (27.1-45.9)

Primary screening
test evaluated Number of patients Patient
Study ID Study design Setting Prevalence of disease
Screening cutoff Inclusion & exclusion criteria characteristics
Collection method
129
Sankaranarayanan 2004 Hybrid Capture 2 4 cross- India CIN2: 99/18,085 = 0.5% 20,053 eligible and consented Age
sectional CIN3: 89/18,085 = 0.5% 1,968 excluded from analysis 25-39: 56.5%
227
Shastri 2005 Positive for high studies Primary health Invasive cancer: (1,945 had abnormal 40-49: 31.1%
oncogenic risk centers or mobile 51/18,085 = 0.3% colposcopy but no biopsy taken 50-65: 12.4%
viruses (HPV types HC2 sample field clinics in due to refusal of women and 23 Ethnicity: NR
16, 18, 31, 33, 35, collected residential had inconclusive biopsy No formal
39, 45, 51, 52, 56, following CC locations in Kolkata results) education: 28.3%
58, 59, and 68) at ≥1 sample at (2 studies), the 18,085 included in analysis Income: NR
pg/mL same visit slums of Mumbai, HIV+: NR
and Trivandrum in Inclusion: Apparently healthy, Other STIs: NR
HC2: Digene cervical Opportunistic the State of Kerala asymptomatic, aged 25-65 Smoking: NR
sampler brush recruitment via

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated Number of patients Patient
Study ID Study design Setting Prevalence of disease
Screening cutoff Inclusion & exclusion criteria characteristics
Collection method
CC: Cervex broom publicity and Apparently healthy Exclusion: Hysterectomy,
brush or Ayre's individual or asymptomatic history of cervical neoplasia
spatula and cotton- group health women
tipped swab education
110
Coste 2003 Hybrid Capture 2 Consecutive France CIN 2-3: 35/1,754 = CC and LBC: 2,585 Total Mean age (SD): 33.3
series, split 2.0% 1,757 routine screening (11.1)
128
de Cremoux 2003 Positive for high sample 2 public university Invasive cancer: 828 referred for colposcopy Ethnicity: NR
oncogenic risk hospitals and 2 6/1,754 = 0.3% HC2: 1,785 Total (enough Education
127
Cochand-Priollet 2001 viruses (HPV types LBC slide private practices residual material) No schooling or
16, 18, 31, 33, 35, prepared from 1,323 routine screening primary only: 4%
39, 45, 51, 52, 56, CC sample Women attending 462 referred for colposcopy Secondary: 53%
58, 59, and 68) at 1.0 and HC2 for routine Higher: 43%
pg/mL assay screening and Inclusion: Women ≥18 years HIV+: 0%
performed on women referred for old undergoing spontaneous Previous
HC2, LBC residual colposcopy due to screening for cervical cancer documented
(ThinPrep), and CC: sample from abnormalities Chlamydia
Cervexbrush or LBC detected on prior Exclusion: Pregnant, no cervix, trachomatis
appropriate brushes screening smears* recent (<1 year) history of infection: 1%
and spatulas surgery or laser treatment of the Current smoker:
*We report results cervix, cervix not visible by 31%
for routine physician, mentally retarded,
screening sample clinical or psychological status
only not allowing collection of
required samples

Application of
reference standard Funding Quality Insufficient
Study ID Applicability Yield
(histologic source rating samples
verification)
129
Sankaranarayanan 2004 Colposcopy in all Bill & Melinda Fair Poor Test Positivity Rate NR
women, and punch Gates HC2
227
Shastri 2005 biopsies from any Foundation Training of Overall: 7.0%
colposcopically- through the specimen Range across sites: 6.1% - 9.0%
assessed abnormal Alliance for collectors
areas on the cervix Cervical Cancer widely vary CC (LSIL+): 5.9%
Prevention and include
high school Concordance
graduates NR

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Variability in
quality of
specimen
collection and
reference
standards
110
Coste 2003 Colposcopy and French Ministry Fair Fair to Good Test Positivity Rate Satisfactory for
directed biopsy of of Health and HC2: 16.02% evaluation
128
de Cremoux 2003 abnormalities in all the Association Probably fairly LBC (ASC-US+): 12.1% HC2: NR
women de Recherche comparable to CC (ASC-US+): 10.0% LBC: 87%
127
Cochand-Priollet 2001 contre le Cancer a US Concordance (calc) CC: 91%
population, (Routine and referred samples combined,
although lack unclear whether cytologic comparison is LBC or Unsatisfactory for
of experience CC) evaluation
with ThinPrep 63.9% of HPV+ samples were ASC-US+ HC2: NR
may mean 67.8% of ASC-US+ samples were HPV+ LBC: 0.4%
results aren't % HPV+ by LBC diagnosis: CC: 0.1%
comparable Carcinoma: 92.3%
HSIL: 82.6% Satisfactory for
LSIL: 68.0% evaluation but
ASC-US/AGUS: 42.6% limited by
Negative: 13.0% HC2: NR
HPV/LBC categories: LBC: 12.7%
HPV-LBC-: 64.9% CC: 9.1%
HPV-LBC+: 8.1%
HPV+LBC+: 17.2%
HPV+LBC-: 9.7%

Positive
Negative False positive
Sensitivity Specificity predictive Other performance
Study ID predictive value rate
(95% CI) (95% CI) value characteristics
(95% CI) (95% CI)
(95% CI)
Sankarana- Detection of CIN2+ (calc): Detection of CIN2+ (calc): Detection of Detection of Detection of Quality assessment to
129
rayanan 2004 HC2 (HR HPV+): 163/239 = 68.2 HC2 (HR HPV+): 16,736/17,846 = CIN2+ (calc): CIN2+ (calc): CIN2+ (calc): investigate statistically
(61.9-74.1) 93.8 (93.4-94.1) HC2 (HR HC2 (HR HPV+): HC2 (HR HPV+): significant variability in
227
Shastri 2005 CC (LSIL+): 109/166 = 65.7 CC (LSIL+): 9,909/10,425 = 95.1 HPV+): 16,736/16,812 = 6.2 (5.9-6.6) sensitivity across study
(57.9-72.8) (94.6-95.5) 163/1,273 = 99.5 (99.4-99.6) CC (LSIL+): 4.9 sites
12.8 (11.0- CC (LSIL+): (4.5-5.4)
Detection of CIN3+ (calc): Detection of CIN3+ (calc): 14.8) 9,909/9,966 = Rate of normal biopsy:
HC2: 113/140 = 80.7 (73.2-86.9) HC2: 16,785/17,945 = 93.5 (93.2- CC (LSIL+): 99.4 (99.3-99.6) Detection of Range = 40.5%
CC: 81/101 = 80.2 (71.1-87.5) 93.9) 109/625 = CIN3+ (calc): (Kolkata1) - 79.8%
CC: 9,946/10,490 = 94.8 (94.4- 17.4 (14.5- Detection of HC2: 6.5 (6.1-6.8) (Mumbai)
Detection of CIN2-3 (excl. inv. 95.2) 20.6) CIN3+ (calc): CC: 5.2 (4.8-5.6)
cancer): HC2: Interobserver

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

HC2 (HR HPV+) Detection of CIN2-3 (excl. inv. Detection of 16,785/16,812 = agreement from review
Kolkata1: 45.7 (30.9 - 61.0) cancer): CIN3+ (calc): 99.8 (99.8-99.9) of 182 histology slides:
Kolkata2: 69.8 (55.7 - 81.7) HC2 (HR HPV+) HC2: CC: 9,946/9,966 = 96.5% (κ 0.90) in Kolkata
Mumbai: 69.1 (52.9 - 82.4) Kolkata1: 91.7 (90.7 - 92.6) 113/1,273 = 99.8 (99.7-99.9) 1&2, 88.2% (κ 0.60) in
Trivandrum: 80.9 (66.7 - 90.9) Kolkata2: 94.5 (93.9 - 95.0) 8.9 (7.4-10.6) Trivandrum
Mumbai: 93.6 (92.7 - 94.4) CC: 81/625 =
CC (LSIL+) Trivandrum: 94.6 (93.9 - 95.3) 13.0 (10.4- Overall agreement from
Kolkata1: 36.6 (22.1 - 53.1) 15.8) reanalysis of 298 HPV
Kolkata2: No cytology CC (LSIL+) samples: 85.9% (range
Mumbai: 70.0 (53.5 - 83.4) Kolkata1: 87.2 (85.9 - 88.4) 81.0 - 92.9); κ 0.72
Trivandrum: 72.3 (57.4 - 84.4) Kolkata2: No cytology (range 0.62 - 0.86)
Mumbai: 98.6 (98.1 - 99.0)
Detection of HSIL:* Trivandrum: 97.9 (97.4 - 98.3)
HC2 and CC
Both results positive: 46.8 (32.1 Detection of HSIL:*
- 61.9) HC2 and CC
Either result positive: 72.3 (57.4 Both results positive: 99.4 (99.1
- 84.4) - 99.7)
Either result positive: 92.8 (91.8
*From Shastri 2005: Sample of - 93.6)
4,039 women from Mumbai site
only; excludes invasive cancer *From Shastri 2005: Sample of
cases 4,039 women from Mumbai site
only; excludes invasive cancer
cases

Positive Negative
Sensitivity Specificity Other performance
Study ID predictive predictive False positive rate Comments
(95% CI) (95% CI) characteristics
value value
110
Coste 2003 Detection of CIN2+: Detection of CIN2+: NR NR Detection of CIN2+ Likelihood Ratio (+/-) *Optimized
HC2 (HR): 96 (88-100) HC2 (HR): 85 (83-87) (calc): Detection of CIN2+: interpretation: if
de Cremoux LBC (optimized LBC (optimized HC2 (HR): 15 HC2 (HR): 6.52/0.05 CC and LBC
128
2003 interpretation)*: 65 (50-80) interpretation)*: 98 (98-99) LBC (optimized LBC (optimized readings disagree,
CC (optimized CC (optimized interpretation)*: 1 interpretation)*: reread to reach
Cochand- interpretation)*: 60 (45-75) interpretation)*: 99 (99-99) CC (optimized 41.29/0.36 consensus
127
Priollet 2001 LBC & HC2 when ASC- LBC & HC2 when ASC- interpretation)*: 1 CC (optimized diagnosis, or read
US/AGUS: 76 (59-93) US/AGUS: 97 (97-98) LBC & HC2 when interpretation)*: by independent
ASC-US/AGUS: 3 60.46/0.40 expert if
LBC & HC2 when disagreement not
ASC-US/AGUS: resolved
29.71/0.25

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated
Number of patients
Prevalence of
Study ID Study design Setting Patient characteristics
Screening cutoff disease
Inclusion & exclusion criteria
Collection method
Cardenas-Turanzas Hybrid Capture 2 Consecutive 3 sites: U.S. CIN 2/3 or cancer 1,850 enrolled For women ≥ 30 years:
125
2008 series of (a cancer (calc): 1,000 in screening group Screening:
Positive for high women center and a Screening: 850 in diagnosis group Mean Age: 46.7 y
oncogenic risk viruses participating in community 16/835=1.9% Ethnicity:
(HPV types 16, 18, 31, a phase II hospital), and Diagnosis: 1,444 ≥ 30 years old Non-Hispanic white: 51.1%
33, 35, 39, 45, 51, 52, clinical trial of Canada 134/518= 25.9% 873 in screening group African-American: 14.7%
56, 58, 59, and 68) at spectroscopic (cancer 571 in diagnosis group Hispanic: 26.1%
≥1 pg/mL cervical center) Asian: 6.6%
inspection 1,353 with complete data included in Other: 1.4%
CC and HC2: Cervical Women analysis Education:
brush Split sample; recruited to 835 in screening group ≤High school: 24.0%
HC2 sample trial through 518 in diagnosis group Some college: 38.4%
obtained by advertising in College: 23.0%
immersing local media, Inclusion: Nonpregnant women ≥ Graduate: 14.6%
cervical brush in expected to 18 years Income: NR
solution after increase Exclusion: History of CIN or HIV+/Other STIs: NR
preparing minority cervical cancer Smoking:
smear participation Ever: 34.9%
Current: 9.8%
Screening Diagnosis:
group: no Mean Age: 42.3y
history of Ethnicity:
abnormal Non-Hispanic white: 63.9%
cytology by African-American: 9.5%
patient’s report Hispanic: 13.7%
Asian: 9.3%
Diagnosis Other: 3.7%
group: self- Education:
reported ≤High school: 27.8%
abnormal Some college: 34.4%
cytology at any College: 23.0%
previous time Graduate: 14.9%
Income: NR
HIV+: NR
Smoking: Ever:
43.6%,Current: 20.7%

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Application of
reference standard Quality Insufficient
Study ID Funding source Applicability Yield
(histologic rating samples
verification)
Cardenas-Turanzas All women had National Cancer Fair Fair Test positivity: NR
125
2008 colposcopic Institute Screening
examination and Separate HC2: 66/835=7.9% (calc)
biopsies reporting of CC (ASC-US+): 59/835=7.1%
“screening”
If colposcopy abnormal, and Diagnosis:
1-2 biopsies taken of “diagnosis” HC2: 203/518=39.2% (calc)
area with worst groups; risk in CC (ASC-US)+: 208/518=40.2%
colposcopic impression each may
differ from that Concordance:
1-2 biopsies also taken in an % of HPV+ samples that were ASC-US+: NR
of squamous and unselected 100% of ASC-US+ samples were HPV+
columnar epithelium screening
from an area of normal population
appearance, typically at
the 6 o’clock and 12
o’clock positions,
regardless of whether
abnormal area identified
by colposcopy

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Positive predictive Negative predictive

Sensitivity Specificity False positive rate Other performance
Study ID value value
(95% CI) (95% CI) (95% CI) characteristics
(95% CI) (95% CI)
Cardenas- Screening group Screening group Screening group Screening group Screening group Screening group
125
Turanzas 2008 Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+ Area under ROC:
HC2+: 0.69 (0.41-0.89) HC2+: 0.93 (0.91- (95% CI NR) (95% CI NR) (calc): HC2+: 0.81
CC (ASC-US+): 0.44 0.95) HC2+: 0.17 HC2+: 0.99 HC2+: 0.07 CC (ASC-US+):0.70
(0.20-0.70) CC (ASC-US+): CC (ASC-US+): 0.12 CC (ASC-US+): 0.99 CC (ASC-US+): 0.06 CC (ASC-US+) or HC2+:
CC (ASC-US+) or 0.94(0.92-0.95) CC (ASC-US+) or CC (ASC-US+) or CC (ASC-US+) or 0.79
HC2+:0.69 (0.41-0.89) CC (ASC-US+) or HC2+: 0.10 HC2+: 0.99 HC2+: 0.12 LR+:
HC2+: 0.88 (0.86- HC2+: 10.24
Diagnosis group 0.91) Diagnosis group Diagnosis group Diagnosis group CC (ASC-US+): 6.89
Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+ CC (ASC-US+) or HC2+:
HC2+: 0.89 (0.82-0.94) Diagnosis group (95% CI NR) (95% CI NR) (calc): 5.93
CC (ASC-US+): 0.78 Detection of CIN2+: HC2+: 0.66* HC2+: 0.95 HC2+: 0.22 LR-:
(0.70-0.85) HC2+: 0.78 (0.74- CC (ASC-US+): 0.50 CC (ASC-US+): 0.91 CC (ASC-US+): 0.27 HC2+: 0.34
CC (ASC-US+) or 0.82) CC (ASC-US+) or CC (ASC-US+) or CC (ASC-US+) or CC (ASC-US+): 0.60
HC2+: 0.96 (0.92-0.99) CC (ASC-US+): 0.73 HC2+: 0.49 HC2+: 0.98 HC2+: 0.35 CC (ASC-US+) or HC2+:
(0.68-0.78) 0.35
CC (ASC-US+) or *According to HPV
HC2+: 0.65 (0.60- and histology results Diagnosis group
0.69) in Table 2, should be Area under ROC:
119/203 = 0.59 HC2+: 0.83
CC (ASC-US+): 0.78
CC (ASC-US+) or HC2+:
0.80
LR+:
HC2+: 4.06
CC (ASC-US+):2.92
CC (ASC-US+) or HC2+:
2.72
LR-:
HC2+: 0.14
CC (ASC-US+): 0.30
CC (ASC-US+) or
HC2+:0.06

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated
Number of patients
Prevalence of
Study ID Study design Setting Patient characteristics
Screening cutoff disease
Inclusion & exclusion criteria
Collection method
131
Qiao 2008 Hybrid Capture 2 Two communes China CIN2: 47/2,388= 3,721 recruited Mean Age: 43.4y (SD 6.2,
selected from 2.0% 2,530 enrolled (68%) range 30-55)
Positive for high each of two Rural Shanxi CIN3: 22/2,388= 2,388 with complete data Ethnicity: NR
oncogenic risk viruses counties using province, two 0.9% Education: NR
(HPV types 16, 18, 31, randomized women and Cancer: Inclusion: Age 30-54 years, married Income: NR
33, 35, 39, 45, 51, 52, cluster children’s 1/2,388=0.04% HIV+: NR
56, 58, 59, and 68) at sampling; all hospitals Exclusion: pregnant; menstruating; Other STIs: NR
≥1 pg/mL eligible women history of CIN, pelvic radiation, or Smoking: 98.7% had never
from the four Unscreened hysterectomy smoked
HC2 and LBC selected population
(SurePath): Collection communes
method NR invited

Consecutive
series, split
sample

Provider-
obtained
cervical
specimens for
LBC and HC2
followed self-
obtained
vaginal
specimens

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Application of
reference standard Quality Insufficient
Study ID Funding source Applicability Yield
(histologic rating samples
verification)
131
Qiao 2008 All women had Bill & Melinda Fair Poor Test positivity (calc): Unsatisfactory
colposcopy, with Gates HC2: 401/2,388 = 16.8% LBC: 50/2,388 =
directed biopsy and Foundation Population- LBC (ASC-H+): 127/2,388 = 5.3% 2.1% (calc)
endocervical curettage based, but in HC2: NR
as necessary an unscreened Concordance (calc):
population in 31.8% of HPV+ samples were ASC-H+
441 women with rural Chinese (based on 2,338 with satisfactory LBC)
negative colposcopy but villages 96.1% of ASC-H+ samples were HPV+
unsatisfactory or
abnormal screening test %HPV+ by LBC diagnosis (calc):
were recalled for <ASC-H: 11.8%
second colposcopy and ASC-H+: 96.1%
4-quadrant biopsy at the Unsatisfactory: 34.0%
squamo-columnar
junction HPV/LBC(ASC-H+) categories (calc):
(based on 2,338 with satisfactory LBC)
HPV-LBC-: 83.4%
HPV-LBC+: 0.2%
HPV+LBC-: 11.2%
HPV+LBC+: 5.2%

Positive predictive Negative predictive

Sensitivity Specificity False positive rate Other performance
Study ID value value
(95% CI) (95% CI) (95% CI) characteristics
(95% CI) (95% CI)

131
Qiao 2008 Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+ Area under ROC:
HC2: 97.1 (93.2-100.0) HC2: 85.6 (84.2-87.1) HC2: 17.0 (13.3-20.6) HC2: 99.9 (99.8-100.0) (calc): Detection of CIN2+:
LBC (ASC-H+): 85.3 LBC (ASC-H+): 97.0 LBC (ASC-H+): 45.7 LBC (ASC-H+): 99.5 HC2: 14.4 HC2: 0.96 (0.94-0.97)
(76.9-93.7) (96.3-97.7) (37.0-54.3) (99.3-99.8) LBC (ASC-H+): 3.0 LBC (ASC-H+): 0.95 (0.92-
Detection of CIN3+: Detection of CIN3+: Detection of CIN3+: Detection of CIN3+: Detection of CIN3+ 0.99)
HC2: 95.7 (87.3-100.0) HC2: 84.0 (82.5-85.5) HC2: 5.5 (3.3-7.7) HC2: 99.9 (99.9-100.0) (calc): Detection of CIN3+:
LBC (ASC-H+): 87.0 LBC (ASC-H+): 95.4 LBC (ASC-H+): 15.7 LBC (ASC-H+): 99.9 HC2: 16.0 HC2: 0.94 (0.89-0.99)
(73.2-100.0) (94.5-96.2) (9.4-22.1) (99.7-100.0) LBC (ASC-H+): 4.6 LBC (ASC-H+): 0.94 (0.87-
1.00)

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening test

evaluated Number of patients
Prevalence of
Study ID Study design Setting Patient characteristics
Screening cutoff disease Inclusion & exclusion
criteria
Collection method
132
Moy 2009 Pap: LBC Screening Rural China CIN3+: 11,424 invited to participate Mean age: 39 y
(ThinPrep/Autocyte) Technologies to Unadjusted (eligible by census data) Age:
HR-HPV DNA test: HC2 Advance Rapid 4 women’s and prevalence: 30-34: 24.5%
Testing (START) children’s 140/9,057= 1.5% 9,057 confirmed eligible, 35-39: 26.8%
HR-HPV DNA testing for Project: age-eligible hospitals in 3 (calc) available, and consented 40-44: 27.5%
HR types (16, 18, 31, 33, women in selected provinces 45-54: 21.1%
35, 39, 45, 51, 52, 56, counties in the 3 (Shanxi, Adjusted prevalence Inclusion: age 30-49 y 2003- Ethnicity: NR (assumed
58, 59, 68) with standard provinces identified Jiangxi, and among all women 2005, age 30-54 y 2006; nonWhite)
RLU cutoff ratio ≥ 1 by census and Gansu) enrolled (9,057): married or history of sexual Education:
(equivalent to 1 pg of recruited door-to- 1.8% activity; able to give informed None: 20.7%
HR-HPV DNA). door Counties consent Primary: 35.3%
Sensitivity analysis All consenting selected based Middle/Junior: 34.5%
conducted for cutoffs of women had both on high rates of Exclusion: history of cervical High/Sr. High: 8.9%
2.0, 3.0, 4.0, 10.0 and screening tests cervical cancer cancer screening; history of College: 0.5%
20.0 (LBC and HC2), mortality CIN, cervical cancer, or Income: NR
with referral to hysterectomy; pregnancy HIV+: NR
Gynecologists used colposcopy Unscreened (LMP required to be less than Other STIs: NR
cytology brush to collect according to population 5 weeks before); Smoking: NR
cervical specimens from screening result and menstruating women invited
transformation zone for year of study to return to participate; no
LBC and HC2 tests after debilitating disease
women self-collected 3 5 screening
vaginal specimens using strategies
plastic-shafted swab or evaluated:
brush 1) Pap only (referral
for ASC-US+)
2) HC2 only
3) Reflex (referral
for either LSIL+, or
ASC-US+ with
HC2+)
4) Cotesting LSIL
5) Cotesting HSIL

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Application of
reference standard Quality Insufficient
Study ID Funding source Applicability Yield
(histologic rating samples
verification)
132
Moy 2009 2003 and 2005: NR Fair Poor Test positivity: Missing*:
Women with positive LBC (ASC-US+): 1,035/9,057=11.4% LBC: 169 (1.9%)
VIA, VILI, Pap (LSIL+) Unscreened HC2+: 1,242/9,057=13.7% HC2: 540 (6.0%)
or HC2 referred to population in
colposcopy rural Chinese Concordance (calc)*: *Table 2 lists as
counties with 515/985=52.3% of those ASC-US+ were HPV+ missing, while text
2004 and 2006: high rates of 515/1215=42.4% of those HPV+ were ASC-US+ on p. 3 (Data
analysis) groups
All women had cervical cancer
missing and
colposcopy, with mortality %HPV+ by LBC diagnosis: inadequate; study
directed biopsy of Negative: 9.5% coded these as test
visible lesions; women ASC-US: 32.7% positive, with
with Pap of ASC-H, ASC-H: 79.3% sensitivity analysis
AGUS, LSIL or higher, AGUS: 62.5% coding as test
or HPV+, had 4- LSIL: 89.6% negative
quadrant biopsy. HSIL: 97.5%
Cancer: 94.4%
Overall colposcopy Missing: 17.4%
attendance (calc):
5,905/9,057 = 65.2% HPV/LBC categories (calc):
HPV-LBC-: 79.8%
HPV-LBC+: 5.6%
HPV+LBC-: 8.4%
HPV+LBC+: 6.2%

*Note: data in text on p. 5 used to calculate concordance.

However, there is a discrepancy in data presented: sum of
denominators for cytology results in women with HPV results
(including missing cytology category) is 8,507, vs. 8,517
reported elsewhere (text p. 5, Table 2) as total number of
participants with HPV results.

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Positive predictive Negative predictive

Sensitivity Specificity False positive rate Other performance
Study ID value value
(95% CI) (95% CI) (95% CI) characteristics
(95% CI) (95% CI)
132
Moy 2009 Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+ ROC AUC:
Pap only (ASC-US+): Pap only (ASC-US+): Pap only (ASC-US+): Pap only (ASC-US+): (calc): 0.9 for all five screening
71.2 (65.7-76.4) 93.5 (93.2-93.8) 14.7 (12.0-17.4) 99.5 (99.3-99.7) Pap only (ASC-US+): strategies
HC2 only (cutoff 1.0): HC2 only (cutoff 1.0): HC2 only (cutoff 1.0): HC2 only (cutoff 1.0): 6.5 (6.2-6.8)
93.6 (90.5-96.4) 85.8 (85.4-86.2) 9.4 (7.9-10.9) 99.9 (99.8-100.0) HC2 only (cutoff 1.0): HC2 cutoffs:
Reflex: 67.2 (61.5-72.6) Reflex: 96.9 (96.7- Reflex: 25.7 (21.2- Reflex: 99.5 (99.4-99.6) 14.2 (13.8-14.6) Test performance also
Cotesting LSIL: 95.5 97.2) 30.2) Cotesting LSIL: 99.9 Reflex: 3.1 (2.8-3.3) reported for HC2 cutoffs
(93.2-98.0) Cotesting LSIL: 85.1 Cotesting LSIL: 9.1 (99.8-100.0) Cotesting LSIL: 14.9 from 2.0 to 20.0
Cotesting HSIL: 95.5 (84.6-85.5) (7.6-10.6) Cotesting HSIL: 99.9 (14.5-15.4)
(93.2-98.0) Cotesting HSIL: 85.1 Cotesting HSIL: 9.2 (99.8-100.0) Cotesting HSIL: 14.9 Authors identify 10.0 pg as
(84.7-85.6) (7.7-10.7) (14.4-15.3) having high specificity and
Detection of CIN3+: Detection of CIN3+: low referral rate
Pap only (ASC-US+): Detection of CIN3+: Detection of CIN3+: Pap only (ASC-US+): Detection of CIN3+
80.2 (74.1-86.2) Pap only (ASC-US+): Pap only (ASC-US+): 99.6 (99.5-99.7) (calc): Do not use ROC to assess
HC2 only (cutoff 1.0): 93.3 (93.0-93.6) 15.8 (13.1-18.5) HC2 only (cutoff 1.0): Pap only (ASC-US+): cutoffs
96.3 (93.6-99.2) HC2 only (cutoff 1.0): HC2 only (cutoff 1.0): 100 (NR) 6.7 (6.4-7.0)
Reflex: 75.4 (68.7-81.9) 85.5 (85.0-85.9) 9.4 (7.9-10.9) Reflex: 99.6 (99.5-99.7) HC2 only (cutoff 1.0): Proportion referred to
Cotesting LSIL: 99.4 Reflex: 96.7 (96.5- Reflex: 26.6 (22.3- Cotesting LSIL: 100 14.5 (14.1-15.0) colposcopy:
(98.2-100) 96.9) 30.9) (NR) Reflex: 3.3 (3.1-3.5) Pap only (ASC-US+): 7.8
Cotesting HSIL: 99.4 Cotesting LSIL: 84.8 Cotesting LSIL: 9.3 Cotesting HSIL: 100 Cotesting LSIL: 15.2 (7.2-8.4)
(98.2-100) (84.3-85.3) (7.8-10.8) (NR) (14.7-15.7) HC2 only (cutoff 1.0): 15.8
Cotesting HSIL: 84.8 Cotesting HSIL: 9.3 Cotesting HSIL: 15.2 (15.0-16.6)
All estimates corrected (84.3-85.3) (7.8-10.8) All estimates corrected (14.7-15.7) Reflex: 4.4 (4.0-4.8)
for verification bias for verification bias Cotesting LSIL: 16.5 (15.7-
All estimates corrected All estimates 17.3)
for verification bias corrected for Cotesting HSIL: 16.5 (15.7-
verification bias 17.3)

All estimates corrected for

verification bias

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated Number of patients
Study ID Study design Setting Prevalence of disease Patient characteristics
Screening cutoff Inclusion & exclusion
criteria
Collection method
Primary Screening with HPV Test Alone: RCTs reporting relative test performance measures
NTCC Phase II Hybrid Capture 2 RCT with two Italy Results at recruitment All ages: Median age: 42 years
recruitment phases, 49,196 randomized Ethnicity: NR
113
Ronco 2010 Positive for high each with two rounds of Nine organized cervical CIN2+ (calc): eligible Education: NR
oncogenic risk viruses screening screening programs IG: 137/24,661 = 0.6% 24,661 IG Income: NR
209
Ronco 2008 (HPV types 16, 18, 31, CG: 55/24,535 = 0.2% 24,535 CG HIV+: NR
33, 35, 39, 45, 51, 52, Phase 2 reported here Women presenting for Other STIs: NR
112
Ronco 2006 56, 58, 59, and 68) at (primary HPV testing), routine screening CIN3+ (calc): Age 25-34: Smoking: NR
≥1 pg/mL Phase 1 reported below IG: 59/24,661 = 0.2% 13,725 randomized
210
Ronco 2007 with HPV cotesting CG: 26/24,535 = 0.1% eligible
Results for 2 pg/mL 6,937 IG
211
Ronco 2007 cutoff also assessed Study arms: 6,788 CG
(not reported here)
Round 1: Age 35-60:
CC: plastic Ayre’s IG: 35,471 randomized
spatula and a cytobrush HPV (HC2) alone eligible
17,724 IG
HC2: Digene CG: CC 17,747 CG
Corporation cervical
sampler (a broomlike Round 2: CC for all Inclusion: Age 25-60
device) women
Exclusion: Pregnant,
hysterectomy, or
treated for CIN in last
five years

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID
Application of reference standard
Quality rating Funding source Yield Insufficient samples
(histologic verification)
Applicability
NTCC Phase II Suspicious areas identified by European Union, Italian Test positivity (at recruitment, varied by site): HC2: no valid test for
colposcopy were biopsied Ministry of Health, All ages (calc): 96/24,661 = 0.4%
113
Ronco 2010 Special Project IG (HPV+): 1,936/24,661 = 7.9%
Cross-sectional data at Phase 2 “Oncology,” Compagnia CG (ASCUS+): 825/24,535 = 4.6% CC: 442/24,535 = 1.8%
209
Ronco 2008 recruitment: di S. Paolo FIRMS, and CG (LSIL+): 318/24,535 = 1.3% with unsatisfactory
participating Italian Age 25-34 (calc): result
112
Ronco 2006 Referral to colposcopy (calc): regions IG (HPV+): 907/6,937 = 13.1%
IG: for HPV+; 1,936/24,661 = 7.9% CG (ASCUS+): 270/6,788 = 4.0%
210
Ronco 2007 referred CG (LSIL+): 136/6,788 = 2.0%
Age 35-60 (calc):
211
Ronco 2007 CG: for ASC-US+ at seven centers, IG (HPV+): 1,029/17,724 = 5.8%
LSIL+ at two centers; 679/24,535 = 2.8% CG (ASCUS+): 555/17,747 = 3.1%
Fair referred CG (LSIL+): 182/17,747 = 1.0%
Concordance: NR
Fair Compliance with colposcopy (calc):
IG: 1,813/1,936 = 93.6% complied with Referred to colposcopy (at recruitment):
referral All ages (calc)
IG: 1,936/24,661 =7.9%
CG: 615/679 = 90.6% complied CG: 679/24,535 = 2.8%
Age 25-34 (calc)
Cumulative Phase 2 colposcopy data: IG: 907/6,937 = 13.1%
NR CG: 244/6,788 = 3.6%
Age 35-60 (calc)
IG: 1,029/17,724 =5.8%
CG: 435/17,747 = 2.5%
Compliance with colposcopy (at recruitment):
All ages (calc)
IG: 1,813/1,936 =93.6%
CG: 615/679 = 90.6%

Invasive cancers (ICC-AD), n:

All ages
R1: IG: 5, CG: 2
R2: IG: 0, CG: 3
C: IG: 5, CG: 5
Age 25-34 (author provided data)
R1: IG: 1, CG: 0
R2: IG: 0, CG: 0
C: IG: 1, CG:05

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID
Application of reference standard
Quality rating Funding source Yield Insufficient samples
(histologic verification)
Applicability
Age 35-60 (author provided data)
R1: IG: 4, CG: 2
R2: IG: 0, CG: 3
C: IG: 4, CG: 5

Relative Positive
Relative Detection Ratio Relative False Positive Positive Predictive
Study ID Detection of CIN2+/CIN3+ Predictive Value
(95% CI) Proportion (95% CI) Value (95% CI)
(95% CI)
NTCC Cross-sectional results at Phase 2 Cross-sectional results at Phase 2 Cross-sectional results at Cross-sectional Cross-sectional
Phase II recruitment (per 1000): recruitment: Phase 2 recruitment results at Phase 2 results at Phase 2
(calc): recruitment: recruitment:
Ronco Age 25-34: HPV ≥ 1 pg/mL vs. CC ≥ ASCUS
113
2010 HPV ≥ 1 pg/mL vs. CC ≥ (95% CI NR) HPV ≥ 1 pg/mL vs.
CIN2+† Age 25-34: ASCUS CC ≥ ASCUS
Ronco IG (HPV ≥ 1 pg/mL): 9.80
209
2008 CG (ASCUS+): 2.80 CIN2+† Age 25-34: Age 25-34: Age 25-34:
3.50 (2.11-5.82)
Ronco CIN3+‡ CIN2+† CIN2+† CIN2+†
112
2006 IG (HPV ≥ 1 pg/mL): 3.46 CIN3+‡ (782/6,937)/(191/6,788) IG (HPV ≥ 1 pg/mL): 0.89 (0.55-1.44)
CG (ASCUS+): 1.33 2.61 (1.21-5.61) = 4.01 (3.43-4.68) 8.0%
Ronco CG (ASCUS+): 9.0%
210
2007 Age 35-60: Age 35-60:

Ronco CIN2+† CIN2+†

211
2007 IG (HPV ≥ 1 pg/mL): 3.89 1.92 (1.28–2.87)
CG (ASCUS+): 2.03
CIN3+‡
CIN3+‡ 2.06 (1.16-3.68)
IG (HPV ≥ 1 pg/mL): 1.97
CG (ASCUS+):0.96

Cumulative Phase 2 results (calc): Cumulative Phase 2 results:

HPV group vs. cytology group
Age 25-34:
Age 25-34:
CIN2+ (author provided data)

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative Positive
Relative Detection Ratio Relative False Positive Positive Predictive
Study ID Detection of CIN2+/CIN3+ Predictive Value
(95% CI) Proportion (95% CI) Value (95% CI)
(95% CI)
Round 1 CIN2+ (author provided data)
IG: 116/6,937 = 1.67% Round 1
CG: 25/6,788 = 0.37% 4.54 (2.95-6.99)
Round 2 Round 2
IG: 7/6,577 = 0.11% 0.40 (0.17-0.95)
CG: 18/6,714 = 0.27% Both rounds
Both rounds 2.80 (1.98-3.95)
IG: 123/6,937 = 1.77%
CG: 43/6,788 = 0.63%

Relative Positive
Relative Detection Ratio Relative False Positive Positive Predictive
Study ID Detection of CIN2+/CIN3+ Predictive Value
(95% CI) Proportion (95% CI) Value (95% CI)
(95% CI)
NTCC CIN3+ (author provided data) CIN3+ (author provided data) CIN3+‡ CIN3+‡ CIN3+‡
Phase II Round 1 Round 1 (826/6,937)/(201/6,788) IG (HPV ≥ 1 pg/mL): 0.66 (0.31-1.40)
IG: 45/6,937 = 0.65% 4.00 (2.07-7.73) = 4.02 (3.46-4.67) 2.8%
Ronco CG: 11/6,788 = 0.16% Round 2 CG (ASCUS+): 4.3%
113
2010 Round 2 0.20 (0.05-0.93)
IG: 2/6,577 = 0.03% Both rounds
Ronco CG: 10/6,714 = 0.15% 2.19 (1.31-3.66)
209
2008 Both rounds
IG: 47/6,937 = 0.68%
Ronco CG: 21/6,788 = 0.31%
112
2006
Age 35-60: Age 35-60: Age 35-60: Age 35-60: Age 35-60:
Ronco
210
2007 CIN2+ (author provided data) CIN2+ (author provided data) CIN2+† CIN2+† CIN2+†
Round 1 Round 1 (893/17,724)/(365/17,747) IG (HPV ≥ 1 pg/mL): 0.80 (0.55-1.18)
Ronco IG: 105/17,724 = 0.58% 2.13 (1.51-3.00) = 2.45 (2.17-2.76) 7.2%
211
2007 CG: 48/17,747 = 0.27% Round 2 CG (ASCUS+): 8.9%
Round 2 0.25 (0.10-0.68)
IG: 5/17,401 = 0.03% Both rounds
CG: 20/17,658 = 0.11% 1.58 (1.16-2.13)
Both rounds
IG: 107/17,724 = 0.60%
CG: 68/17,747 = 0.38%
CIN3+‡
CIN3+ (author provided data) CIN3+ (author provided data) (927/17,724)/(384/17,747) CIN3+‡ CIN3+‡
Round 1 Round 1 = 2.42 (2.15-2.72) IG (HPV ≥ 1 pg/mL): 0.86 (0.49-1.52)
IG: 52/17,724 = 0.29% 2.37 (1.44-3.89) 3.6%

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative Positive
Relative Detection Ratio Relative False Positive Positive Predictive
Study ID Detection of CIN2+/CIN3+ Predictive Value
(95% CI) Proportion (95% CI) Value (95% CI)
(95% CI)
CG: 22/17,747 = 0.12% Round 2 Cumulative Phase 2 CG (ASCUS+): 4.2% Cumulative Phase 2
Round 2 0.23 (0.07-0.82) results: results:
IG: 3/17,401 = 0.02% Both rounds Cumulative Phase 2
CG: 13/17,658 = 0.07% 1.57 (1.03-2.54) Neither PPV nor the results: Neither PPV nor the
Both rounds number of participants with number of
IG: 55/17,724 = 0.31% false positive results Neither PPV nor the participants with false
CG: 35/17,747 = 0.20% reported number of participants positive results
with false positive reported
results reported

Primary
screening test Number of
Application of
evaluated patients
Prevalence of Patient reference standard Funding
Study ID Screening Study design Setting
disease character-istics (histologic source
cutoff Inclusion &
verification)
Collection exclusion criteria
method
Sankaran- Hybrid Capture 2 Cluster randomized India CIN2 or 3: 131,806 women Mean age Women with positive Bill & Melinda
arayanan trial, 497 villages in HC2: 245/27,192 eligible and (range): screening tests Gates
118
2009 Positive for high 52 clusters, Rural = 0.9% randomized (52 HC2: 39 (38-40) evaluated with Foundation
oncogenic risk assigned to four Osmanabad CC: 262/25,549 clusters) CC: 39 (39-40) colposcopy and
viruses (HPV groups of 13 district = 1.0% Control: 40 (39- directed biopsy of
types 16, 18, 31, clusters each 110,994 women 41) abnormal areas.
33, 35, 39, 45, (HPV, cytology, Unscreened Cancer: completed Ethnicity: NR
51, 52, 56, 58, VIA, control) population HC2: 73/27,192 screening or were Education: Baseline colposcopy
59, 68) at ≥1.0 (except for = 0.3% assigned to control (average data (within 3 months
pg/mL Study reports eight CC: 83/25,549 = group: proportion in of screening):
baseline data individuals) 0.3% clusters with no
HC2: Collection (screening test HC2: 27,192 formal Colposcopy rates
device NR results, colposcopy CC: 25,549 education]) among women
rates, and CIN and VIA: 26,765 HC2: 70% screened (calc):
CC: Cervex baseline cancer Control: 31,488 CC: 73% HC2: 2,505/27,192 =
brushes outcomes) Control: 71% 9.2%
collected within 3 Inclusion: Ages Income: NR CC: 1,570/25,549 =
Nurse-midwives months of 30-59 years, HIV+: NR 6.1%
trained using screening, and “healthy,” currently Other STIs: NR
IARC manuals in cumulative data or previously Smoking: NR Colposcopy rates
the collection of over 8 years for married, intact among women with
cervical cells for cancer outcomes uterus, living in positive screening
HPV and only study cluster tests:

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

cytologic testing HC2: 2,505/2,812 =

Exclusion: 89.1%
Pregnant, uterine CC: 1,570/1,787 =
prolapse, history of 87.9%
cervical cancer

Study ID Relative Relative False

Positive predictive Relative positive
Insufficient Detection of Detection Positive
Applicability Yield value predictive value
Quality samples CIN2+/CIN3+ Ratio Proportion
(95% CI) (95% CI)
rating (95% CI) (95% CI)

Sankarana- Fair to Poor Test positivity NR Baseline HC2 vs. CC HC2 vs. CC Baseline PPV for HC2 vs. CC
rayanan (baseline screening): detection of CIN2+ (CIs calc):
118
2009 Unscreened HC2: 2,812/27,192 = CIN2+ (calc): CIN2+ CIN2+ (baseline, HC2: 318/2,812 = CIN2+ (baseline,
population in 10.3% HC2: (baseline, calc): 11.3% (10.2-12.5) calc): 11.3%/19.3%
Fair rural India CC: 1,787/25,549 = 318/27,192 = calc): (2,187/27,192)/ CC: 345/1,787 = = 0.59 (0.51-0.67)
7.0% 1.17% (1.05- 1.17%/1.35 (1,225/25,549) 19.3% (17.5-21.2)
3 weeks' to 3 Concordance: NR 1.30) % = 0.87 = 1.68 (1.57-1.80)
months' special CC: (0.74-1.01) Denominators include
training as part Colposcopy rates 345/25,549 = all participants with
of study for among women 1.35% (1.21- positive screening
nurse-midwives, screened 1.50) tests, though not all of
doctors, and R1 (calc): these underwent
laboratory IG: 2,505/27,192 = 9.2% Cumulative colposcopy
technicians, plus CG: 1,570/25,549 = incidence rate
periodic 6.1% of all cervical
refresher cancer (per
courses Colposcopy rates 100,000 p/y)
among women with HC2 47.4
positive screening CC 60.7
tests:
R1: Stage II or
IG: 2,505/2,812 = 89.1% higher
CG: 1,570/1,787 = HC2 14.5
87.9% CC 23.2

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated
Number of patients
Patient
Study ID Study design Setting Prevalence of disease
Screening cutoff characteristics
Inclusion & exclusion criteria
Collection method
HPV Testing with Cytology Triage of Positive HPV (Reflex Cytology): RCTs reporting relative test performance measures
Finnish Trial Hybrid Capture 2 RCT with two Finland CIN2+ (calc): 108,425 randomized Mean Age:
arms: IG: 146/35,837 = 0.41% 71,337 attended screening IG: 45.2 years
Kotaniemi-Talonen Positive for high Nine municipalities CG: 108/35,500 = 0.30% IG: 35,837 CG: 45.3 years
120
2008 oncogenic risk viruses IG: HPV within the Finnish CG: 35,500 Ethnicity: NR
(HPV types 16, 18, 31, screening with cervical screening CIN3+ (calc): Education: NR
212
Anttila 2006 33, 35, 39, 45, 51, 52, cytology triage, program IG: 42/35,837 = 0.12% Extended follow-up: HIV+: NR
56, 58, 59, and 68) at split sample CG: 34/35,500 = 0.10% Other STIs: NR
Kotaniemi-Talonen ≥1 pg/mL (smears Data from eight 58,282 randomized Smoking: NR
213
2005 analyzed only for municipalities 38,670 attended screening
HC2: Cervical sampler women testing included in 2010 IG: 19,449
133
Leinonen 2009 brush from HC2 test positive for HPV) report of extended CG: 19,221
kit Round 1 follow-up
134
Anttila 2010 CC: Ayre spatula and CG: (five years Inclusion:
cytobrush Conventional maximum) Aged 25-65 years
cytology alone Extended follow-up:
Women presenting Aged 30-64 years
for routine
screening Exclusion: NR

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Application of
reference standard Quality Insufficient
Study ID Funding source Applicability Yield
(histologic rating samples
verification)
Finnish Trial Referred for colposcopy European Union Fair Fair Test positivity rate (calc) IG:
action program All ages: HPV not available
Kotaniemi-Talonen IG: 424/35,837=1.2% Europe Against IG (HPV+): 2,628/35,837 = 7.3% for 2,737/35,837 =
120
2008 CG:420/35,500=1.2% Cancer, IG (LSIL+): 424/35,387 = 1.2% 7.6%, mostly
Academy of CG (LSIL+): 420/35,500 = 1.2% because of
212
Anttila 2006 Finland, and Women < 35 technical reasons
Finnish Cancer IG (HPV+): 983/5,869 = 16.7% (e.g. proper brush
Kotaniemi-Talonen Organizations IG (LSIL+): 166/5,869 = 2.8% or tube missing)
213
2005 CG (LSIL+): 127/5,711 = 2.2%
HPV tests Women 35+ Cytology
133
Leinonen 2009 provided at IG (HPV+): 1,645/29,968 = 5.5% uninterpretable for
reduced price by IG (LSIL+): 258/29,968 = 0.9% 16/5,363 = 0.3%
134
Anttila 2010 Digene CG (LSIL+): 293/29,789 = 1.0% of those with
Corporation primary or triage
CC (ASC-H or LSIL+) cytology (calc)
IG: 7.9%
CG: 1.2% CG: 79/35,475 =
0.2% with
Concordance uninterpretable
NR cytology (calc)

Colposcopy Referrals
All ages:
IG: 424/35,837= 1.2%
CG: 420/35,500=1.2%
Women < 35 (calc)
IG: 166/5,869 = 2.8%
CG: 127/5,711 = 2.2%
Women 35+ (calc)
IG: 258/29,968 = 0.9%
CG: 293/29,786 = 1.0%

Invasive cancers, n:
R1: IG: 6, CG: 4
Extended R1 Followup:
ICC: IG: 6, CG: 3
ACIS: IG: 5, CG : 3

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative Positive Relative Risk of

Relative Detection Ratio Positive Predictive
Study ID Detection of CIN Predictive Value Colposcopy Referral Comments
(95% CI) Value (95% CI)
(95% CI) (95% CI)
Finnish Trial CIN2+ (calc): HPV & CC vs. CC: CIN2+ CIN2+ HPV & CC vs. CC:
IG: 146/35,837 = 0.41% CIN2+ (calc): HPV + CC triage: HPV + CC triage: 1.00 (0.87-1.14)
Kotaniemi-Talonen CG: 108/35,500 = 0.30% 0.41%/0.30% = 1.34 34.4% (29.9-39.2) 1.34 (1.04-1.72)
120
2008 (1.04-1.72) HPV alone: 0.21
CIN3+ (calc): HPV alone: 5.6% (0.16-0.27)
212
Anttila 2006 IG: 42/35,837 = 0.12% Women < 35 (4.7-6.5) CC: 1.00 (Ref)
CG: 34/35,500 = 0.10% 1.29 (0.88-1.89)
Kotaniemi-Talonen CC: 25.7% (21.6- RFPP
213
2005 Women 35+ 30.2) R1:
Extended follow-up:
1.36 (0.98-1.89) IG: 0.88
133
Leinonen 2009 CIN3+ (0.75-1.04)
CIN3+ (calc):
CIN3+: 1.22 (0.78-1.92) HPV + CC triage: CG: 1.00 (Ref)
134 IG: 59/19,449 = 0.30%
Anttila 2010 9.9% (7.2-13.2)
CG: 33/19,221 = 0.17%
Women < 35 (calc) Women aged 25-34
0.88 (0.38-2.08) HPV alone: 1.6% IG: 1.26 (0.95-1.69)
(1.1-2.2) CG: 1.00 (Ref)
Women 35+ (calc)
1.38 (0.81-2.36) CC: 8.1% (5.7-11.1) CIN3+
HPV + CC triage:
Extended follow-up: Extended follow-up: 1.22 (0.78-1.92)
HPV alone: 0.19
CIN3+: CIN3+ (calc) (0.12-0.30)
1.77 (1.16-2.74) HPV + CC triage: CC: 1.00 (Ref)
59/1,354 = 4.36%
(3.4-5.6) RFPP
IG:0.98(0.85-1.13)
CC: 33/1,125 = CG: 1.00 (NR)
2.34% (2.1-4.1)
IG:
Aged 35-44
0.98(0.77-1.26)
45-54
0.57(0.40-0.82)
≥55
0.88(0.61-1.26)

CG: 1.00 (Ref)

Extended follow-up:

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative Positive Relative Risk of

Relative Detection Ratio Positive Predictive
Study ID Detection of CIN Predictive Value Colposcopy Referral Comments
(95% CI) Value (95% CI)
(95% CI) (95% CI)
CIN3+ (calc)
HPV + CC triage:
4.21%/2.31% - 1.49
(0.98-2.26)
CC: 1.00 (Ref)

RFPP (calc)
IG: (1,297/19,449)/
(1,099/19,221) = 1.17
(1.08-1.27)
CG: 1.00 (Ref)

Primary screening test

evaluated
Number of patients
Study Patient
Study ID Setting Prevalence of disease
Screening cutoff design characteristics
Inclusion & exclusion criteria
Collection method
Combination HPV and Cytology Testing (Co-Testing): Studies reporting absolute test performance measures
123
Petry 2003 Hybrid Capture 2 Consecutive Germany All women (calc): 8,466 recruited Mean Age: 42.7
series 8,101 met inclusion criteria Age 30-60 years:
Positive for high 28 urban, suburban CIN2+: 46/7,908 = 0.6% 8,083 with cytology and HC2 94.6%
oncogenic risk viruses HC2 sample or rural, office-based CIN3+: 37/7,908 = 0.5% results Ethnicity: NR
(HPV types 16, 18, 31, collected gynacological (includes 1 case of 7,908 included in test Education: NR
33, 35, 39, 45, 51, 52, following CC practices from invasive cervical performance analysis (excludes Income: NR
56, 58, 59, and 68) at ≥1 sample at Hannover and carcinoma) 175 with positive test who HIV+: NR
pg/mL same visit Tuebingen and the refused colposcopy) Other STIs: NR
surrounding areas Women with Smoking: NR
HC2: Digene cervical colposcopy/biopsy Inclusion: Attending for routine
sample device Women attending results: annual screening
CC: Followed routine routine cervical
procedure in each cancer screening CIN2+: 46/536 = 8.6% Exclusion: Genital warts (43),
gynacologocal practice CIN3+: 37/536 = 6.9% history of conization or
(most, but not all, used hysterectomy (13), pregnant
cotton-tipped swab) (11), abnormal cytology within 1
year of study entry (8), under
age 30 (167), no written consent
(123)

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Application of
Quality Insufficient
Study ID reference standard Funding source Applicability Yield
rating samples
(histologic verification)
123
Petry 2003 Colposcopy and punch Cancer Society of Fair Good Test Positivity Rate NR
biopsy of any regions Lower Saxony, HC2: 6.4%
suspicious for CIN in Hannover, CC (PapIIw+): 3.1%
women with any degree Germany, the Ria-
of cytologic abnormality Freifrau von Concordance (calc)
and/or positive for HPV Fritsch Stiftung, 11.7% of HPV+ samples were PapIIw+
test and a random and an 24.3% of PapIIw+ samples were HPV+
sample of 3.4% of unconditional
women who were formal grant from % HPV+ by CC diagnosis:
negative on both DIGENE PapIV+V: 100%
screening tests corporation to the PapIIId: 50.8%
University of PapIII: 21.4%
Hannover and PapIIw: 10.8%
Tuebingen Negative: 5.9%

HPV/CC categories (calc):

HPV-CC-: 91.2%
HPV-CC+: 2.4%
HPV+CC+: 0.8%
HPV+CC-: 5.7%

Positive predictive Negative predictive

Sensitivity Specificity False positive rate Other performance
Study ID value value
(95% CI) (95% CI) (95% CI) characteristics
(95% CI) (95% CI)
123
Petry 2003 Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+: Detection of CIN2+ % referred to
CC (PapIIw+): 20/46 = CC (PapIIw+): CC (PapIIw+): 11.4 CC (PapIIw+): 99.7 (98.7- (calc): colposcopy:
43.5 (30.0-58.0) 7,706/7,862 = 98.0 (96.7- (7.5-16.9) 99.9) CC (PapIIw+): 2.0 CC: CIN2+ 2.2, CIN3+
HC2 and CC: 100.0 98.8) HC2 and CC: 8.6 HC2 and CC: 100.0 (98.8- (1.2-3.3) 2.2
(93.7-100) HC2 and CC: 93.8 (91.8- (6.5-11.3) 100) HC2 and CC: 6.2 HC2 and CC: CIN2+
95.3) (4.7-9.2) 6.8, CIN3+ 5.6
Detection of CIN3+: Detection of CIN3+: Detection of CIN3+:
CC: 17/37 = 46.0 (30.8- Detection of CIN3+: CC: 9.7 (6.1-15) CC: 99.7 (98.8-99.9) Detection of CIN3+ Quality control:
61.9) CC: 7,712/7,871 = 98.0 HC2 and CC HC2 and CC (PapIII+): (calc): 719/925 (77.7%) of CC
HC2 and CC (PapIII+): (96.7-98.8) (PapIII+): 8.4 (6.2- 100.0 (99.1-100) CC: 2.0 (1.2-3.3) samples reviewed by
100.0 (93.7-100) HC2 and CC: 94.9 (93.1- 11.4) HC2 and CC an independent expert
96.2) (PapIII+): 5.1(3.8-6.9) were in agreement
96.6% of 600 HC2
samples retested were
in agreement (κ 0.75)

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated Number of patients
Study ID Study design Setting Prevalence of disease Patient characteristics
Screening cutoff Inclusion & exclusion
criteria
Collection method
CCCaST Hybrid Capture 2 RCT with 2 arms: Canada All women (calc): 14,953 assessed for Age
Focus on HPV: HC2 eligibility 30-39: 38.5%
121
Mayrand 2007 Positive for high followed by CC 30 selected medical CIN2+ 40-49: 35.0%
oncogenic risk viruses practices in Montreal Conservative Case 10,154 randomly 50-59: 20.4%
126
Mayrand 2006 (HPV types 16, 18, 31, Focus on Pap: CC and surrounding Definition*: 41/10,154 = assigned to screening 60-69: 6.1%
33, 35, 39, 45, 51, 52, followed by HC2 municipalities (province 0.4% 5,059 assigned to Ethnicity (10,019
56, 58, 59, and 68) at of Quebec) and St. Focus on Pap group participants)
≥1 pg/mL Both screening tests John's (province of Liberal Case Definition*: 5,095 assigned to French Canadian: 36.7%
included in each arm, Newfoundland) 54/10,154 = 0.5% Focus on HPV group English Canadian:
HC2: Digene cervical but order of collection 56.9%
sampler kit was randomized. Tests Physicians recruited Women with 9,977 received Other: 6.4%
CC: Per protocol at performed sequentially from medical practices colposcopy/biopsy assigned intervention Education (10,064)
each medical practice at same visit identified by cytology results: 5,020 in Focus on Pap Elementary school:
laboratories as active in group 10.3%
cervical cancer CIN2+ 4,957 in Focus on HPV High school: 22.7%
screeningWomen Conservative Case group Junior college: 29.0%
attending routine Definition*: 41/1,365 = University: 38.0%
cervical cancer 3.0% Inclusion: Age 30-69 Income: NR
screening HIV+: NR
Liberal Case Definition*: Exclusion: Attending Other STIs: NR
54/1,365 = 4.0% colposcopy clinic for Smoking: NR
evaluation, treatment
or follow up of a
cervical lesion, without
a cervix, pregnant,
previous history of
invasive cervical
cancer, received
cytology test within 12
months

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID
Application of
reference standard Funding Insufficient Sensitivity Specificity
Quality rating Yield
(histologic source samples (95% CI) (95% CI)
verification)
Applicability
CCCaST Colposcopy and Canadian Test Positivity Rate HC2: NR Comparison of Screening Comparison of Screening
biopsy in 90.9% Institutes of HC2: CC: 1.4% in Approaches Using Combined Approaches Using Combined
Mayrand (723/795) of women Health 6.3% in Focus on both arms Groups (n = 9,959 women in two Groups (n = 9,959 women in two
121
2007 positive for at least Research, HPV groups who had available HC2 and groups who had available HC2
one test and 7.1% Merck Frosst 5.8% in Focus on Pap CC results) and CC results)
Mayrand (665/9,359) random Canada, Detection of CIN2+: Detection of CIN2+:
126
2006 sample of women National CC: Conservative Case Definition* Conservative Case Definition*
negative for both tests Cancer 2.7% in Focus on (95% CI NR) (95% CI NR)
Fair Institute of HPV CC (ASC-US+): 56.4 CC (ASC-US+): 97.3
Canada, 3.0% in Focus on Pap CC (LSIL+): 42.2 CC (LSIL+): 99.1
Good Fonds de la HC2 and Pap: 100.0 HC2 and Pap: 92.5
Recherche en Concordance: NR
Santé due All estimates corrected for All estimates corrected for
Québec verification bias verification bias

Positive predictive value Negative predictive value Other performance

Study ID False positive rate Comments
(95% CI) (95% CI) characteristics

CCCaST Comparison of Screening Comparison of Screening Comparison of Screening Test Performance *According to the
Approaches Using Combined Groups Approaches Using Combined Groups Approaches Using Combined by Sampling Order conservative
Mayrand (n = 9,959 women in two groups who (n = 9,959 women in two groups who Groups (n = 9,959 women in two Performance of HC2 definition, cases
121
2007 had available HC2 and CC results) had available HC2 and CC results) groups who had available HC2 and and CC not were considered
CC results) influenced by order only if confirmed
Mayrand Detection of CIN2+: Detection of CIN2+: of specimen on the LEEP
126
2006 Conservative Case Definition* Conservative Case Definition* Detection of CIN2+: collection (i.e., first or specimen or in the
(95% CI NR) (95% CI NR) Conservative Case Definition* second), as judged confirmatory
CC (ASC-US+): 8.5 CC (ASC-US+): 99.8 CC (ASC-US+): 2.7 by test positivity, biopsy when
CC (LSIL+): 17.5 CC (LSIL+): 99.7 CC (LSIL+): 0.9 unsatisfactory ablative treatment
HC2 and Pap: 5.5 HC2 and Pap: 100.0 HC2 and Pap: 7.5 smears or those was used. The
showing ASC-US, liberal definition
All estimates corrected for verification All estimates corrected for verification All estimates corrected for viral load, and includes all cases
bias bias verification bias sensitivity or of CIN2-3,
specificity adenocarcinoma
in situ, or cervical
Referrals for cancers confirmed

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Colposcopy(using by histologic
combined groups) examination of
any of the
Conservative Case ectocervical or
Definition* endocervical
CC (ASC-US+): 2.9 biopsy specimens.
CC (LSIL+): 1.0
HC2 and Pap: 7.9

All estimates
corrected for
verification bias

Primary
screening test
evaluated
Number of patients Application of
Prevalence of Patient reference standard
Study ID Screening Study design Setting Funding source
disease Inclusion & characteristics (histologic
cutoff
exclusion criteria verification)
Collection
method
Combination HPV and Cytology Testing (Co-Testing): RCTs reporting relative test performance measures
NTCC Hybrid Capture RCT with two Italy Results at Phase 1 33,364 randomized Median age at Suspicious areas European Union,
Phase I 2 recruitment recruitment: (age ≥ 35) recruitment: 45 identified by Italian Ministry of
phases, each with Nine 16,706 IG Ethnicity: NR colposcopy were Health, Special
Ronco Positive for two rounds of organized CIN2+ (calc) 16,658 CG Education: NR biopsied Project “Oncology,”
112
2006 high oncogenic screening cervical IG Income: NR Referral to Compagnia di S.
risk viruses screening 75/16,706 = 0.4% 32,638 completed HIV+: NR colposcopy (women Paolo FIRMS, and
Ronco (HPV types 16, Phase 1 programs baseline testing Other STIs: NR with complete participating Italian
210
2007 18, 31, 33, 35, (cotesting) CG 16,255 IG Smoking: NR baseline testing): regions
39, 45, 51, 52, reported here, Women 51/16,658 = 0.3% 16,383 CG
Ronco 56, 58, 59, and Phase 2 reported presenting IG: ASC-US+ or
211
2007 68) at ≥1 above with for routine CIN3+ (calc) Inclusion: Age 35- HPV+; 1,730/16,255
pg/mL primary HPV screening IG 60 = 10.6%
Ronco testing 39/16,706 = 0.2%
113
2010 HC2, LBC Women age 25-34 CG: ASC-US+ at
(ThinPrep) & Study arms: CG years also included, seven centers
CC: plastic 31/16,658 = 0.2% but protocol for (72%), LSIL+ at two
Ayre’s spatula Round 1: colposcopy referral centers (28%);
and a IG: in the intervention 495/16,383 = 3.0%
cytobrush HPV (HC2) & LBC group differed for (calc)
this age group in Compliance with

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

HC2 assay Phase 1 colposcopy (women

performed on with complete
residual cytology Exclusion: baseline testing)
sample Pregnant, (calc):
hysterectomy, or IG: 1,625/1,730 =
CG: CC treated for CIN in 93.9%
last five years CG: 449/495 =
Round 2: CC for 90.7%
all women

Study ID
Insufficient Relative Detection Ratio Relative positive predictive
Quality rating Yield Detection of CIN2+/CIN3+
samples (95% CI) value (95% CI)
Applicability
NTCC Test Positivity Rate Results at Cross-sectional results at Phase 1 Cross-sectional results at Cross-sectional results at
Phase I (at recruitment, Phase 1 recruitment (per 1000): Phase 1 recruitment: Phase 1 recruitment:
varied by site and recruitment:
112
Ronco 2006 age) CIN2+† CIN2+† CIN2+†
≥1 IG IG IG
210
Ronco 2007 All ages (calc): Unsatisfactory LBC (ASC-US+) or HPV+: 4.49 LBC (ASC-US+) or HPV+: LBC (ASC-US+) or HPV+: 0.40
IG(HPV+): smear HPV: 4.37 1.47 (1.03-2.09) (0.23-0.66)
211
Ronco 2007 2,021/22,708 = 8.9% IG: 2.5% LBC (ASC-US+): 3.23 LBC (ASC-US+) or HPV+ LBC (ASC-US+) or HPV+
CG: 3.7% LBC (LSIL+): 2.39 (restricted to centers with (restricted to centers with ASC-
113
Ronco 2010 IG (ASC-US+): p<0.001 LBC (ASC-US+) and HPV+: 3.11 ASC-US+ referral criteria)*: US+ referral criteria)*: 0.43
1435/22,708 = 6.3% 1.44 HPV: 0.58 (0.33-0.98)
Fair No valid HPV CG HPV: 1.43 (1.00-2.04) LBC (ASC-US+): 0.57 (0.39-
CG (ASC-US+): test due to ASC-US+: 3.06 LBC (ASC-US+): 1.06 (0.72- 0.82)
Fair 855/22,466=3.8% insufficient LSIL+: 2.52 1.55) LBC (LSIL+): 1.11 (0.75-1.64)
material (calc) LBC (LSIL+): 0.78 (0.52-1.18) LBC (ASC-US+) and HPV+:
CG (LSIL+): 14/16,706 = CIN3+‡ LBC (ASC-US+) and HPV+: 1.66 (1.16-2.36)
341/22,466 = 1.5% 0.08% IG 1.02 (0.69-1.50)
LBC (ASC-US+) or HPV+: 2.33 CG
Age 25-34 (calc): HPV: 2.27 CG ASC-US+: 1.00 (referent)
IG (ASC-US+): LBC (ASC-US+): 1.86 ASC-US+: 1.00 (referent) LSIL+: 1.88 (1.60-2.06)
530/6,002 = 8.8% LBC (LSIL+): 1.50 LSIL+: 0.82 (0.69-0.95)
LBC (ASC-US+) and HPV+: 1.80 CIN3+‡
CG (ASC-US+): CIN3+‡ IG
261/5,808 = 4.5% CG IG LBC (ASC-US+) or HPV+: 0.34
ASC-US+: 1.86 LBC (ASC-US+) or HPV+: (0.21-0.54)
CG (LSIL+): LSIL+: 1.56 1.25 (0.78-2.01) LBC (ASC-US+) or HPV+
129/5,808 = 2.2% LBC (ASC-US+) or HPV+ (restricted to centers with ASC-
Cumulative Phase 1 results (calc): (restricted to centers with US+ referral criteria)*: 0.38
Age 35-60: ASC-US+ referral criteria)*: HPV: 0.50 (0.32-0.79)
IG (ASC-US+ or All ages 1.28 LBC (ASC-US+): 0.54 (0.33-
HPV+) (calc): CIN3+(author provided data) HPV: 1.22 (0.76-1.96) 0.87)

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID
Insufficient Relative Detection Ratio Relative positive predictive
Quality rating Yield Detection of CIN2+/CIN3+
samples (95% CI) value (95% CI)
Applicability
1,789/16,706 = R1: LBC (ASC-US+): 1.00 (0.61- LBC (LSIL+): 1.14 (0.69-1.90)
10.7% IG: 75/22,708 = 0.33% (0.26-0.41) 1.64) LBC (ASC-US+) and HPV+:
CG: 58/22,466 = 0.26% (0.20-0.33) LBC (LSIL+): 0.80 (0.48-1.36) 1.57 (0.97-2.54)
CG (ASC-US+): R2: LBC (ASC-US+) and HPV+:
594/16,658 = 3.6% IG: 13/22,093 = 0.06% (0.03-0.10) 0.96 (0.58-1.59) CG
CG: 19/22,330 = 0.09% (0.05-0.13) ASC-US+: 1.00 (referent)
CG (LSIL+)(calc): C: CG LSIL+: 1.92 (1.53-2.13)
212/16,658 = 1.3% IG: 88/22,708 = 0.39% (0.31-0.48) ASC-US+: 1.00 (referent)
CG: 77/22,466 = 0.34% (0.27-0.43) LSIL+: 0.84 (0.66-0.95) *data received from author,
Concordance (calc): 95% CI not provided
HPV+ samples that CIN2+(author provided data) *data received from author,
were ASC-US+: R1: 95% CI not provided Cumulative Phase 1 results:
300/1,185 = 25.3% IG: 187/22,708 = 0.82% (0.71-0.95)
CG: 99/22,466 = 0.44% (0.36-0.54) Cumulative Phase 1 results: Neither PPV nor the number of
HPV+ samples that R2: participants with false positive
were LSIL+: IG: 22/22,093 = 0.09% (0.06-0.15) HPV group vs. cytology group results reported
167/1,185 = 14.1% CG: 34/22,330 = 0.15% (0.11-0.21)
C: CIN2+(author provided data)
ASC-US+ samples IG: 209/22,708 = 0.92%(0.80-1.05)
that were HPV+: CG: 133/22,466 = 0.59%(0.50-0.70) All ages (calc)
300/894 = 33.6% R1: 1.87 (1.47-2.38)
Women 35-60: R2: 0.65 (0.38-1.12)
LSIL+ samples that CIN3+(author provided data) C: 1.55 (1.25-1.93)
were HPV+: 167/345 Round 1
= 48.4% IG*: 52/16,706 = 0.31% Women 35-60 (from author)
CG: 33/16,658 = 0.20% R1: 1.78 (1.30-2.44)
Referred to R2: 0.59 (0.28-1.24)
colposcopy (calc): Round 2 C: 1.50 (1.13-1.98)
IG*: 5/16,332 = 0.03%
All ages: CG: 11/16,561 = 0.07% Women 25-34 (from author)
IG: 2,485/22,708 = R1: 1.99 (1.35-2.92)
10.9% Both rounds R2: 0.73 (0.34-1.60)
CG: 735/22,466 = IG*: 57/16,706 = 0.34% C: 1.63 (1.16-2.28)
3.3% CG: 44/16,658 = 0.26%
CIN3+(author provided data)
Age 25-34: CIN2+(author provided data)
IG: 712/6,002 = Round 1 All ages (calc)
11.9% IG*: 109/16,706 = 0.65% R1: 1.28 (0.91-1.80)
CG: 237/5,808 = CG: 61/16,658 = 0.37% R2: 0.69 (0.34-1.40)
4.1% C: 1.13 (0.83-1.53)
Round 2
Age 35-60: IG*: 11/16,332 = 0.07% Women 35-60

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID
Insufficient Relative Detection Ratio Relative positive predictive
Quality rating Yield Detection of CIN2+/CIN3+
samples (95% CI) value (95% CI)
Applicability
IG: 1,773/16,706 = CG: 19/16,561 = 0.11% R1: 1.57 (1.02-2.43)
10.6% R2: 0.46 (0.16-1.33)
CG: Both rounds C: 1.30 (0.87-1.91)
498/16,658=3.0% IG*: 120/16,706 = 0.72%
CG: 80/16,658 = 0.48% Women 25-34
Invasive cancers R1: 0.89 (0.51-1.57)
(ICC-AD), Women 25-34 R2: 1.00 (0.38-2.67)
All ages CIN3+(author provided data) C: 0.91 (0.56-1.48)
R1: IG: 2, CG: 7 Round 1
R2: IG: 0, CG: 6 IG*: 23/6,002 = 0.38%
C: IG: 2, CG: 13 CG: 25/5,808 = 0.43%

Age 25-34 (author Round 2

provided data) IG*: 8/5,761 = 0.14%
R1: IG: 0, CG: 1 CG: 8/5,769 = 0.14%
R2: IG: 0, CG: 2
C: IG: 0, CG: 3 Both rounds
IG*: 31/6,002 = 0.52%
Age 35-60 (author CG: 33/5,808 = 0.57%
provided data)
R1: IG: 2, CG: 6 CIN2+(author provided data)
R2: IG: 0, CG: 4 Round 1
C: IG: 2, CG: 10 IG*: 78/6,002 = 1.30%
CG: 38/5,808 = 0.65%

Round 2
IG*: 11/5,761 = 0.19%
CG: 15/5,769 = 0.26%

Both rounds
IG*: 89/6,002 = 1.48%
CG: 53/5,808 = 0.91%

*LBC (ASC-US+) or HPV+

†Data include CIN2, CIN3, and AIS
‡Data include CIN3 and AIS

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated Number of patients
Prevalence of
Study ID Study design Setting Patient characteristics
Screening cutoff disease Inclusion & exclusion
criteria
Collection method
POBASCAM PCR (GP5+/GP6+) RCT with two arms: The Round 1: 49,220 eligible Median age: 41.0 (range
IG: Conventional cytology and HPV Netherlands 44,938 enrolled 29-56)
Bulkmans Positive for high CIN2+ IG: 22,420 Ethnicity: NR
114
2007 oncogenic risk Women with normal cytology and Conducted IG: 98/8,575 = CG: 22,518 Education: NR
viruses (HPV types HPV- recalled at 5 years. Repeat within the 1.1% 18,403 enrolled and ≥6.5 yrs Income: NR
Bulkmans 16, 18, 31, 33, 35, testing at 6 and 18 months advised Dutch CG: 63/8,580 = follow up by Feb 2007 HIV+: NR
214
2004 39, 45, 51, 52, 56, for normal cytology/HPV+ and ASC- nationwide 0.7% 17,155 eligible at baseline Other STIs: NR
58, 59, 66 and 68) US+ cytology. Women HPV- and screening CIN3+ IG: 8,575 Smoking: NR
LSIL or better at 18 months were program IG: 68/8,575 = CG: 8,580
CC and PCR: recalled at 5 years. 0.8% 16,869 eligible at round 2
Cervex-Brush or CG: 40/8,580 = IG: 8,413
cytobrush CG: Conventional cytology alone 0.5% CG: 8,456
(HPV test results blinded)
Both rounds: Inclusion: women aged 30-56
Women with normal cytology recalled years, live in a defined semi-
at 5 years. Women with ASC-US+ at CIN2+ urbanized region to the
baseline were recalled at 6 and 18 IG: 137/8,575 = southwest of Amsterdam
months. Women with normal 1.6%
cytology at 6 and 18 months recalled CG: 137/8,580 = Exclusion: history of CIN2+ or
at 5 years. 1.6% abnormal cytology in last 2
CIN3+ years, hysterectomy
At 5 years, all women managed IG: 92/8,575 =
according to protocol for IG 1.1%
CG: 94/8,580 =
PCR assay performed on CC 1.1%
specimen

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID
Application of
reference standard Funding Insufficient
Quality rating Yield Detection of CIN2+/CIN3+
(histologic source samples
verification)
Applicability
POBASCAM Colposcopically directed Zorg Test Positivity Rate Inadequate CIN2+ (95% CI)
biopsies from suspected Onderzoek HSIL+ cytology Round 1
114
Bulkmans 2007 areas on cervix Nederland IG: 0.1% IG: 98/8,575 = 1.1% (0.9-1.4)
according to standard (Netherlands Round 1: Round 1, 0.3% CG: 63/8,580 = 0.7% (0.6-0.9)
214
Bulkmans 2004 procedures in the Organization IG: 56/8,575 = 0.7% Round 2 p=0.006
Netherlands for Health CG: 54/8,580 = 0.6% Round 2
Research and CG: 0.1% Round 1, IG: 39/8,413 = 0.5% (0.3-0.6)
Fair Referral criteria: Development) Round 2: 0.4% Round 2 CG: 74/8,456 = 0.9% (0.7-1.1)
IG: HSIL+ at any time; IG: 38/6,887 = 0.6% p=0.001
Fair ASC-US+ at baseline CG: 50/6,838 = 0.7% Both rounds
and ASC-US+/HPV+ at IG: 137/8,575 = 1.6% (1.4-1.9)
nd
6 months; HPV+ on 2 Both rounds (calc): CG: 137/8,580 = 1.6% (1.4-1.9)
repeat smear at 18 IG: 94/8,575 = 1.1%
months CG: 104/8,580 = 1.2% CIN3+ (95% CI)
Round 1
CG: HSIL+ at any time; Concordance IG: 68/8,575 = 0.8% (0.6-1.0)
ASC-US+ at baseline % of ASC-US+ that were HPV+ CG: 40/8,580 = 0.5% (0.4-0.6)
and 6 or 18 months. (calc) 70% higher in IG (15-151), p=0.007
Round 1: Round 2
Round 1 IG: 46.1% IG: 24/8,413 = 0.3% (0.2-0.4)
IG: 201/8,575 = 2.3% CG: 44.7% CG: 54/8,456 = 0.6% (0.5-0.8)
(2.0-2.7) Round 2: 55% lower in IG (28-72), p=0.001
CG: 115/8,580=1.3% IG: 36.6% Both rounds
(1.1-1.6), p<0.0001 CG: 41.8% IG: 92/8,575 = 1.1% (0.9-1.3)
CG: 94/8,580 = 1.1% (0.9-1.3)
Round 2 % of HSIL+ that were HPV+ p=0.89
IG: 87/6,887=1.3% (1.0- Round 1:
1.6) IG: 85.7% Invasive cancers, n:
CG: 129/6,838 = 1.9% CG: 84.9% ICC:
(1.6-2.2), p=0.003 Round 2: R1: IG: 5, CG: 2
IG: 77.8% R2: IG: 2, CG: 7
Both rounds (calc) CG: 77.8% C: IG: 7, CG: 9
IG: 288/8,575=3.4% ACIS:
CG: 244/8,580=2.8% R1: IG: 3, CG: 1
R2: IG: 0, CG: 3
C: IG: 3, CG: 4

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative 5-Year Cumulative Risk of Colposcopy Referral Rates and

Positive Predictive Value Relative Positive Predictive
Study ID Detection Ratio CIN2+/CIN3+ per Woman CIN2+/CIN3+ Rate per Woman
(95% CI) Value (95% CI)
(95% CI) Screened Referred

POBASCAM IG vs. CG Neither PPV nor the number of Neither PPV nor the number of % (95% CI)* Colposcopy Referral Rate per
participants with false positive participants with false positive CIN2+ Woman Screened (95% CI)
Bulkmans CIN2+ (calc) results reported results reported IG: IG:
114
2007 Round 1 Normal cytology and HPV Round 1: 201/8575 = 2.3% (2.0-2.7)
1.1%/0.7% = 1.56 negative: 0.4% (0.2-0.5) Round 2: 87/6887 = 1.3% (1.0-1.6)
Bulkmans (1.14-2.13) HPV negative: 0.5% (0.3-0.6)
214
2004 CG:
Round 2 CG: Round 1: 115/8580 = 1.3% (1.1-1.6),
0.5%/0.9% = 0.52 Normal cytology: 1.1% (0.8-1.4) p<0.0001
(0.36-0.77) Round 2: 129/6838 = 1.9% (1.6-2.2),
CIN3+ p=0.003
Both rounds IG:
1.6%/1.6% = 1.00 Normal cytology and HPV CIN2+ Rate per Woman Referred
(0.79-1.27) negative: 0.1% (0.1-0.2) (95% CI)
HPV negative: 0.2% (0.1-0.3) IG:
CIN3+ (calc) Round 1: 47% (40-54)
Round 1 CG: Round 2: 40% (31-51)
0.8%/0.5% = 1.70 Normal cytology: 0.8% (0.6-1.0)
(1.15-2.51) CG:
Round 1: 49% (40-58)
Round 2 Round 2: 52% (43-60)
0.3%/0.6% = 0.44 *Adjusted for loss to follow-up
(0.27-0.71) CIN3+ Rate per Woman Referred
(95% CI)
Both rounds IG:
1.1%/1.1% = 0.98 Round 1: 33% (27-40)
(0.74-1.30) Round 2: 25% (17-35)

CG:
Round 1: 32% (24-41), p=0.90
Round 2: 40% (32-48), p=0.03

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
test evaluated Number of patients
Study ID Study design Setting Prevalence of disease Patient characteristics
Screening cutoff Inclusion & exclusion
criteria
Collection method
Swedescreen PCR (GP5+/GP6+) RCT with two arms: Sweden First screening: 12,527 randomized Mean age: 35.1
IG: 6,257 Ethnicity: NR
115
Naucler 2007 Positive for high IG: Conventional cytology Conducted CIN2+ (calc) CG: 6,270 Education: NR
oncogenic risk plus HPV test (HPV+ within the IG: 114/6,257 = 1.8% Income: NR
160
Naucler 2009 viruses (HPV types women with no record of Swedish CG: 76/6,270 = 1.2% Inclusion: women aged 32-38 HIV+: NR
16, 18, 31, 33, 35, abnormal cytology were cervical years participating in the Other STIs: NR
215 nd
Elfgren 2005 39, 45, 51, 52, 56, offered 2 round of HPV cancer CIN3+ (calc) screening program from May Smoking: NR
58, 59, 66, and 68) testing and cytology ≥ 12 screening IG: 72/6,257 = 1.2% 1997-November 2000 in 5
months later; women with program CG: 55/6,270 = 0.9% Swedish cities
CC and PCR: persistent type-specific
cytologic brush HPV infection were offered Entire study (calc): Exclusion: none
colposcopy)
CIN2+
CG: Conventional cytology IG: 139/6,257 = 2.2%
alone CG: 119/6,270 = 1.9%
(similar number of
randomly selected women CIN3+
nd
offered 2 cytology IG: 88/6,257 = 1.4%
screening and colposcopy) CG: 85/6,270 = 1.4%

Follow up included annual Invasive cancers, pooled

cytology and HPV tests, data only:
with colposcopy in cases ICC: IG: 1, CG: 2
of persistent high-risk HPV ACIS-AD: IG: 4, CG: 4
infection in addition to
routine clinical practice for
abnormal cytology

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID Application of
Relative Relative
reference Positive
Funding Insufficient Detection of CIN Detection Positive
Quality rating standard Yield Predictive
source samples (95% CI) Ratio Predictive
(histologic Value
(95% CI) Value
Applicability verification)
Swedescreen Ectocervical biopsy Swedish Test Positivity Rate PCR (calc) CIN2+ (calc) IG vs. CG Neither PPV Neither PPV
specimens taken Cancer (varied by site) 2.7% First screening nor the nor the
115
Naucler 2007 from all lesions that Society inadequate IG: 114/6,257 = 1.82% CIN2+ number of number of
turned white when and R1: at baseline (1.51-2.18) First screening participants participants
160
Naucler 2009 treated with acetic Europe IG (ASC-US+): 0.7% CG: 76/6,270 = 1.21% 1.51 (1.13- with false with false
acid and lesions against 146/6,257 = 2.3% inadequate (0.96-1.51) 2.02) positive positive
215
Elfgren 2005 that were not Cancer at second results results
stained by Lugol’s IG (HSIL+): NR test Second screening Second reported reported
Fair iodine solution. If IG: 25/6,257 = 0.40% screening
no lesions seen, 2 CG (ASC-US+): CC (0.26-0.59) 0.58 (0.36-
Fair specimens taken at 150/6270=2.4% NR CG: 43/6,270 = 0.69% 0.96)
12 o-clock and 6 (0.50-0.92)
o’clock positions on CG (HSIL+): NR Entire study
ectocervix, close to Entire study (calc)
squamo-columnar R2: NR IG: 139/6,257 = 2.22% 2.22%/1.90%
junction. (1.87-2.62) = 1.17 (0.92-
Endocervical cell C: NR CG: 119/6,270 = 1.90% 1.49)
sample also (1.57-2.27)
obtained from all Concordance CIN3+
women NR CIN3+ (calc) First screening
First screening 1.31 (0.92-
ASC-US+ referred Colposcopy referrals IG: = 72/6,257 = 1.15% 1.87)
to colposcopy in (0.90-1.45)
Stockholm; in other R1: NR CG: = 55/6,270 = 0.88% Second
cities, repeat (0.66-1.14) screening
cytology was option R2: NR 0.53 (0.29-
for ASC-US or LSIL Second screening 0.98)
C: NR IG: 16/6,257 = 0.26%
In IG, women with (0.15-0.41) Entire study
persistent type- Compliance with CG: 30/6,270 = 0.48% (calc)
specific HPV referral: (0.32-0.68) 1.41%/1.36%
infection referred to = 1.04 (0.77-
colposcopy R1: NR Entire study 1.39)
R2: NR IG: 88/6,257 = 1.41%
Random sample of C: NR (1.13-1.73)
111 women in CG: 85/6,270 = 1.36%
control group also (1.08-1.67)
referred to
colposcopy

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary
screening
Number of
test Application of
patients
evaluated Prevalence of Patient reference standard
Study ID Study design Setting Funding source
Screening disease characteristics (histologic
Inclusion &
cutoff verification)
exclusion criteria
Collection
method
ARTISTIC Hybrid ARTISTIC trial England Round 1: Round 1: Age: Referral protocol: National Institute of
Capture 2 randomized 25,078 enrolled Mean: NR Health Research
117
Kitchener 2009 participants in Greater CIN2+: and randomized <30: 21% (calc) Colposcopy for Health Technology
Positive for 3:1 ratio to two Manchester Revealed: 2.46% ≥30: 79% (calc) positive screening Assessment
216
Kitchener 2006 high arms: county Concealed: 24,856 confirmed Ethnicity: NR test only, with Programme
oncogenic 2.17% eligible after Education: NR biopsy of
217
Sargent 2010 risk viruses HPV-revealed: Women randomization Income: NR abnormalities
(HPV types LBC + HPV recruited in CIN3+: HIV+: NR
218
Sargent 2008 16, 18, 31, results acted on general Revealed: 1.27% 24,510 analyzed Other STIs: NR Colposcopy in those
33, 35, 39, practice and Concealed: Revealed (IG): Smoking: NR with HSIL in both
197
Kitchener 2009 45, 51, 52, HPV-concealed: family 1.31% 18,386 arms
56, 58, 59, LBC results planning Concealed (CG):
68) at ≥1.0 alone acted on clinics during Both rounds: 6,124 ASC-US or LSIL
pg/mL routine followed with repeat
Two screening screening CIN2+: screening, with
HPV and rounds; (National Revealed: 3.01% Round 2: colposcopy for
LBC participants Health Concealed: 16,080 with follow- persistent
nd
(ThinPrep): invited for 2 Service 3.03% up data at time of abnormality
Collection screen 36 Cervical analysis
st
method NR months after 1 Screening CIN3+: Those with HPV+
screen Programme) Revealed: 1.51% Women with test had repeat HPV
Concealed: CIN2+ histology at at 12-month
Round 2 defined 1.77% R1 excluded from intervals, with
as first analysis of R2 colposcopy for
cytologically Prevalence over results persistent positive
adequate both rounds test
sample taken 26 combines 15,542 analyzed
to 54 months prevalence over Revealed: 11,676 With this protocol,
after Round 1 Rounds 1 and 2 Concealed: 3,866 histology obtained
sample using the up to 30 months
formula: Inclusion: age 20- after corresponding
64 years at round 1 screening test
log(1-p) = log(1-
p1) + log (1-p2) Exclusion: NR Colposcopy data:
Colposcopies

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary
screening
Number of
test Application of
patients
evaluated Prevalence of Patient reference standard
Study ID Study design Setting Funding source
Screening disease characteristics (histologic
Inclusion &
cutoff verification)
exclusion criteria
Collection
method
among women
screened, unclear
whether referred or
attending (calc):

All ages
R1:
Revealed:
1,247/18,386 =
6.8%
Concealed:
320/6,124 = 5.2%

R2:
Revealed:
284/11,676 = 2.4%
Concealed:
74/3,866 = 1.9%

C:
Revealed:
1,531/18,386 =
8.3%
Concealed:
394/6,124 = 6.4%

Women <30
R1:
Revealed:
540/3879=13.9%
Concealed:
123/1287=9.6%

R2:
Revealed: 124
Concealed: 32
(sample size NR for

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary
screening
Number of
test Application of
patients
evaluated Prevalence of Patient reference standard
Study ID Study design Setting Funding source
Screening disease characteristics (histologic
Inclusion &
cutoff verification)
exclusion criteria
Collection
method
R2)

C:
Revealed:
664/3879-17.1%
Concealed:
115/1287=12.0%

Women ≥ 30
R1:
Revealed:
707/14507=4.9%
Concealed:
197/4837=4.1%

R2:
Revealed: 160
Concealed:42
(sample size NR for
R2)

C:
Revealed:
867/14507=6.0%
Concealed:
239/4837=4.9%

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative Relative False

Positive predictive Relative positive
Quality Applicabilit Insufficient Detection of Detection Positive
Study ID Yield value predictive value
rating y samples CIN2+/CIN3+ Ratio Proportion (95%
(95% CI) (95% CI)
(95% CI) CI)

ARTISTIC Fair Good Test positivity Round 1 CIN2+ (95% CI) CIN2+ (95% All ages: CIN2+ (95% CI NR) CIN2+ (calc)
(calc): (calc) Round 1 CI, p-value) Round 1 Round 1
Kitchener HSIL+ Revealed:453/18, Round 1 CIN2+ (calc) Revealed: Revealed:
117
2009 R1: 346/24,856 386 = 2.46% 1.14 (0.94- Round 1 LBC (ASCUS+): LBC (ASCUS+):
Revealed = 1.4% with (2.24-2.70) 1.38) (3,566/18,386)/ 421/2,344 = 18.0% 18.0%/16.9% =
Kitchener 358/18,386 = inadequate Concealed: p>0.2 (653/6,124) = 1.82 (16.4-19.6) 1.06 (0.89-1.27)
216
2006 2.0% or missing 133/6,124 = Round 2 (1.68-1.97) LBC (ASCUS+) or LBC (ASCUS+) or
Concealed: screening 2.17% (1.82- 0.63 (0.42- Round 2 HPV+ (calc): HPV+:
Sargent 105/6,124 = tests 2.57) 0.96) p=0.035 (1,178/11,676)/ 453/4,019 = 11.3% 11.3%/16.9% =
217
2010 1.7% Both rounds (139/3,866) = 2.81 (10.3-12.3) 0.67 (0.56-0.80)
Round 2 Round 2 0.99 (0.83- (2.36-3.33) Concealed: 1.00
Sargent R2: (calc) Revealed: 1.19) Both rounds Concealed: (Ref)
218
2008 Revealed : 65/11,676 = p>0.2 (4,744/18,386)/ LBC (ASCUS+):
47/11,676 = 90/16,080 = 0.56% (0.43- (792/6,124) = 2.00 133/786 = 16.9% Round 2
Kitchener 0.4% 0.6% with 0.71) Women <30 (1.86-2.14) (14.4-19.7) Revealed:
197
2009 Concealed: no Concealed: (calc): LBC (ASCUS+):
16/3,866 = adequate 34/3,866 = 0.88% 1.07(0.83- CIN3+ (calc) Round 2 11.3%/16.2% =
0.4% cytology (0.61-1.23) 1.38) Round 1 Revealed: 0.70 (0.48-1.02)
Women ≥30 (3,786/18,386)/ LBC (ASCUS+): LBC (ASCUS+) or
C: Both rounds (calc): (706/6,124) = 1.79 65/575 = 11.3% HPV+: 6.4%/16.2%
Revealed : See prevalence 1.21(0.91- (1.66-1.93) (8.8-14.2) = 0.39 (0.27-0.57)
405/18,386 = above for 1.60) Round 2 (p<0.001 comparing Concealed: 1.00
2.2% methods (1,224/11,676)/ R1 and R2) (Ref)
Concealed: Revealed: 3.01% CIN3+ (95% (192/3,866) = 2.11 LBC (ASCUS+) or
121/6,124 = (2.75-3.28) CI. p) (1.82-2.45) HPV+ (calc):
2.0% Concealed: Round 1 Both rounds 80/1,258 = 6.4% CIN3+ (calc)
3.03% (2.59- 0.97 (0.75- (5,010/18,386)/ (5.1-7.9) Round 1
Women aged 3.53) 1.25) (898/6,124) = 1.86 Revealed:
<30 p>0.2 (1.74-1.98) Concealed: LBC (ASCUS+):
R1: CIN3+ (95% CI) Round 2 LBC (ASCUS+): 9.5%/10.2% = 0.93
Revealed : Round 1 0.53 (0.30- Age 20-29: 34/210 = 16.2% (0.73-1.19)
164/3,879 = Revealed: 0.96) (11.5-21.9) LBC (ASCUS+) or
4.2% 233/18,386 = p=0.042 CIN2+ (calc) HPV+: 5.8%/10.2%
Concealed: 1.27% (1.11- Both rounds Round 1 CIN3+ (calc) = 0.57 (0.45-0.73)
51/1,287 = 1.44) 0.85 (0.67- (1,318/3,879)/ Round 1 Concealed: 1.00
4.0% Concealed: 1.08) (205/1,287) = 2.13 Revealed: (Ref)
80/6,124 = 1.31% p>0.2 (1.87-2.44) LBC (ASCUS+):

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative Relative False

Positive predictive Relative positive
Quality Applicabilit Insufficient Detection of Detection Positive
Study ID Yield value predictive value
rating y samples CIN2+/CIN3+ Ratio Proportion (95%
(95% CI) (95% CI)
(95% CI) CI)

(1.04-1.62) Round 2 223/2,344 = 9.5% Round 2

R2: NR Women <30 NR (8.4-10.8) Revealed:
Round 2 (calc): Both rounds LBC (ASCUS+) or LBC (ASCUS+):
C: NR Revealed: 0.92 (0.65- NR HPV+: 233/4,019 = 5.0%/8.6% = 0.59
29/11,676 = 1.31) 5.8% (5.1-6.6) (0.33-1.04)
Women aged 0.25% (0.17- Women ≥30 CIN3+ (calc) LBC (ASCUS+) or
≥30 0.36) (calc): 1.02 Round 1 Concealed: HPV+: 2.7%/8.6%
R1: Concealed: (0.71-1.47) (1,437/3,879)/ LBC (ASCUS+): = 0.32 (0.18-0.55)
Revealed 18/3,866 = 0.47% (236/1,287) = 2.02 80/786 = 10.2% Concealed: 1.00
194/14,507 = (0.28-0.73) (1.79-2.28) (8.2-12.5) (Ref)
1.3% Round 2
Concealed: Both rounds Reported as NR Round 2
54/4,837 = See prevalence Odds Ratio in Both rounds Revealed:
1.1% above for Table 4 of NR LBC (ASCUS+):
methods manuscript 29/575 = 5.0% (3.4-
R2: NR Revealed: 1.51% (revealed vs. Age 30-64: 7.2)
(1.33-1.71) concealed) LBC (ASCUS+) or
C: NR Concealed: CIN2+ (calc) HPV+: 34/1,258 =
1.77% (1.43- Round 1 2.7% (1.9-3.8)
Concordance 2.16) (2,248/14,507)/
(calc): (448/4,837) = 1.67 Concealed:
% of HPV+ (1.52-1.84) LBC (ASCUS+):
samples that Round 2 18/210 = 8.6% (5.2-
were ASC- NR 13.2)
US+ Both rounds
Round 1: NR
Revealed:
1,185/2,860 = CIN3+ (calc)
41.4% Round 1
Concealed: (2,349/14,507)/
402/953 = (470/4,837) = 1.67
42.2% (1.52-1.83)
Round 2: Round 2
Revealed: NR
249/932 = Both rounds
26.7% NR
Concealed:
92/316 =
29.1%

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative Relative False

Positive predictive Relative positive
Quality Applicabilit Insufficient Detection of Detection Positive
Study ID Yield value predictive value
rating y samples CIN2+/CIN3+ Ratio Proportion (95%
(95% CI) (95% CI)
(95% CI) CI)

% of ASC-US+
that were
HPV+
Round 1:
Revealed:
1,185/2,344 =
50.6%
Concealed:
402/786 =
51.1%
Round 2:
Revealed:
249/575 =
43.3%
Concealed:
92/210 =
43.8%

Invasive
cancers, (ICC-
AD), pooled
from both
rounds, n:
IG: 8
CG: 4

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
Number of patients
test evaluated Study Patient
Study ID Setting Prevalence of disease
Screening cutoff design characteristics
Inclusion & exclusion criteria
Collection method
Cytology Testing with HPV Triage of Positive Cytology (Reflex HPV): Studies reporting absolute test performance measures
136
Andersson 2005 Hybrid Capture 2 Consecutive Sweden All 177 enrolled Mean Age: 34 (23-60)
series, split CIN2: 27/177 = 15.3% Ethnicity: NR
Positive for high sample Gynecologic CIN3: 11/177 = 6.2% Inclusion: Referred with low- Education: NR
oncogenic risk viruses departments of three grade atypia (ASC-US or LSIL) Income: NR
(HPV types 16, 18, 31, HC2 assay university hospitals of Referred with ASC-US HIV+: NR
33, 35, 39, 45, 51, 52, performed Stockholm CIN2: 6/52 = 11.5% Exclusion: NR Other STIs: NR
56, 58, 59, and 68) at on CC CIN3: 4/52 = 7.7% Smoking: NR
1.0 pg/mL sample 4-6 months after
referral cytology Referred with LSIL
HC2 and CC: Cervical CIN2: 21/125 = 16.8%
brush Women with low- CIN3: 7/125 = 5.6%
grade atypia (ASC-
US or LSIL) detected
at a population-based
screening

Application of reference
Quality Insufficient
Study ID standard Funding source Applicability Yield
rating samples
(histologic verification)
136
Andersson 2005 Colposcopy and biopsy in Swedish Cancer Fair Good Test Positivity Rate NR
all women Foundation, the HC2
Karolinska All: 65.5%
Punch biopsies were Institutet Referred with ASC-US: 44.2%
obtained from acetowhite Foundation, and Referred with LSIL: 74.4%
areas; if no acetowhite AFA, Sweden
area was observed, a CC (ASC-US+)
biopsy was taken close to All: 47.5%
the squamocolumnar Referred with ASC-US (calc): 38.5%
junction, at 12 o'clock Referred with LSIL (calc): 51.2%

Concordance
72.4% of HPV+ samples were ASC-US+
81.0% of ASC-US+ samples were HPV+

% HPV+ by CC diagnosis:
ASC-US+: 81.0%
Negative: 51.6%

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

HPV/CC categories:
HPV-CC-: 25.4%
HPV-CC+: 9.0%
HPV+CC+: 38.4%
HPV+CC-: 27.1%

Positive Negative False positive Other

Sensitivity Specificity
Study ID predictive value predictive value rate performance Comments
(95% CI) (95% CI)
(95% CI) (95% CI) (95% CI) characteristics
136
Andersson 2005 Detection of CIN2+: Detection of CIN2+: Detection of Detection of Detection of 42% of women HPV
HC2 (all) : 82 (67-91) HC2 (all): 39 (31-47) CIN2+: CIN2+: CIN2+ (calc): ≤30 years old accuracy
CC (all) (ASC-US+): 61 CC (all, calc): 78/139 = HC2 (all): 27 (18- HC2 (all): 89 (80- HC2 (all): 61.2 without any signs available
(45-74) 56.1* (47.5-64.5) 35) 97) (52.5-69.3) of CIN were HPV grouped by
HC2 (referred with ASC- HC2 (referred with ASC- CC (all, calc): CC (all, calc): CC (all): 43.9 positive, referral smear
US, calc): 6/10 = 60.0 US, calc): 25/42 = 59.5 23/84 = 27.4 (18.2- 78/93 = 83.9 (74.8- (35.5-52.5) compared to 23% (ASC-US vs
(26.2-87.8) (43.3-74.4) 38.2) 90.7) HC2 (referred of women >30 LSIL), but
CC (referred with ASC- CC (referred with ASC- HC2 (referred with HC2 (referred with with ASC-US): repeat
US, calc): 6/10 = 60.0 US, calc): 28/42 = 66.7 ASC-US, calc): ASC-US, calc): 40.5 (25.6-56.7) cytology
(26.2-87.8) (50.5-80.4) 6/23 = 26.1 (10.2- 25/29 = 86.2 (68.3- CC (referred with accuracy only
HC2 (referred with LSIL, HC2 (referred with LSIL, 48.4) 96.1) ASC-US): 33.3 presented for
calc): 25/28 = 89.3 (71.8- calc): 29/97 = 29.9 (21.0- CC (referred with CC (referred with (19.6-49.5) all patients
97.7) 40.0) ASC-US, calc): ASC-US, calc): HC2 (referred combined
CC (referred with LSIL, CC (referred with LSIL, 6/20 = 30.0 (11.9- 28/32 = 87.5 (71.0- with LSIL): 70.1 (ASC-US and
calc): 17/28 = 60.7 (40.6- calc): 50/97 = 51.5 (41.2- 54.3) 96.5) (60.0-79.0) LSIL referral
78.5) 61.8) HC2 (referred with HC2 (referred with CC (referred with smears)
LSIL, calc): 25/93 = LSIL, calc): 29/32 = LSIL): 48.5 (38.2-
Detection of CIN3+ 26.9 (18.2-37.1) 90.6 (75.0-98.0) 58.8)
Detection of CIN3+ (calc): CC (referred with CC (referred with Detection of
(calc): HC2 (all): 60/166 = 36.1 LSIL, calc): 17/64 = LSIL, calc): 50/61 = CIN3+ (calc):
HC2 (all): 10/11 = 90.9 (28.8-44.0) 26.6 (16.3-39.1) 82.0 (70.0-90.6) HC2 (all): 63.9
(58.7-99.8) CC (all): 90/166 = 54.2 Detection of Detection of (56.0-71.2)
CC (all) (ASC-US+): 8/11 (46.3-62.0) CIN3+ (calc): CIN3+ (calc): CC (all): 45.8
= 72.7 (39.0-94.0) HC2 (referred with ASC- HC2 (all): 10/116 = HC2 (all): 60/61 = (38.0-53.7)
HC2 (referred with ASC- US): 28/48 = 58.3 (43.2- 8.6 (4.2-15.3) 98.4 (91.2-100.0) HC2 (referred
US): 3/4 = 75.0 (19.4- 72.4) CC (all): 8/84 = 9.5 CC (all): 90/93 = with ASC-US):
99.4) CC (referred with ASC- (4.2-17.9) 96.8 (90.9-99.3) 41.7 (27.6-56.8)
CC (referred with ASC- US): 31/48 = 64.6 (49.5- HC2 (referred with HC2 (referred with CC (referred with
US): 3/4 = 75.0 (19.4- 77.8) ASC-US): 3/23 = ASC-US): 28/29 = ASC-US): 35.4
99.4) HC2 (referred with LSIL): 13.0 (2.8-33.6) 96.6 (82.2-99.9) (22.2-50.5)
HC2 (referred with LSIL): 32/118 = 27.1 (19.3-36.1) CC (referred with CC (referred with HC2 (referred
7/7 = 100.0 (59.0-100.0) CC (referred with LSIL): ASC-US): 3/20 = ASC-US): 31/32 = with LSIL): 72.9
CC (referred with LSIL): 59/118 = 50.0 (40.7-59.3) 15.0 (3.2-37.9) 96.9 (83.8-99.9) (63.9-80.7)

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Positive Negative False positive Other

Sensitivity Specificity
Study ID predictive value predictive value rate performance Comments
(95% CI) (95% CI)
(95% CI) (95% CI) (95% CI) characteristics
5/7 = 71.4 (29.0-96.3) HC2 (referred with HC2 (referred with CC (referred with
*Reported as 34% in text LSIL): 7/93 = 7.5 LSIL): 32/32 = LSIL): 50.0 (40.7-
(3.1-14.9) 100.0 (89.1-100.0) 59.3)
CC (referred with CC (referred with
LSIL): 5/64 = 7.8 LSIL): 59/61 = 96.7
(2.6-17.3) (88.7-99.6)

Primary screening
test evaluated
Number of patients
Prevalence of Patient
Study ID Study design Setting
Screening cutoff disease characteristics
Inclusion & exclusion criteria
Collection method
Bergeron Hybrid Capture 2 Consecutive series France All 1,037 eligible Mean Age: 35 (15-75)
137
2000 CIN2+: 26/378 = 404 consented Ethnicity: NR
Positive for high HC2 sample 41 participating 6.9% 378 included (26 inadequate Education: NR
oncogenic risk collected following gynecologists; number of biopsy specimens) Income: NR
viruses (HPV types CC sample at same clinics NR Referred with ASC- HIV+: NR
16, 18, 31, 33, 35, 39, visit US Inclusion: Referred with ASC- Other STIs: NR
45, 51, 52, 56, 58, 59, Within 2 months after referral CIN2+: 12/111 = US or LSIL Smoking: NR
and 68) at 1.0 pg/mL cytology 10.8%
Exclusion: NR
HC2: Cone brush Women referred for ASC-US Referred with LSIL
CC: Wooden spatula or LSIL smears in the CIN2+: 14/267 =
(ectocervix) and Laboratoire Pasteur Cerba, a 5.2%
cytobrush private laboratory
(endocervix)
100
Manos 1999 Hybrid Capture 2 Consecutive series US HSIL (CIN2-3): 1,632 women with ASC-US Median Age: 37 (15-
(prototype) 64/973 = 6.6% 1,340 returned for colposcopy 78)
HC2 sample Participants identified from Invasive cancer: 995 participated in study Ethnicity (850
Positive for high collected following cohort of 46,009 women 1/973 = 0.1% 973 definitive histologic participants)
oncogenic risk CC sample at initial belonging to Kaiser diagnosis and HPV result White: 64%
viruses (HPV types visit (referral Permanente Medical Care available Black: 9%
16, 18, 31, 33, 35, 39, cytology) Program, Northern California 957 repeat cytology results Hispanic: 14%
45, 51, 52, 56, and Repeat CC Region, who had routine available Asian/Pacific Islander:
58) at 1.0 pg/mL collected at cervical cytology at 1 of 12 11%
colposcopy gynecology clinics at 4 Inclusion: ASC-US cytology Other: 2%
HC2: Conical brush examination and participating centers results Education: NR
CC: Cervical broom used to estimate Income: NR

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

results of repeat Median of 67 days (range, Exclusion: Pregnant, treated for HIV+: NR
cytology conducted 12-240 days) after referral CIN within previous 6 m, no Other STIs: NR
within 6 months cytology longer Kaiser Permanente Smoking: NR
members, moved, provider
Women with initial ASC-US deemed them ineligible (e.g., due
cytology results to serious illness)

Application of
Quality Insufficient
Study ID reference standard Funding source Applicability Yield
rating samples
(histologic verification)
137
Bergeron 2000 All women had Digene Fair Good Test Positivity Rate NR
colposcopies, and biopsy Diagnostics, Inc. HC2
specimens were taken All: 53.7%
from the abnormal Referred with ASC-US: 43.2%
transformation zone Referred with LSIL: 58.1%
seen in all but 20 women
CC (ASC-US+)
All: 49.7%
Referred with ASC-US: 32.4%
Referred with LSIL: 56.9%

HC2 and CC
All: 66.4%
Referred with ASC-US: 57.7%
Referred with LSIL: 70.0%

Concordance
NR
100
Manos 1999 Colpsocopy with biopsy Kaiser Good Good Test Positivity Rate NR
and/or ECC in all women Permanente HC2: 39.5%
Innovations CC (ASC-US+): 38.9%
In cases in which no Program, Cytyc
lesion requiring biopsy Corporation, Concordance
was seen, an ECC was Digene NR
performed. In other Corporation
cases, ECCs were
performed at the
discretion of the
colposcopist

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Positive predictive Negative predictive Other

Sensitivity Specificity False positive rate
Study ID value value performance
(95% CI) (95% CI) (95% CI)
(95% CI) (95% CI) characteristics
137
Bergeron 2000 Detection of CIN2+: Detection of CIN2+: Detection of CIN2+ Detection of CIN2+: Detection of CIN2+
All All (calc): All (calc):
HC2: 23/26 = 88 (69.8-97.6) HC2: 172/352 = 49 (43.5- All HC2: 172/175 = 98.3 All
CC: 22/26 = 85 (65.1-95.6) 54.2) HC2: 23/203 = 11.3 (95.1-99.6) HC2: 51 (45.8-56.5)
HC2 and CC: 25/26 = 96 CC: 186/352 = 53 (47.5- (7.3-16.5) CC: 186/190 = 97.9 CC: 47 (41.8-52.5)
(80.4-99.9) 58.2) CC: 22/188 = 11.7 (94.7-99.4) HC2 and CC: 64
p = 0.17 (vs CC) HC2 and CC: 126/352 = 36 (7.5-17.2) HC2 and CC: 126/127 (59.0-69.2)
(30.8-41.0) HC2 and CC: 25/251 = 99.2 (95.7-100.0)
Referred with ASC-US p<.001 (vs CC) = 10.0 (6.5-14.4) Referred with ASC-
HC2: 10/12 = 83 (51.6-97.9) Referred with ASC-US US
CC: 8/12 = 66 (34.9-90.1) Referred with ASC-US Referred with ASC-US HC2: 61/63 = 96.8 HC2: 38 (28.8-48.7)
p = 0.31 (vs HC2) HC2: 61/99 = 62 (51.3-71.2) HC2: 10/48 = 20.8 (89.0-99.6) CC: 29 (19.7-38.2)
HC2 and CC: 11/12 = 92 CC: 71/99 = 71 (61.8-80.3) (10.5-35.0) CC: 71/75 = 94.7 HC2 and CC: 54
(61.5-99.8) HC2 and CC: 46/99 = 46 CC:8/36 = 22.2 (10.1- (86.9-98.5) (43.2-63.6)
p = 0.13 (vs CC) (36.4-56.8) 39.2) HC2 and CC: 46/47 =
p<.001 (vs CC) HC2 and CC: 11/64 = 97.9 (88.7-99.9) Referred with LSIL
Referred with LSIL 17.2 (8.9-28.7) HC2: 56 (49.8-62.3)
HC2: 13/14 = 93 (66.1-99.8) Referred with LSIL Referred with LSIL CC: 55 (48.2-60.8)
CC: 14/14 = 100 (76.8-100.0) HC2: 111/253 = 44 (37.7- Referred with LSIL HC2: 111/112 = 99.1 HC2 and CC: 68
HC2 and CC: 14/14 = 100 50.2) HC2: 13/155 - 8.4 (95.1-100.0) (62.3-74.1)
(76.8-100.0) CC: 115/253 = 45 (39.2- (4.5-13.9) CC: 115/115 = 100.0
51.8) CC: 14/152 = 9.2 (5.1- (96.8-100.0)
HC2 and CC: 80/253 = 32 15.0) HC2 and CC: 80/80 =
(25.9-37.7) HC2 and CC: 14/187 100.0 (95.5-100.0)
p=.001 (vs CC) = 7.5 (4.2-12.2)
100
Manos 1999 Detection of HSIL+: Detection of HSIL+: Detection of HSIL+: Detection of HSIL+: Detection of HSIL+ Referral to
HC2: 58/65 = 89.2 (78.4-95.2) HC2: 582/908 = 64.1 (60.9- HC2: 15.1 (11.7-19.2) HC2: 98.8 (97.4-99.5) (calc): colposcopy
CC: 48/63 = 76.2 (63.5-85.7) 67.2) CC: 12.9 (9.8-16.8) CC: 97.4 (95.7-98.5) HC2: 35.9 (32.8- HC2: 39.5%
p = 0.09 CC (calc): 570/894 = 63.8 39.1) CC: 38.9%
(60.5-66.9) CC: 36.2 (33.1-39.5)

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary screening
Number of patients
test evaluated Patient
Study ID Study design Setting Prevalence of disease
Screening cutoff characteristics
Inclusion & exclusion criteria
Collection method
138
DelMistro 2010 Hybrid Capture 2 Comparison of: Italy CIN2 (calc): 749 enrolled Median Age: 42
(1) immediate 14/749=1.9% Age range: 25-64 y
Positive for high colposcopy, (2) Five centers in Veneto CIN3 (calc): Inclusion: ASC-US result in <35y: 26.4%
oncogenic risk repeat Pap, region in Northeast Italy 15/749=2.0% routine screening in past 12 >35y: 73.6%
viruses (HPV types and (3) HPV participating in ICC: None reported months (median was 72.2 days) Ethnicity: NR
16, 18, 31, 33, 35, 39, test for triage organized cervical Education: NR
45, 51, 52, 56, 58, 59, of ASC-US screening program Income: NR
and 68) at 1.0 pg/mL HIV+: NR
All participants Other STIs: NR
HC2 and CC: received all Smoking: NR
Collection methods three tests at
NR baseline and
12 months
later

Women with
any positive
screening test
invited for
repeat Pap
and HPV test
at 6 months

Application of
reference standard Quality Insufficient
Study ID Funding source Applicability Yield
(histologic rating samples
verification)
138
DelMistro 2010 All women received NR Fair Good Test positivity: Pap smears at
colposcopy at baseline HPV+: 24.2% enrollment were
and at 12 months, with Pap (ASC-US+): 29.4% inadequate for 16
biopsy when indicated women (2.2% of
Concordance: those tested)
Biopsies (cervical NR
and/or vaginal) taken in
338 women (45.1%)
either at enrollment or
during follow-up;
histology data appear to
pool results from
different time points.

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Positive predictive Negative False positive Other

Sensitivity Specificity
Study ID value predictive value rate performance Comments
(95% CI) (95% CI)
(95% CI) (95% CI) (95% CI) characteristics
DelMistro Detection of CIN2+: Detection of CIN2+: Detection of NR Detection of ROC area:
138
2010 All women: All women: CIN2+: CIN2+ (calc): Pap: 0.73
Pap test: 74.1 (70.9-77.3) Pap test: 72.3 (69.0-75.6) All women: All women: HC2: 0.85
HC2: 93.1 (91.3-94.9) HC2: 78.6 (75.7-81.6) Pap test: 9.5 (7.3- Pap test: 27.7
HC2 + Pap: 100 (100-100) HC2 + Pap: 62.5 (58.9- 11.6) HC2: 21.4
66.0) HC2: 14.9 (12.4- HC2 + Pap: 37.5
<35 years: 17.5)
Pap test: 66.7 (60.0-73.3) <35 years: HC2 + Pap: 9.4 <35 years:
HC2: 87.5 (82.9-92.1) Pap test: 65.5 (58.8-72.3) (7.3-11.6) Pap test: 34.5
HC2 + Pap: 100 (100-100) HC2: 60.4 (53.6-67.2) HC2: 39.6
HC2 + Pap: 50.3 (43.2- <35 years: HC2 + Pap: 49.7
>35 years: 57.3) Pap test: 14.1 (9.2-
Pap test: 83.3 (80.1-86.5) 19.0) >35 years:
HC2: 100 (100-100) >35 years: HC2: 16.3 (11.1- Pap test: 25.3
HC2 + Pap: 100 (100-100) Pap test: 74.7 (70.9-78.4) 21.4) HC2: 15.2
HC2: 84.8 (81.8-87.8) HC2 + Pap: 14.6 HC2 + Pap: 33.3
HC2 + Pap: 66.7 (62.6- (9.6-19.6)
70.7)
>35 years:
Pap test: 7.1 (4.9-
9.3)
HC2: 13.7 (10.8-
16.6)
HC2 + Pap: 6.6
(4.4-8.7)

Screening for Cervical Cancer 206 Oregon Evidence-based Practice Center

Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary
screening Number of
Application of
test patients
reference
evaluated Prevalence of Funding
Study ID Study design Setting Patient characteristics standard
Screening disease Inclusion & source
(histologic
cutoff exclusion
verification)
Collection criteria
method
Cytology Testing with HPV Triage of Positive Cytology (Reflex HPV): RCTs reporting relative test performance measures
ALTS Hybrid RCT with 3 US Baseline data: 5,060 total Overall Colposcopically- National
116
2003 Capture 2 arms: 3,488 with Mean Age: 27 (18-81) directed cervical Cancer
IC: Immediate 4 clinical Referred with ASC-US History of Other STIs biopsies obtained Institute
ALTS Positive for colposcopy (all centers: ASC-US (calc) 1,163 IC Chlamydia trachomatis: 21% from any lesion
219
2003 high referred to University of CIN2: 143/3,488 1,161 HPV Vulvar warts: 13% suspicious for SIL, Support in
oncogenic colposcopy) Alabama, = 4.1% 1,164 CM Trichomonas vaginalis: 13% taken in order from the form of
ALTS risk viruses University of CIN3+: 1,572 with Neisseria gonorrhoeae: 8% worst to least equipment or
220
2000 (HPV types CM: Oklahoma, 180/3,488 = LSIL Genital herpes simplex virus: 6% severity. ECC supplies at
16, 18, 31, Conservative Magee- 5.2% 673 IC Syphilis: 1% performed reduced or
Schiffman 33, 35, 39, management Women’s (CIN3+ includes 224 HPV* according to no cost from:
221
2000 45, 51, 52, (cytologic follow Hospital of 1 case of SCC 675 CM clinician's Cytyc
56, 58, 59, up at 6 month the University and 1 case of 4,234 had exit judgment in cases Corporation,
Solomon and 68) at intervals, of Pittsburgh AIS) colposcopy where DenVu,
222
2001 1.0 pg/mL referral to Medical (retention did transformation National
colposcopy if Center, and Referred with not differ by zone or proximal Testing
Sherman LBC HSIL or University of LSIL (IC arm study arm) extent of a cervical Laboratories,
176
2002 (ThinPrep) carcinoma) Washington only; 4 did not lesion not Digene
and HC2: attend Inclusion: adequately Corporation,
Papette HPV triage Within 6 colposcopy) Community- visualized. NeoPath,
broom (addition of months after CIN2: 76/669 = read cytologic Roche
one-time HPV referral 11.4% diagnosis of After histologic Molecular
triage to cytology CIN3: 34/669 = ASC-US or interpretation at Systems
cytologic follow (average of 2 5.1% LSIL within six the clinical center, Inc., and
up, referral to months) months of all slides sent to TriPath
colposcopy if Cumulative enrollment, Pathology QC Imaging
HPV test Women with diagnoses over age ≥18 years, group at Johns
positive or cytologic course of able to provide Hopkins Hospital
missing or diagnosis of study: informed for re-evaluation;
cytologic ASC-US or consent, likely however, the

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary
screening Number of
Application of
test patients
reference
evaluated Prevalence of Funding
Study ID Study design Setting Patient characteristics standard
Screening disease Inclusion & source
(histologic
cutoff exclusion
verification)
Collection criteria
method
diagnosis of LSIL from Referred with to participate Referred with Referred with management of
HSIL or each clinical ASC-US for full duration ASC-US LSIL the participant was
carcinoma) center's CIN2: 232/3,488 of trial Age Age based on the
referral base = 6.7% Mean: 29 Mean: 25, clinical center
HC2 assay consisting of CIN3+: Exclusion: <35: 77.5% p<0.001 reading. Any case
performed on gynecology, 306/3,488 = Prior ≥35: 22.5% <35: 91.4% with a CIN2+
LBC specimen general 8.8% hysterectomy, Ethnicity ≥35: 8.6% diagnosis by either
practice, and (CIN3+ includes history of White: 63.6% Ethnicity pathology QC or
All women family 2 cases of ablative or Black: 31.2% White: 63.4% clinical center
followed every planning invasive cancer excisional Nat Am/Alaskan Black: 30.4% automatically went
six months for clinics in its and 1 case of therapy to nat: 1.9% Nat Am/Alaskan to panel review
two years with immediate AIS) cervix, Asian/Pacific nat: 2.8% composed of 2 of
LBC, masked geographical pregnant Islander: 3.4% Asian/Pacific 4 QC pathologists
HPV testing, location Referred with Education Islander: 3.4% unmasked to
and LSIL *HPV triage Elementary: Education previous histology
cervicography; CIN2: 165/1,572 arm closed for 14.9% (initially significant diagnoses. For all
all women = 10.5% LSIL referrals High school/GED: difference other cases, first
received CIN3+: in first year 30.3% explained by QC review
colposcopy at 236/1,572 = because Vocational/some younger age) diagnosis
24-month exit 15.0% majority of college: 37.7% Elementary: compared with
visit (CIN3+ includes women with Completed 18.8% clinical center
5 cases of LSIL tested college: 12.4% High school/GED: diagnosis and, if
invasive cancer positive Some graduate 31.5% concordant,
and 1 case of work: 4.7% Vocational/some served as final
AIS) Income: NR college: 37.5% diagnosis. If
Smoking Completed disagreement
Never: 54.5% college: 8.8% between clinical
Former: 13.3% Some graduate center and first QC
Current: 32.2% work: 3.4% reviewer, case
Smoking sent to panel
Never: 49.8% review and that
Former: 9.7% review constituted
Current: 40.5% the final diagnosis.

Screening for Cervical Cancer 208 Oregon Evidence-based Practice Center

Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Primary
screening Number of
Application of
test patients
reference
evaluated Prevalence of Funding
Study ID Study design Setting Patient characteristics standard
Screening disease Inclusion & source
(histologic
cutoff exclusion
verification)
Collection criteria
method
Bjerre Hybrid Women with Sweden CIN2+ (calc): 803 identified Mean Age: 36.7 y Women with Health
119
2008 Capture 2 ASC-US or 197/674=29.2% with ASC-US Age range: 22-60y positive repeat Authorities of
LSIL detected Trial nested in or LSIL Ethnicity: NR screening tests Värmland and
Positive for in routine population- CIN3+ (calc; Education: NR treated with Örebro
high screening based one case of 674 fulfilled the Income: NR LEEP (n=275), Counties
oncogenic randomized to screening ICC): inclusion HIV+: NR laser conization
risk viruses treatment for program in 132/674=19.6% criteria, Other STIs: NR (n=70), or
(HPV types (1) positive two counties, consented and Smoking: hysterectomy
16, 18, 31, repeat Pap with 74% were Non-smoker: 61.4% (n=1) (procedures
33, 35, 39, and/or HPV test population randomized, Smoker: 38.6% (calc) which also
45, 51, 52, or (2) positive coverage in 337 in each provided tissue
56, 58, 59, repeat Pap only one county arm for histology),
and 68) at and 83% in regardless of
≥1 pg/mL Repeat the other in Inclusion: Age colposcopy
screening 2002 23-60 y findings
HC2: conducted 4 mo (invitations to
collected (±1) after index cervical IG: 62% treated
from cervical smear, screening CG: 41% treated
canal with treatment 7 mo program)
cervical (±1) after index
brush Exclusion:
CC: Pregnant or
Collected treated for
with wooden dysplasia in
spatula from last two years
posterior
fornix and
ectocervix,
and
CytoBrush
Plus from
endocervix

Screening for Cervical Cancer 209 Oregon Evidence-based Practice Center

Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative
Study ID
Relative Detection Relative False Positive positive
Quality Insufficient Detection of
Yield Ratio Positive Proportion predictive predictive
rating samples CIN
(95% CI) (95% CI) value value
Applicability
(95% CI)
ALTS Referred with ASC-US Referred with LSIL HC2 (missing CIN3+ (HPV/CM) NR NR NR
116
2003 Test Positivity Rate Test Positivity results due to Referred with Referred with ASC-US
HC2: 50.7% Rate insufficient ASC-US 6.3%/5.1% = 1.24
ALTS LBC (ASC-US+): 57.9% HC2: 84.1% residual IC: 52/1163 = (0.88-1.73)
219
2003 LBC (ASC-US+): material after 4.5% (3.4-5.9)
Concordance (calc) 81.2% ThinPrep) HPV: 73/1161 Referred with LSIL
ALTS 74.3% of HPV+ samples ASC-US: = 6.3% (5.0- 12.1%/6.7% = 1.81*
220
2000 were ASC-US+ Concordance 4.6% 7.9)
68.0% of ASC-US+ (calc) LSIL: 5.0% CM: 59/1164 *Unequal number of
Schiffman samples were HPV+ 86.7% of HPV+ = 5.1% (3.9- women in groups
221
2000 samples were LBC 6.5) makes this number
% HPV+ by LBC ASC-US+ (unsatisfactor invalid
Solomon diagnosis (p<0.001): 90.3% of ASC-US+ y or missing) Referred with
222
2001 HSIL (CIN3): 100% samples were ASC-US: LSIL Timing of CIN3+
HSIL (CIN2): 96.5% HPV+ 0.5% IC: 57/673 = diagnosis
Sherman LSIL: 88.6% LSIL: 0.4% 8.5% Referred with ASC-US
176
2002 ASC-US: 50.6% % HPV+ by LBC HPV: 27/224 Enrollment: IC 59.8%,
Negative: 32.6% diagnosis = 12.1% CM 40.7%, HPV 75.2%
Good (p<0.001): CM: 45/675 = Follow up: IC 14.4%,
HPV/LBC categories: HSIL (CIN3): 100% 6.7% CM 20.4%, HPV 5.9%
Good HPV-LBC-: 28.2% HSIL (CIN2): Exit: IC 25.8%, CM
HPV-LBC+: 18.6% 98.8% ‡
Includes 2 38.9%, HPV 18.8%
HPV+LBC+: 39.5% LSIL: 94.8% cases of p < 0.001
HPV+LBC-: 13.7% ASC-US: 77.1% invasive
Negative: 58.4% cancer (1 in IC Referred with LSIL
Referral to colposcopy & 1 in CM) & 1 Enrollment: IC 62.7%,
(%) HPV/LBC case of ACIS CM 36.6%, HPV 68.3%
Referred with ASC-US categories: in the HPV Follow up: IC 19.6%,
IC: 100 (99.7-100) HPV-LBC-: 8.0% arm CM 26.9%, HPV 9.8%
CM: 12.3 (10.5-14.3) HPV-LBC+: 7.9% Exit: IC 17.6%, CM
HPV: 55.6 (52.6-58.4) HPV+LBC+: 72.9% 36.6%, HPV 22.0%
p < 0.001 HPV+LBC-: 11.2% p < 0.001

Referral to
Compliance with colposcopy (%) The management
colposcopy (%) (calc) Referred with LSIL strategy performance
Referred with ASC-US IC: 100 (99.4-100) calculations consider as
IC: 1148/1163 (98.7%) CM: 18.8 (15.9- "successes" only those
CM: 94/100 (94%) 22.0) cases of CIN3+

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Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Relative
Study ID
Relative Detection Relative False Positive positive
Quality Insufficient Detection of
Yield Ratio Positive Proportion predictive predictive
rating samples CIN
(95% CI) (95% CI) value value
Applicability
(95% CI)
V: 585/649 (90.1%) HPV: 85.3 (79.9- detected by the clinical
89.6) application of the
p < 0.001 management strategy
at the centers within the
a priori-defined period
for that strategy (i.e.,
enrollment period for IC
and HPV triage, and
enrollment plus follow
up periods for CM).
Cases of CIN3+ missed
by the strategy but
detected by safety net
interventions and cases
detected after the
defined period for that
strategy are not
included in the
numerator for
calculating sensitivity.

Screening for Cervical Cancer 211 Oregon Evidence-based Practice Center

Appendix C Table 3. Evidence Table for Benefits of HPV Testing (KQ3)

Study ID
Relative
Relative Detection Relative False Positive positive
Quality Insufficient Detection of
Yield Ratio Positive Proportion predictive predictive
rating samples CIN
(95% CI) (95% CI) value value
(95% CI)
Applicability
Bjerre Test positivity: Cytology*: CIN2+ (calc) IG (HPV+ or ASC-US+) IG (HPV+ or ASC- CIN2+ IG (HPV+
119
2008 HPV+: 201/337=59.6% For 2 women IG (HPV+ or vs. CG (ASC-US+) US+) vs. CG (ASC- (calc) or ASC-
Pap (ASC-US+): 291/674=43.2% (calc) in HPV/Pap ASC-US+): US+) IG (HPV+ or US+) vs.
IG (ASC-US+): 143/337= group (and no 112/337 = CIN2+ (calc) ASC-US+): CG (ASC-
42.4% women in the 33.2% 33.2%/25.2% = 1.32 All ages: 112/208 = US+)
CG (ASC-US+): 148/337= Pap-only CG (ASC- (1.04-1.67) CIN2+ (calc) 53.8%
43.9% group), Pap US+): 85/337 (96/337)/(53/337) (46.8-60.8) CIN2+
was = 25.2% Women <35: = 1.81 (1.34-2.44) CG (ASC- (calc)
Women <35 unreadable 1.34 (1.00-1.79) CIN3+ (calc) US+): 53.8%/61.
IG (HPV+): 126/165= 76.4% (2/673 = CIN3+ (calc)* (136/337)/(78/337) 85/138 = 6% = 0.87
IG (ASC-US+): 77/165=46.7% 0.3%, calc) IG (HPV+ or Women ≥35: = 1.74 (1.38-2.20) 61.6% (0.73-1.05)
CG (ASC-US+): 88/175=50.3% ASC-US+): 1.32 (0.89-1.97) (52.9-69.7)
*Table 3; 72/337 = Age < 35 years: CIN3+
Women ≥35 reported as 3 21.4% CIN3+ (calc) CIN2+ (calc) CIN3+ (calc)
IG (HPV+): 75/172= 43.6% unsatisfactory CG (ASC- 21.4%/17.8% = 1.20 (50/165)/(28/175) = (calc) 34.6%/43.
samples in
IG (ASC-US+): 66/172= 38.4% US+): 60/337 (0.88-1.63) 1.89 (1.26-2.86) IG (HPV+ or 5% = 0.80
Methods
CG (ASC-US+): 60/162= 37.0% = 17.8% CIN3+ (calc) ASC-US+): (0.61-1.04)
Women <35: (77/165)/(42/175) = 72/208 =
Concordance (calc): *includes 1 1.09 (CI) 1.94 (1.43-2.65) 34.6%
113/187 = 60.4% of HPV+ samples were ASC- case of (28.2-41.5)
US+ invasive Women ≥35: Age ≥ 35 years: CG (ASC-
113/134 = 85.0% of ASC-US+ samples were cancer 1.44 (0.86-2.38) CIN2+ (calc) US+):
HPV+ (46/172)/(28/162) = 60/138 =
HPV/CC categories (calc): 1.55 (1.02-2.35) 43.5%
HPV-CC-: 35.8% CIN3+ (calc) (35.1-52.2)
HPV-CC+: 6.5% (59/172)/(39/162) =
HPV+CC-: 22.4% 1.42 (1.01-2.01)
HPV+CC+: 35.2%

ACIS-adenocarcinoma in situ; AGC-atypical glandular cells; AGUS-atypical glandular cells of undetermined significance; AIS-adenocarcinoma in situ; ALTS-ASC-US-LSIL Triage
Study; ASC-H-atypical squamous cells cannot exclude HSIL; ASC-US- atypical squamous cells of undetermined significance; calc-calculation; B: baseline; C-cumulative; CC-
conventional cytology; CI- confidence interval; CIN-cervical intraepithelial neoplasia; CM-conservative management; ColpoBx-colposcopically directed biopsy; ECC-endocervical
curettage; HC2-Hybrid Capture 2; HIV-human immunodeficiency virus; HPV-human papillomavirus; HR-high risk; HSIL- high-grade squamous intraepithelial lesion; IARC-
International Agency for Research on Cancer; IC- immediate colposcopy; LBC-liquid-based cytology; LEEP-loop electrosurgical excision procedure; LMP-last menstrual period; LR-
likelihood ratio; LSIL- low-grade squamous intraepithelial lesion; Mo-month; NR-not reported; PCR-polymerase chain reaction; pg/mL-picogram/milliliter; PPV-positive predictive
value; QC-quality control; R1-round one; R2-round two; RLU-relative light unit; SCC-squamous cell carcinoma; SD-standard deviation; STI-sexually transmitted infection; STM-
standard transport medium; VIA-visual inspection with acetic acid;VILI-visual inspection with Lugol’s Iodine; y-year

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Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

Number of patients
Study ID Study design Setting Patient characteristics Funding source
Inclusion & exclusion criteria
Maissi Cross sectional questionnaire England Initial Sample Initial Sample Follow-up Sample Policy Research
140
2004 2,183 sent questionnaires Programme of the
Recruited all women with Two of the three 1,376 (63%) returned Mean Age (SD) Mean Age (SD) Department of
Maissi borderline or mildly dyskaryotic centers taking questionnaire Normal: 40.2 (12.2) Normal: 40.5 (12.1) Health
143
2005 test results over five month part in the Normal cytology: 366 HPV-: 40.5 (11.3) HPV-: 41.6 (11.1)
period and the first 13 women English Borderline/mildly dyskaryotic HPV+: 31.6 (9.7) HPV+: 32.7 (9.8)
each week who received a HPV/LBC pilot cytology, HPV-: 331 No HPV test: 35.4 No HPV test: 36.6
normal test result; all borderline study Borderline/mildly dyskaryotic (10.4) (11.1)
or mildly dyskaryotic smear cytology, HPV+: 536 White Ethnicity White Ethnicity
samples tested for HPV; after Women Borderline/mildly dyskaryotic Normal: 96% Normal: 97.9%
pilot completed, recruited the presenting for cytology, not tested for HPV: 143 HPV-: 96% HPV-: 96.8%
first 42 women each week over a routine cervical HPV+: 97% HPV+: 97.0%
five week period with borderline smear Follow-up Sample No HPV test: 98% No HPV test: 97.9%
or mildly dyskaryotic results but 1,011 completed 2nd College Education College Education
no HPV results, half from each questionnaire (74%)* Normal: 45% Normal: 46.7%
center Normal cytology: 288 HPV-: 36% HPV-: 37.5%
Borderline/mildly dyskaryotic HPV+: 50% HPV+: 48.5%
Questionnaires sent to women cytology, HPV-: 252 No HPV test: 42% No HPV test: 46.8%
within one week of research Borderline/mildly dyskaryotic Income: NR Income: NR
team being informed that smear cytology, HPV+: 369 HIV+: NR HIV+: NR
test results had been sent to Borderline/mildly dyskaryotic Other STIs: NR Other STIs: NR
them cytology, not tested for HPV: 102 Smoking: NR Smoking: NR

Second questionnaire sent 6 Inclusion: Normal or borderline

months after receipt of test or mildly dyskaryotic cytology
results test result

Four study groups: Exclusion: NR

1) Normal cytology
2) Borderline/mildly dyskaryotic *Response rate varied
cytology, HPV- significantly between groups (p =
3) Borderline/mildly dyskaryotic 0.006)
cytology, HPV+
4) Borderline/mildly dyskaryotic
cytology, not tested for HPV

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Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

Quality
Study ID Outcome measures Results Other results Applicability
rating
Maissi Initial questionnaire: Baseline adjusted mean scores (SE) Follow-up adjusted Baseline means Follow-up means Fair Fair
140
2004 Short form of S-STAI-6 mean scores (SE) (SE) (SE) Predominantly
Spielberger State-Trait Normal: 36.4 (0.7) S-STAI-6 Perceived severity Perceived White and
Maissi Anxiety Inventory (S- HPV-: 37.6 (0.7) Normal: 36.8 (0.8) (Two 7-point scales) severity: NR highly
143
2005 STAI-6); General HPV+: 39.6 (0.6) HPV-: 35.7 (0.8) Normal: 12.4 (0.1) educated
Health Questionnaire No HPV test : 37.7 (1.2) HPV+: 36.7 (0.7) HPV-: 12.3 (0.1) Perceived risk
(GHQ-12) to measure F=4.44, p=0.004 for all groups No HPV test: 36.7 (1.3) HPV+: 12.3 (0.1) (7-point scale)
general distress; t=3.11, p=0.002 for HPV+ vs. other F=0.40, p=0.752 for all No HPV test: 12.1 Normal: 3.0 (0.2)
EuroQoL EQ-5D to groups groups (0.2) HPV-: 3.3 (0.2)
measure health-related p<.05 for HPV+ vs. HPV- ns for HPV+ vs. HPV- F=1.13, p=0.334 HPV+: 4.1 (0.1)
quality of life; concern No HPV test: 4.7
about the smear result; GHQ-12 GHQ-12 Perceived risk (7- (0.3)
perceived risk of Normal: 2.0 (0.1) Normal: 2.0 (0.2) point scale) F=14.88, p<0.001
developing cervical HPV-: 2.1 (0.2) HPV-: 2.0 (0.2) Normal: 3.7 (0.1)
cancer; understanding HPV+: 2.8 (0.2) HPV+: 2.3 (0.2) HPV-: 3.9 (0.1) Perceived
of smear result No HPV test: 2.4 (0.3) No HPV test: 1.9 (0.3) HPV+: 4.4 (0.1) importance of
F=5.37, p=0.001 for all groups F=0.81, p=0.487 for all No HPV test: 4.1 HPV in the
6 month followup: t=3.252, p=0.001 for HPV+ vs. other groups (0.1) development of
Short form of groups ns for HPV+ vs. HPV- F=25.51, p<0.0001 cervical cancer:
Spielberger State-Trait p<.05 for HPV+ vs. HPV- NR
Anxiety Inventory (S- Concern about test Perceived
STAI-6); General Concern about test result result importance of HPV Unsure what
Health Questionnaire Normal: 5.2 (0.1) Normal: 2.0 (0.1) in the development HPV is: NR
(GHQ-12); EuroQoL HPV-: 8.8 (0.1) HPV-: 3.5 (0.1) of cervical cancer
EQ-5D to measure HPV+: 9.7 (0.1) HPV+: 3.8 (0.1) Normal: 5.9 (0.1) Sexual health
health-related quality No HPV test: 9.1 (0.2) No HPV test: 4.4 (0.2) HPV-: 5.9 (0.1) worries
of life; concern about F=242.46, p<0.001 for all groups F=83.39, p<0.001 HPV+: 5.8 (0.1) Normal: NA
smear result; t=13.391, p<0.001 for HPV+ vs. other ns for HPV+ vs. HPV- No HPV test: 5.3 HPV-: 1.0 (0.1)
perceived risk of groups (0.3) HPV+: 1.8 (0.1)
developing cervical p<.05 for HPV+ vs. HPV- HRQoL (EQ-5D) F=3.42, p=0.017 No HPV test: 1.1
cancer; Psychosocial Normal: 0.86 (0.02) (0.1)
Effects of Abnormal HRQoL (EQ-5D)* HPV-: 0.90 (0.02) Unsure what HPV F=30.64, p<0.001
Pap Smear (PEAPS- Normal: 0.91 (0.02) HPV+: 0.89 (0.02) is for all groups
Q) to measure sexual HPV-: 0.89 (0.02) No HPV test: 0.88 Normal: 54% p<.05 for HPV+
health worries HPV+: 0.88 (0.02) (0.04) HPV-: 38% vs. HPV-
No HPV test: 0.87 (0.02) F=0.70, p=0.554 HPV+: 25%
F=0.91, p=0.340 No HPV test: 62%
p value NR
*In followup sample (n = 1,011)

Screening for Cervical Cancer 214 Oregon Evidence-based Practice Center

Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

Number of patients
Study ID Study design Setting Inclusion & exclusion Patient characteristics Funding source
criteria
141
McCaffery 2004 Cross sectional survey using London, England 428 recruited Age Cancer Research UK
postal questionnaire sent one 311 (73%) returned Mean age: 32 (SD 8.0,
week after receipt of HPV and National Health questionnaire range 20-61)
cytology screening results Service well- 271 included in analysis <30: 55%
woman clinic Normal cytology, HPV-: 185 30-34: 18%
At screening, all women given (68%) 35-39: 10%
standard information about HPV Women presenting Normal cytology, HPV+: 46 ≥40: 17%
and HPV testing; information for routine (17%) Ethnicity
covered sexually transmitted screening Abnormal/unsatisfactory White: 90%
nature of HPV, its high cytology, HPV-: 17 (6%) Black: 2%
prevalence, association with CIN, Abnormal/unsatisfactory Asian: 3%
and potential for long periods of cytology, HPV+: 23 (8%) Other: 6%
latency Age left full-time
Inclusion: Women presenting education (years)
Women sent cervical smear and for routine screening Under 16: 8%
HPV results by post and those 17-18: 14%
who tested HPV+ were sent Exclusion: Completed follow- 19+: 78%
second copy of HPV information; up questionnaire after Income: NR
women with borderline or colposcopy (n=28), part of HIV+: NR
abnormal cytology, unsatisfactory randomly selected control Other STIs: NR
smears, or positive HPV results group of cytology and HPV Smoking
were invited for colposcopy negative women who were Yes: 32%
invited and attended No: 68%
All psychosocial measures were colposcopy (n=12)
taken prior to colposcopic follow
up

Four study groups:

1) Normal cytology, HPV-
2) Normal cytology, HPV+
3) Abnormal/unsatisfactory
cytology, HPV-
4) Abnormal/unsatisfactory
cytology, HPV+

STAI assessed before screening

to examine differences between
HPV/cytology groups - no
significant differences found

Screening for Cervical Cancer 215 Oregon Evidence-based Practice Center

Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

Study ID Outcome measures Results Other results Quality rating Applicability

141
McCaffery 2004 Short form of Spielberger Normal cytology, HPV+ vs HPV- Normal Cytology Fair Fair
State-Trait Anxiety STAI: F(1,267) = 39, p < 0.0001 Feelings about current partner Predominantly
Inventory (STAI); Cervical CSQ: F(1,267) = 69, p < 0.0001 HPV+: worse/much worse = 3 (8%), white and highly
Screening Questionnaire better/same = 33 (92%) educated
(CSQ); feelings towards Abnormal/unsatisfactory HPV-: worse/much worse = 2 (1%),
current, previous, and cytology, HPV+ vs HPV- better/same = 160 (99%), p = 0.04
future sexual partners STAI: F(1,267) = 1.3, ns
CSQ: F(1,267) = 8.8, p = 0.002 Feelings about previous partners
HPV+: worse/much worse = 15 (33%),
HPV+, normal vs better/same = 230 (67%)
abnormal/unsatisfactory cytology HPV-: worse/much worse = 2 (1%),
STAI: F(1,267) = 0.55, ns better/same = 167 (99%), p < 0.0001
CSQ: F(1,267) = 15, p = 0.0001
Feelings about future partners
HPV-, normal vs HPV+: worse/much worse = 12 (27%),
abnormal/unsatisfactory cytology better/same = 32 (73%)
STAI: F(1,267) = 11, p = 0.0008 HPV-: worse/much worse = 3 (2%),
CSQ: F(1,267) = 21, p < 0.0001 better/same = 173 (98%), p < 0.0001

Mean STAI scores (95% CI) Abnormal/unsatisfactory cytology

Normal cytology, HPV-: 29.8 (27.9- Feelings about current partner
31.7) HPV+: worse/much worse = 2 (13%),
Normal cytology, HPV+: 43.5 (39.7- better/same = 14 (87%)
47.3) HPV-: worse/much worse = 0 (0%),
Abnormal/unsatisfactory cytology, better/same = 16 (100%), ns
HPV-: 41.1 (34.9-47.5)
Abnormal/unsatisfactory cytology, Feelings about previous partners
HPV+: 46 (40.6-51.4) HPV+: worse/much worse = 8 (35%),
better/same = 15 (65%)
Mean CSQ scores (95% CI) HPV-: worse/much worse = 0 (0%),
Normal cytology, HPV-: 8.9 (8.4-9.3) better/same = 15 (100%), p = 0.01
Normal cytology, HPV+: 13 (12-14)
Abnormal/unsatisfactory cytology, Feelings about future partners
HPV-: 14 (12-15) HPV+: worse/much worse = 7 (32%),
Abnormal/unsatisfactory cytology, better/same = 15 (68%)
HPV+: 17 (16-18) HPV-: worse/much worse = 0 (0%),
better/same = 15 (100%), p = 0.02

Screening for Cervical Cancer 216 Oregon Evidence-based Practice Center

Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

Number of patients
Patient Funding Outcome
Study ID Study design Setting Inclusion & exclusion
characteristics source measures
criteria
Kitchener Consecutive series within an RCT Manchester, England 3,582 sent questionnaires Age: NR Health General
139
2007 2,700 HPV-revealed Ethnicity: NR Technology Health
Women with normal or mildly abnormal cytology General practices in 882 HPV-concealed Education: NR Assessment Questionnaire
who had been recruited into the ARTISTIC trial primary care within the 2,508 (70.0%*) returned Income: NR Programme (GHQ-28);
were mailed a booklet of questionnaires National Cervical questionnaire HIV+: NR and National Spielberger
†
approximately two weeks after they had Screening Programme 1904 (70.5% )HPV- Other STIs: NR Health State-Trait
received the results of their baseline cytology revealed Smoking: NR Service Anxiety
‡
Women presenting for 604 (68.5% )HPV- Research Inventory
In the ARTISTIC trial, women presenting for routine screening concealed and (STAI);
routine screening were randomized 3:1 into two Development Sexual Rating
study groups: HPV-revealed and HPV- Inclusion: Women aged 20- Scale (SRS)
concealed; women in the HPV-revealed group 64 years with normal or mildly
received the results of their HPV test along with abnormal cytology test result
their baseline cytology results while women in
the HPV-concealed group were only informed of Exclusion: NR
their cytology result

Initially the data was collected in face-to-face

interviews; later switched to postal delivery for
economic reasons; there was evidence of
differences in outcome for the two modes of
data collection so the face-to-face interview data
were excluded from the main analysis *69% reported in text
†
70.7% reported in text
‡
71.1% reported in text

Screening for Cervical Cancer 217 Oregon Evidence-based Practice Center

Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

Quality
Study ID Results Other results Applicability
rating

Kitchener GHQ Age-adjusted Observational comparison of HPV+ with Fair Good

139
2007 HPV-revealed HPV-concealed mean difference HPV- in revealed arm
Mean (SD) Mean (SD) (95% CI) P
HPV-/Normal smear 3.31 (5.18) 3.22 (4.80) GHQ
HPV+/Normal smear 4.77 (6.21) 4.02 (5.77) 0.74 (-0.63-1.91) 0.220 Mean
HPV-/abnormal smear 4.22 (5.63) 4.29 (5.83) difference (95%CI) P
HPV+/abnormal smear 4.57 (5.44) 5.75 (6.50) -1.19 (-2.98-0.40) 0.121 Normal smear 1.43 (0.75-2.10) <0.0001
Total 4.26 (5.73) 4.18 (5.71) -0.01 (-0.65-0.60) 0.968 Abnormal smear 0.28 (-0.76-1.24) 0.581

STAI-STATE Age-adjusted STAI-STATE

HPV-revealed HPV-concealed mean difference Mean
Mean (SD) Mean (SD) (95% CI) P difference (95%CI) P
HPV-/Normal smear 35.85 (11.92) 36.00 (11.49) Normal smear 2.90 (1.40-4.39)
HPV+/Normal smear 38.87 (13.33) 37.10 (12.58) 1.73 (-1.27-4.53) 0.202 <0.0001
HPV-/abnormal smear 37.99 (12.43) 40.66 (13.57) Abnormal smear 1.56 (-0.59-3.80) 0.174
HPV+/abnormal smear 39.77 (12.05) 39.97 (12.35) -0.25 (-3.79-3.03) 0.885
Total 38.10 (12.64) 38.27 (12.61) -0.31 (-1.27-1.13) 0.618 STAI-TRAIT
Mean
STAI-TRAIT Age-adjusted difference (95%CI) P
HPV-revealed HPV-concealed mean difference Normal smear 1.53 (0.16-2.92) 0.023
Mean (SD) Mean (SD) (95% CI) P Abnormal smear 0.98 (-1.05-2.97) 0.354
HPV-/Normal smear 38.84 (11.34) 39.00 (11.13)
HPV+/Normal smear 40.54 (11.83) 39.39 (10.80) 1.07 (-1.30-3.41) 0.386 SRS
HPV-/abnormal smear 39.95 (11.08) 41.57 (12.43) Mean
HPV+/abnormal smear 41.28 (10.89) 40.88 (11.54) 0.36 (-2.80-3.53) 0.819 difference (95%CI) P
Total 40.12 (11.40) 40.13 (11.49) -0.10 (-1.27-1.13) 0.858 Normal smear 1.46 (-1.34-4.27) 0.306
Abnormal smear 8.66 (4.30-13.02)
SRS Age-adjusted <0.0001
HPV-revealed HPV-concealed mean difference
Mean (SD) Mean (SD) (95% CI) P GHQ caseness (≥4)
HPV-/Normal smear 51.28 (20.89) 50.81 (22.50)
HPV+/Normal smear 55.32 (22.95) 61.10 (23.74) -7.28 (-12.60- -1.96) 0.007 Odds ratio (95%CI) P
HPV-/abnormal smear 48.73 (23.34) 50.53 (21.26) Normal smear 1.70 (1.33-2.17)
HPV+/abnormal smear 62.67 (23.00) 62.46 (22.97) 0.15 (-6.44-6.74) 0.965 <0.0001
Total 53.32 (23.02) 54.90 (23.00) -2.40 (-4.70- -0.09) 0.042 Abnormal smear 1.07 (0.74-1.56)
0.724

Screening for Cervical Cancer 218 Oregon Evidence-based Practice Center

Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

Number of patients
Patient Funding Outcome
Study ID Study design Setting Inclusion & exclusion
characteristics source measures
criteria

McCaffery Multi-center RCT of triage testing Australia 314 women randomized Age (calc): Australian Primary:
142
2010 HPV: 104 30+: 66% National Quality of life
Randomized to three arms: 18 urban and rural IC: 104 <30: 34% Health measured using
family planning RS: 106 Ethnicity: NR and the mental
HPV: HPV testing (HC2) arranged as soon as clinics across the Education Medical health
possible country 235 (75%) included in primary (calc): Research component of
IC: Choice of HPV or repeat smear, informed by analysis, 305 (97%) in Secondary: 34% Council the Short Form
decision aid Women attending sensitivity analysis Tertiary: 24% (36) Health
RS: Repeat smear 6 months after randomization routine cervical University: 42% Survey ( SF-36)
screening Inclusion: Age 16-70, women Income: NR
Clinical management: with Pap smear categorized as HIV+: NR Other
“non-specific minor changes Other STIs: NR measures:
HPV: followed ALTS protocol with HPV+ women with or without HPV effect,” Smoking (calc): Cognitive,
referred for colposcopy and HPV- recalled for equivalent to ASC-US Yes: 24% emotional, and
repeat smear at 12 months No: 76% behavioral
Exclusion: Pregnant, unable outcomes and
Repeat smear: followed Australian guidelines; to complete questionnaire in knowledge
those with negative or borderline results referred for English, history of previous measured using
second repeat smear 6 months later, those with abnormal cervical smears, a variety of
moderate dyskaryosis or above referred to history of external visible instruments and
colposcopy, and those with mild dyskaryosis genital warts in previous two questions
offered choice of colposcopy or repeat smear years

Questionnaires:

Baseline questionnaire assessing psychosocial

wellbeing was conducted immediately after
consent, close to receipt of first abnormal smear
result

Follow-up questionnaires conducted at regular

intervals during the 12 months after triage testing

Screening for Cervical Cancer 219 Oregon Evidence-based Practice Center

Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

Quality
Study ID Results Other results Applicability
rating
McCaffery Psychosocial outcomes at two weeks after triage Psychosocial outcomes at two weeks after triage Fair Fair
142
2010
Trial arm mean Trial arm mean Highly
score score educated

Measure HPV IC RS Overall Pairwise Measure HPV IC RS Overall Pairwise

P value P values P value P values

SF36 mental 44.3 47.0 46.3 0.35 ─ Worry about 25% 23% 24% 0.98 ─
health combined getting cervical
score cancer**
STAI (anxiety)** 11.5 10.5 10.6 0.25 ─
CSQ (distress)** 18.7 17.9 18.2 0.62 ─ Relationship 9.2 9.4 9.0 0.39 ─
PEAPS-Q: 3.1 3.0 2.9 0.68 ─ concern: worry
infectivity** about current,
PEAPS-Q: 4.7 4.5 4.3 0.74 ─ previous and future
relationships** sexual partners

Psychosocial outcomes over one year* Psychosocial outcomes over one year

Trial arm mean Trial arm mean

score score

Measure HPV IC RS Overall Pairwise Measure HPV IC RS Overall Pairwise

P value P values P value P values

SF36 mental 46.2 48.5 45.5 0.16 ─ Worry about getting 16% 8% 15% 0.4 ─
health combined cervical cancer**
score
STAI (anxiety)** 10.9 10.5 11.4 0.27 ─ Relationship 8.7 9.1 9.0 0.15 ─
CSQ (distress)** 16.6 17.5 18.4 0.01 HPV vs. concern: worry
RS: about current,
<0.01 previous and future
PEAPS-Q: 2.7 2.8 2.5 0.53 ─ sexual partners
infectivity**
PEAPS-Q: 4.1 4.0 4.1 0.99 ─ **Higher score indicates poorer psychological outcome; for all
relationships** other measures, higher score indicates better outcome

*Area under the curve analysis used to estimate average

score per day for all outcomes
**Higher score indicates poorer psychological outcome; for all
other measures, higher score indicates better outcome

Screening for Cervical Cancer 220 Oregon Evidence-based Practice Center

Appendix C Table 4. Evidence Table for Harms of HPV Testing (KQ5)

ALTS-ASCUS-LSIL Triage Study; ASCUS-atypical squamous cells of undetermined significance; CSQ-Caregiver Survey Questionnaire; GHQ-12- General Health Questionnaire;
HIV-human immunodeficiency virus; HPV-human papillomavirus; IC-informed choice; LBC-liquid-based cytology; NR-not reported; ns-not significant; PEAPS-Q-Psychosocial Effects
of Abnormal Pap Smears Questionnaire; RS-repeat smear; SD-standard deviation; SE-standard error; S-STAI-6- Short form of Spielberger State-Trait Anxiety Inventory; STAI-state
trait anxiety inventory; STI-sexually-transmitted infection;

Screening for Cervical Cancer 221 Oregon Evidence-based Practice Center

Appendix D Table 1. Studies Excluded From the Review for KQ1

Key Question 1: When should cervical cancer screening begin, and does this vary by screening
technology or by age, sexual history, or other patient characteristics?
Reference Reason for exclusion*
Acladious NN, Mandal D. Cervical cytology screening for sexually-active teenagers. Reported outcomes do not
International Journal of STD & AIDS. 2000;11:648-650. address a key question
Baay MF, Tjalma WA, Lambrechts HA et al. Combined Pap and HPV testing in Reported outcomes do not
primary screening for cervical abnormalities: should HPV detection be delayed until address a key question
age 35? Eur J Cancer. 2005;41:2704-2708.
Bacon J, Francoeur D, Goldfarb AF, Breech LL. Abnormal pap smears in adolescents. Editorials; letters; non-
J Pediatr Adolesc Gynecol. 2003;16:157-166. systematic reviews;
opinions
Bano F, Kolhe S, Zamblera D et al. Cervical screening in under 25s: a high-risk young Provides prevalence data
population. European Journal of Obstetrics, Gynecology, & Reproductive Biology. only
2008;139:86-89.
Barnholtz-Sloan J, Patel N, Rollison D, Kortepeter K, MacKinnon J, Giuliano A. Ecological study without
Incidence trends of invasive cervical cancer in the United States by combined race link to screening
and ethnicity. Cancer Causes & Control. 2009;20:1129-1138.
Benard VB, Eheman CR, Lawson HW et al. Cervical screening in the National Breast Data not stratified by age,
and Cervical Cancer Early Detection Program, 1995-2001. Obstetrics & Gynecology. age groupings not
2004;103:564-571. appropriate, or
denominators not known
Bos AB, Rebolj M, Habbema JD, van Ballegooijen M. Nonattendance is still the main Data not stratified by age,
limitation for the effectiveness of screening for cervical cancer in the Netherlands. Int J age groupings not
Cancer. 2006;119:2372-2375. appropriate, or
denominators not known
Bray F, Loos AH, McCarron P et al. Trends in cervical squamous cell carcinoma Ecological study without
incidence in 13 European countries: changing risk and the effects of screening. link to screening
Cancer Epidemiology, Biomarkers & Prevention. 2005;14:677-686.
Bulk S, Visser O, Rozendaal L, Verheijen RH, Meijer CJ. Cervical cancer in the Ecological study without
Netherlands 1989-1998: Decrease of squamous cell carcinoma in older women, link to screening
increase of adenocarcinoma in younger women. Int J Cancer. 2005;113:1005-1009.
Bulkmans NW, Berkhof J, Bulk S et al. High-risk HPV type-specific clearance rates in Data not stratified by age,
cervical screening. Br J Cancer. 2007;96:1419-1424. age groupings not
appropriate, or
denominators not known
Canfell K, Barnabas R, Patnick J, Beral V. The predicted effect of changes in cervical Modeling study
screening practice in the UK: results from a modelling study. Br J Cancer.
2004;91:530-536.
Canfell K, Sitas F, Beral V. Cervical cancer in Australia and the United Kingdom: Data not stratified by age,
comparison of screening policy and uptake, and cancer incidence and mortality. Med J age groupings not
Aust. 2006;185:482-486. appropriate, or
denominators not known
Cecchini S, Ciatto S, Zappa M, Biggeri A. Trends in the prevalence of cervical Poor reporting
intraepithelial neoplasia grade 3 in the district of Florence, Italy. Tumori. 1995;81:330-
333.
Cervical Cancer Screening Programme. Cervical Cancer Screening Programme, Reported outcomes do not
England: 2002-03. 1-44. 2003. England, Government Statistical Service. address a key question
Chan PG, Sung HY, Sawaya GF. Changes in cervical cancer incidence after three Ecological study without
decades of screening US women less than 30 years old. Obstet Gynecol. link to screening
2003;102:765-773.
Chan PK, Chang AR, Yu MY et al. Age distribution of human papillomavirus infection Data not stratified by age,
and cervical neoplasia reflects caveats of cervical screening policies. Int J Cancer. age groupings not
2010;126:297-301. appropriate, or
denominators not known
Cohen D. BMA meeting: Doctors urge government to lower age limit for cervical Editorials; letters; non-
cancer screening. BMJ. 2009;339:b2711. systematic reviews;
opinions
Coldman A, Phillips N, Kan L, Matisic J, Benedet L, Towers L. Risk of invasive cervical Data not stratified by age,
cancer after three consecutive negative Pap smears. J Med Screen. 2003;10:196-200. age groupings not
appropriate, or
denominators not known

Screening for Cervical Cancer 222 Oregon Evidence-based Practice Center

Appendix D Table 1. Studies Excluded From the Review for KQ1

Key Question 1: When should cervical cancer screening begin, and does this vary by screening
technology or by age, sexual history, or other patient characteristics?
Reference Reason for exclusion*
Coldman A, Phillips N, Kan L, Matisic J, Benedet L, Towers L. Risk of invasive cervical Data not stratified by age,
cancer after Pap smears: the protective effect of multiple negatives. J Med Screen. age groupings not
2005;12:7-11. appropriate, or
denominators not known
Colgan TJ, Clarke A, Hakh N, Seidenfeld A. Screening for cervical disease in mature Reported outcomes do not
women: strategies for improvement. Cancer. 2002;96:195-203. address a key question
Coppell K, Paul C, Cox B. An evaluation of the National Cervical Screening Reported outcomes do not
Programme Otago site. N Z Med J. 2000;113:48-51. address a key question
Cotton SC, Sharp L, Seth R et al. Lifestyle and socio-demographic factors associated Reported outcomes do not
with high-risk HPV infection in UK women. Br J Cancer. 2007;97:133-139. address a key question
Coupe VM, Berkhof J, Bulkmans NW, Snijders PJ, Meijer CJ. Age-dependent Reported outcomes do not
prevalence of 14 high-risk HPV types in the Netherlands: implications for prophylactic address a key question
vaccination and screening. Br J Cancer. 2008;98:646-651.
Crowther S, Turner L, Magee D, Gibbons D. Role of age stratification for colposcopy Reported outcomes do not
referral following initial diagnosis of mild dyskaryosis. J Clin Pathol. 2008;61:665-668. address a key question
Fiander AN. Cervical screening in young women aged 20-24 years. Journal of Family Editorials; letters; non-
Planning & Reproductive Health Care. 2008;34:19. systematic reviews;
opinions
Fraser A, Hellmann S, Leibovici L, Levavi H. Screening for cervical cancer--an Reported outcomes do not
evidence-based approach. Eur J Gynaecol Oncol. 2005;26:372-375. address a key question
Ghosh A, Rao S, Pramanik T. Is it relevant to screen women younger than 26 years Reported outcomes do not
for precancerous and malignant cervical lesions ?[see comment]. Asian Pacific Journal address a key question
of Cancer Prevention: Apjcp. 2005;6:123-124.
Giannopoulos T, Butler-Manuel S, Tailor A, Demetriou E, Daborn L. Prevalence of Conducted solely in
high-grade CIN following mild dyskaryotic smears in different age groups.[see referred population or does
comment]. Cytopathology. 2005;16:277-280. not report routine and
referred population
outcomes separately
Guido R. Guidelines for screening and treatment of cervical disease in the adolescent. Editorials; letters; non-
Journal of Pediatric & Adolescent Gynecology. 2004;17:303-311. systematic reviews;
opinions
Hall HI, Rogers JD, Weir HK, Miller DS, Uhler RJ. Breast and cervical carcinoma Ecological study without
mortality among women in the Appalachian region of the U.S., 1976-1996. Cancer. link to screening
2000;89:1593-1602.
Hartmann, KE, Hall, SA, Nanda, K, Boggess, JF, and Zolnoun, D. Screening for Data covered in other
Cervical Cancer. ii-74. 2002. Agency for Healthcare Research and Quality. articles
Hemminki K, Li X, Mutanen P. Age-incidence relationships and time trends in cervical Ecological study without
cancer in Sweden. Eur J Epidemiol. 2001;17:323-328. link to screening
Herbert A, Anshu, Gregory M, Gupta SS, Singh N. Screen-detected invasive cervical Data not stratified by age,
carcinoma and its clinical significance during the introduction of organized screening. age groupings not
BJOG: An International Journal of Obstetrics & Gynaecology. 2009;116:854-859. appropriate, or
denominators not known
Herbert A, Holdsworth G, Kubba AA. Cervical screening: why young women should be Ecological study without
encouraged to be screened. Journal of Family Planning & Reproductive Health Care. link to screening
2008;34:21-25.
Howell LP, Tabnak F, Tudury AJ, Stoodt G. Role of Pap Test terminology and age in Data not stratified by age,
the detection of carcinoma invasive and carcinoma in situ in medically underserved age groupings not
California women. Diagn Cytopathol. 2004;30:227-234. appropriate, or
denominators not known
Hoyer H, Scheungraber C, Kuehne-Heid R et al. Cumulative 5-year diagnoses of Data not stratified by age,
CIN2, CIN3 or cervical cancer after concurrent high-risk HPV and cytology testing in a age groupings not
primary screening setting. Int J Cancer. 2005;116:136-143. appropriate, or
denominators not known
Insinga RP, Dasbach EJ, Elbasha EH, Liaw KL, Barr E. Incidence and duration of Ecological study without
cervical human papillomavirus 6, 11, 16, and 18 infections in young women: an link to screening
evaluation from multiple analytic perspectives. Cancer Epidemiology, Biomarkers &
Prevention. 2007;16:709-715.

Screening for Cervical Cancer 223 Oregon Evidence-based Practice Center

Appendix D Table 1. Studies Excluded From the Review for KQ1

Key Question 1: When should cervical cancer screening begin, and does this vary by screening
technology or by age, sexual history, or other patient characteristics?
Reference Reason for exclusion*
Insinga RP, Dasbach EJ, Elbasha EH, Liaw KL, Barr E. Progression and regression of Ecological study without
incident cervical HPV 6, 11, 16 and 18 infections in young women. Infectious Agents & link to screening
Cancer. 2007;2:15.
Jacobs MV, Walboomers JM, Snijders PJ et al. Distribution of 37 mucosotropic HPV Reported outcomes do not
types in women with cytologically normal cervical smears: the age-related patterns for address a key question
high-risk and low-risk types. Int J Cancer. 2000;87:221-227.
Kahn JA, Hillard PJ. Cervical cytology screening and management of abnormal Editorials; letters; non-
cytology in adolescent girls. J Pediatr Adolesc Gynecol. 2003;16:167-171. systematic reviews;
opinions
Kyndi M, Frederiksen K, Kruger KS. Cervical cancer incidence in Denmark over six Ecological study without
decades (1943-2002). Acta Obstet Gynecol Scand. 2006;85:106-111. link to screening
Lawson HW, Lee NC, Thames SF, Henson R, Miller DS. Cervical cancer screening Data not stratified by age,
among low-income women: results of a national screening program, 1991-1995. age groupings not
Obstet Gynecol. 1998;92:745-752. appropriate, or
denominators not known
Liu S, Semenciw R, Probert A, Mao Y. Cervical cancer in Canada: changing patterns Ecological study without
in incidence and mortality. International Journal of Gynecological Cancer. 2001;11:24- link to screening
31.
Luke C, Nguyen AM, Heard A, Kenny B, Shorne L, Roder D. Benchmarking Data not stratified by age,
epidemiological characteristics of cervical cancer in advance of change in screening age groupings not
practice and commencement of vaccination. Australian & New Zealand Journal of appropriate, or
Public Health. 2007;31:149-154. denominators not known
Massad SL, Markwell S, Cejtin HE, Collins Y. Risk of high-grade cervical intraepithelial Conducted solely in
neoplasia among young women with abnormal screening cytology. Journal of Lower referred population or does
Genital Tract Disease. 2005;9:225-229. not report routine and
referred population
outcomes separately
Mitchell H, Medley G, Higgins V. An audit of the women who died during 1994 from Data not stratified by age,
cancer of the cervix in Victoria, Australia. Aust N Z J Obstet Gynaecol. 1996;36:73-76. age groupings not
appropriate, or
denominators not known
Monteiro DL, Trajano AJ, da Silva KS, Russomano FB. Pre-invasive cervical disease Conducted solely in
and uterine cervical cancer in Brazilian adolescents: prevalence and related factors. referred population or does
Cad Saude Publica. 2006;22:2539-2548. not report routine and
referred population
outcomes separately
Moscicki AB, Cox JT. Practice improvement in cervical screening and management Editorials; letters; non-
(PICSM): symposium on management of cervical abnormalities in adolescents and systematic reviews;
young women. Journal of Lower Genital Tract Disease. 2010;14:73-80. opinions
Moscicki AB. HPV infections in adolescents. Dis Markers. 2007;23:229-234. Editorials; letters; non-
systematic reviews;
opinions
Mount SL, Papillo JL. A study of 10,296 pediatric and adolescent Papanicolaou smear Reported outcomes do not
diagnoses in northern New England. Pediatrics. 1999;103:539-545. address a key question
Nair MS, Bhandari HM, Nordin AJ. Cervical cancer in women aged less than 25: East Editorials; letters; non-
Kent experience. Journal of Obstetrics & Gynaecology. 2007;27:706-708. systematic reviews;
opinions
O'Mahony C, Steedman N, Yong M, Anderson ER, Finnegan V, Price L. Cervical Editorials; letters; non-
screening by age: let's not screen women under 25 throughout the UK. BMJ. systematic reviews;
2009;339:b3426. opinions
Omar H, Callahan P, Aggarwal S, Perkins K, Young K. Cervical pathology in West Reported outcomes do not
Virginia adolescents. W V Med J. 2000;96:408-409. address a key question
Partridge EE, bu-Rustum N, Campos S et al. Cervical cancer screening. Journal of the Editorials; letters; non-
National Comprehensive Cancer Network. 2008;6:58-82. systematic reviews;
opinions

Screening for Cervical Cancer 224 Oregon Evidence-based Practice Center

Appendix D Table 1. Studies Excluded From the Review for KQ1

Key Question 1: When should cervical cancer screening begin, and does this vary by screening
technology or by age, sexual history, or other patient characteristics?
Reference Reason for exclusion*
Petignat P, Faltin D, Goffin F et al. Age-related performance of human papillomavirus Data not stratified by age,
testing used as an adjunct to cytology for cervical carcinoma screening in a population age groupings not
with a low incidence of cervical carcinoma. Cancer. 2005;105:126-132. appropriate, or
denominators not known
Prussia PR, Gay GH, Bruce A. Analysis of cervico-vaginal (Papanicolaou) smears, in Reported outcomes do not
girls 18 years and under. West Indian Med J. 2002;51:37-39. address a key question
Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality Ecological study without
from cancer of cervix in England: evaluation based on routinely collected statistics. link to screening
BMJ. 1999;318:904-908.
Rieck GC, Tristram A, Hauke A, Fielder H, Fiander AN. Cervical screening in 20-24- Insufficient information
year olds. J Med Screen. 2006;13:64-71.
Rodriguez AC, Burk R, Herrero R et al. The natural history of human papillomavirus Data not stratified by age,
infection and cervical intraepithelial neoplasia among young women in the Guanacaste age groupings not
cohort shortly after initiation of sexual life. Sex Transm Dis. 2007;34:494-502. appropriate, or
denominators not known
Saleh MM, Seoud AA, Zaklama MS. Abnormal cervical smears in adolescents: a ten- Conducted solely in
year comparative study of demographic criteria and management. Clinical & referred population or does
Experimental Obstetrics & Gynecology. 2007;34:139-142. not report routine and
referred population
outcomes separately
Saleh MM, Seoud AA, Zaklama MS. Study of the demographic criteria and Conducted solely in
management of adolescents referred with abnormal cervical smears. Journal of referred population or does
Obstetrics & Gynaecology. 2007;27:824-827. not report routine and
referred population
outcomes separately
Saraiya M, Ahmed F, Krishnan S, Richards TB, Unger ER, Lawson HW. Cervical Ecological study without
cancer incidence in a prevaccine era in the United States, 1998-2002. Obstetrics & link to screening
Gynecology. 2007;109:t-70.
Sasieni P, Adams J, Cuzick J. Benefit of cervical screening at different ages: evidence Data not stratified by age,
from the UK audit of screening histories. Br J Cancer. 2003;89:88-93. age groupings not
appropriate, or
denominators not known
Sasieni P, Adams J. Effect of screening on cervical cancer mortality in England and Ecological study without
Wales: analysis of trends with an age period cohort model. BMJ. 1999;318:1244-1245. link to screening
Sasieni P, Castanon A, Cuzick J. What is the right age for cervical cancer screening? Editorials; letters; non-
Women's health. 2010;6:1-4. systematic reviews;
opinions
Sasieni P, Castanon A, Parkin DM. How many cervical cancers are prevented by Modeling study
treatment of screen-detected disease in young women? Int J Cancer. 2009;124:461-
464.
Sasieni, P. and Castanon, A. Call and recall cervical screening programme: screening Editorials; letters; non-
interval and age limits. Current Diagnostic Pathology 12, 114-126. 2006. systematic reviews;
opinions
Sawaya GF. Should routine screening Papanicolaou smears be done for women older Editorials; letters; non-
than 65 years? Arch Intern Med. 2004;164:243-245. systematic reviews;
opinions
Sellors JW, Karwalajtys TL, Kaczorowski J et al. Incidence, clearance and predictors Reported outcomes do not
of human papillomavirus infection in women. CMAJ Canadian Medical Association address a key question
Journal. 2003;168:421-425.
Sigurdsson K, Adalsteinsson S. Risk variables affecting high-grade Pap smears at Data not stratified by age,
second visit: effects of screening interval, year, age and low-grade smears. Int J age groupings not
Cancer. 2001;94:884-888. appropriate, or
denominators not known
Sigurdsson K, Sigvaldason H. Effectiveness of cervical cancer screening in Iceland, Data not stratified by age,
1964-2002: a study on trends in incidence and mortality and the effect of risk factors. age groupings not
Acta Obstet Gynecol Scand. 2006;85:343-349. appropriate, or
denominators not known

Screening for Cervical Cancer 225 Oregon Evidence-based Practice Center

Appendix D Table 1. Studies Excluded From the Review for KQ1

Key Question 1: When should cervical cancer screening begin, and does this vary by screening
technology or by age, sexual history, or other patient characteristics?
Reference Reason for exclusion*
Sigurdsson K, Sigvaldason H. Longitudinal trends in cervical cytological lesions and Reported outcomes do not
the effect of risk factors. A 30-year overview. Acta Obstet Gynecol Scand. address a key question
2006;85:350-358.
Sigurdsson K, Sigvaldason H. Longitudinal trends in cervical histological lesions (CIN Data covered in other
2-3+): a 25-year overview. Acta Obstet Gynecol Scand. 2006;85:359-365. articles
Sigurdsson K. Trends in cervical intra-epithelial neoplasia in Iceland through 1995: Reported outcomes do not
evaluation of targeted age groups and screening intervals. Acta Obstet Gynecol address a key question
Scand. 1999;78:486-492.
Silva CS, Souza MA, Angelo AG, Pavani R, Adad SJ, Murta EF. Increased frequency Reported outcomes do not
of abnormal Papanicolaou smears in adolescents. Archives of Gynecology & address a key question
Obstetrics. 2002;266:154-156.
Soren K, Kharbanda EO, Chen S, Westhoff C. A 6-year experience with Pap smears Provides prevalence data
in an urban adolescent practice: the scope and burden of abnormalities. Journal of only
Pediatric & Adolescent Gynecology. 2009;22:217-222.
Stuart G, Taylor G, Bancej CM et al. Report of the 2003 pan-Canadian forum on Editorials; letters; non-
cervical cancer prevention and control. J Obstet Gynaecol Can. 2004;26:1004-1028. systematic reviews;
opinions
Sykes P, Harker D, Peddie D. Findings and outcome of teenage women referred for Conducted solely in
colposcopy at Christchurch Women's Hospital, New Zealand. N Z Med J. referred population or does
2005;118:U1350. not report routine and
referred population
outcomes separately
Syrjanen S, Shabalova I, Petrovichev N et al. Acquisition of high-risk human Reported outcomes do not
papillomavirus infections and pap smear abnormalities among women in the New address a key question
Independent States of the Former Soviet Union. J Clin Microbiol. 2004;42:505-511.
Syrjanen S, Shabalova I, Petrovichev N et al. Age-specific incidence and clearance of Reported outcomes do not
high-risk human papillomavirus infections in women in the former Soviet Union. address a key question
International Journal of STD & AIDS. 2005;16:217-223.
Tiews S, Steinberg W, Schneider W, Hanrath C. Determination of the diagnostic Data not stratified by age,
accuracy of testing for high-risk (HR) human papillomavirus (HPV) types 16, 18 and 45 age groupings not
in precancerous cervical lesions: preliminary data. J Clin Virol. 2009;46:Suppl-5. appropriate, or
denominators not known
Tota J, Franco EL. Effectiveness of cervical cancer screening at different ages. Editorials; letters; non-
Women's health. 2009;5:613-616. systematic reviews;
opinions
van den Akker-van Marle ME, van Ballegooijen M, Habbema JD. Low risk of cervical Data not stratified by age,
cancer during a long period after negative screening in the Netherlands. Br J Cancer. age groupings not
2003;88:1054-1057. appropriate, or
denominators not known
van der Aa MA, de Kok IM, Siesling S, van Ballegooijen M, Coebergh JW. Does Data not stratified by age,
lowering the screening age for cervical cancer in The Netherlands make sense? Int J age groupings not
Cancer. 2008;123:1403-1406. appropriate, or
denominators not known
Vetrano G, Lombardi G, Di LG et al. Cervical intraepithelial neoplasia: risk factors for Conducted solely in
persistence and recurrence in adolescents. Eur J Gynaecol Oncol. 2007;28:189-192. referred population or does
not report routine and
referred population
outcomes separately
Wang SS, Sherman ME, Hildesheim A, Lacey JV, Jr., Devesa S. Cervical Ecological study without
adenocarcinoma and squamous cell carcinoma incidence trends among white women link to screening
and black women in the United States for 1976-2000. Cancer. 2004;100:1035-1044.
Wise J. Age for starting cervical cancer screening in England will not be lowered. BMJ. Editorials; letters; non-
2009;338:b2583. systematic reviews;
opinions

Screening for Cervical Cancer 226 Oregon Evidence-based Practice Center

Appendix D Table 1. Studies Excluded From the Review for KQ1

Key Question 1: When should cervical cancer screening begin, and does this vary by screening
technology or by age, sexual history, or other patient characteristics?
Reference Reason for exclusion*
Wright VC, Riopelle MA. Age at beginning of coitus versus chronologic age as a basis Conducted solely in
for Papanicolaou smear screening: an analysis of 747 cases of preinvasive disease. referred population or does
Am J Obstet Gynecol. 1984;149:824-830. not report routine and
referred population
outcomes separately
Wu S, Meng L, Wang S, Ma D. A comparison of four screening methods for cervical Data not stratified by age,
neoplasia. International Journal of Gynaecology & Obstetrics. 2005;91:189-193. age groupings not
appropriate, or
denominators not known
* See Appendix B Table 2 for more detailed exclusion criteria

Screening for Cervical Cancer 227 Oregon Evidence-based Practice Center

Appendix D Table 2. Studies Excluded From the Review for KQ2

Key Question 2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?
Reference Reason for exclusion*
Abulafia O, Pezzullo JC, Sherer DM. Performance of ThinPrep liquid-based cervical Includes studies that do not
cytology in comparison with conventionally prepared Papanicolaou smears: a meet design criteria
quantitative survey. Gynecol Oncol. 2003;90:137-144.
Almonte M, Ferreccio C, Winkler JL et al. Cervical screening by visual inspection, Colposcopy and/or histology
HPV testing, liquid-based and conventional cytology in Amazonian Peru. Int J only in positives
Cancer. 2007;121:796-802.
Angstetra D, Tait T, Tan J, Symonds I. Should liquid-based cytology be performed Screening conducted solely in
prior to colposcopy? A comparison of the accuracy, unsatisfactory rates and cost in referred population or does
a tertiary referral setting. Australian & New Zealand Journal of Obstetrics & not report routine and referred
Gynaecology. 2009;49:681-684. outcomes separately
Anton RC, Ramzy I, Schwartz MR, Younes P, Chakraborty S, Mody DR. Should the Reported outcomes do not
cytologic diagnosis of "atypical squamous cells of undetermined significance" be address a key question
qualified? An assessment including comparison between conventional and liquid-
based technologies. Cancer. 2001;93:93-99.
Aponte-Cipriani SL, Teplitz C, Rorat E, Savino A, Jacobs AJ. Cervical smears Does not systematically apply
prepared by an automated device versus the conventional method. A comparative reference standard
analysis. Acta Cytol. 1995;39:623-630.
Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid Includes studies that do not
Compared With Conventional Cervical Cytology: A Systematic Review and Meta- meet design criteria
analysis. Obstet Gynecol. 2008;111:167-177.
Ashfaq R, Gibbons D, Vela C, Saboorian MH, Iliya F. ThinPrep Pap Test. Accuracy Does not systematically apply
for glandular disease. Acta Cytol. 1999;43:81-85. reference standard
Atkins KA, Jeronimo J, Stoler MH, ALTS Group. Description of patients with Reported outcomes do not
squamous cell carcinoma in the atypical squamous cells of undetermined address a key question
significance/low-grade squamous intraepithelial lesion triage study. Cancer.
2006;108:212-221.
Australian Health Technology Advisory Committee. Review of Automated and Semi- Focus on excluded screening
Automated Cervical Screening Devices. 1-86. 1998. Canberra, Commonwealth methods
Department of Health and Family Services.
Awen C, Hathway S, Eddy W, Voskuil R, Janes C. Efficacy of ThinPrep preparation Does not systematically apply
of cervical smears: a 1,000-case, investigator-sponsored study. Diagn Cytopathol. reference standard
1994;11:33-36.
Bacon J, Francoeur D, Goldfarb AF, Breech LL. Abnormal pap smears in Editorials, letters, non-
adolescents. J Pediatr Adolesc Gynecol. 2003;16:157-166. systematic review, opinion or
case-control
Bai H, Sung CJ, Steinhoff MM. ThinPrep Pap Test promotes detection of glandular Editorials, letters, non-
lesions of the endocervix. Diagn Cytopathol. 2000;23:19-22. systematic review, opinion or
case-control
Baker JJ. Conventional and liquid-based cervicovaginal cytology: a comparison Physician choice of cytology
study with clinical and histologic follow-up. Diagn Cytopathol. 2002;27:185-188.
Bastian, L., Datta, S., Hasselblad, V., Hickey, J., Myers, E., and Nanda, K. Evidence Precedes search period
Report No. 5, Summary. Evaluation of Cervical Cytology. 5. 1999. Rockville, MD,
Agency for Heath Care Policy and Research.
Beerman H, van-Dorst EB, Kuenen B, V, Hogendoorn PC. Superior performance of Does not systematically apply
liquid-based versus conventional cytology in a population-based cervical cancer reference standard
screening program. SO: Gynecologic oncology. 2009;112:572-576.
Belinson J, Qiao YL, Pretorius R et al. Shanxi Province Cervical Cancer Screening No comparison to
Study: a cross-sectional comparative trial of multiple techniques to detect cervical conventional cytology
neoplasia. Gynecol Oncol. 2001;83:439-444.
Bergeron C, Fagnani F. Performance of a new, liquid-based cervical screening Colposcopy and/or histology
technique in the clinical setting of a large French laboratory. Acta Cytol. only in positives
2003;47:753-761.
Bergeron C. Accuracy of thin-layer cytology in patients undergoing cervical cone Screening conducted solely in
biopsy. Acta Cytol. 2001;519-524. referred population or does
not report routine and referred
outcomes separately

Screening for Cervical Cancer 228 Oregon Evidence-based Practice Center

Appendix D Table 2. Studies Excluded From the Review for KQ2

Key Question 2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?
Reference Reason for exclusion*
Bernstein SJ, Sanchez-Ramos L, Ndubisi B. Liquid-based cervical cytologic smear Precedes search period
study and conventional Papanicolaou smears: a metaanalysis of prospective studies
comparing cytologic diagnosis and sample adequacy. Am J Obstet Gynecol.
2001;185:308-317.
Biscotti CV, O'Brien DL, Gero MA, Gramlich TL, Kennedy AW, Easley KA. Thin- Does not systematically apply
layer Pap test vs. conventional Pap smear. Analysis of 400 split samples. J Reprod reference standard
Med. 2002;47:9-13.
Bishop JW, Bigner SH, Colgan TJ et al. Multicenter masked evaluation of AutoCyte Does not systematically apply
PREP thin layers with matched conventional smears. Including initial biopsy results. reference standard
Acta Cytol. 1998;42:189-197.
Bishop JW. Comparison of the CytoRich system with conventional cervical cytology. Does not systematically apply
Preliminary data on 2,032 cases from a clinical trial site. Acta Cytol. 1997;41:15-23. reference standard
Bolick DR, Hellman DJ. Laboratory implementation and efficacy assessment of the Physician choice of cytology
ThinPrep cervical cancer screening system. Acta Cytol. 1998;42:209-213.
Boon ME, Rijkaart DC, Ouwerkerk-Noordam E, Korporaal H. Dutch solutions for Reported outcomes do not
liquid-based cytology: analysis of unsatisfactory slides and HPV testing of equivocal address a key question
cytology. Diagn Cytopathol. 2006;34:644-648.
Bratti MC, Rodriguez AC, Schiffman M et al. Description of a seven-year prospective Reference standard not
study of human papillomavirus infection and cervical neoplasia among 10000 independent of screening
women in Guanacaste, Costa Rica. Rev Panam Salud Publica. 2004;15:75-89. ‡
test
Bur M, Knowles K, Pekow P, Corral O, Donovan J. Comparison of ThinPrep Does not systematically apply
preparations with conventional cervicovaginal smears. Practical considerations. Acta reference standard
Cytol. 1995;39:631-642.
Canda MT, Demir N, Sezer O, Doganay L, Ortac R. Clinical results of the liquid- Does not systematically apply
based cervical cytology tool, Liqui-PREP, in comparison with conventional smears reference standard
for detection of squamous cell abnormalities. Asian Pacific Journal of Cancer
Prevention: Apjcp. 2009;10:399-402.
Carpenter AB, Davey DD. ThinPrep Pap Test: performance and biopsy follow-up in Editorials, letters, non-
a university hospital. Cancer. 1999;87:105-112. systematic review, opinion or
case-control
Celik C, Gezginc K, Toy H, Findik S, Yilmaz O. A comparison of liquid-based Colposcopy and/or histology
cytology with conventional cytology. International Journal of Gynaecology & only in positives
Obstetrics. 2008;100:163-166.
Cheung AN, Szeto EF, Leung BS, Khoo US, Ng AW. Liquid-based cytology and Reported outcomes do not
conventional cervical smears: a comparison study in an Asian screening population. address a key question
Cancer. 2003;99:331-335.
Cheuvront DA, Elston RJ Bishop JW. Effect of a thin-layer preparation system on Does not systematically apply
workload in a cytology laboratory. Laboratory Medicine 29, 174-179. 1998. reference standard
Chung JH, Park EJ, Choi YD et al. Efficacy assessment of CellSlide in liquid-based Focus on excluded screening
gynecologic cytology. Gynecol Oncol. 2005;99:597-602. methods
Clavel C, Masure M, Bory JP et al. Human papillomavirus testing in primary Poor reporting
screening for the detection of high-grade cervical lesions: a study of 7932 women.
Br J Cancer. 2001;84:1616-1623.
Cochand-Priollet B, Cartier I, de Cremoux P et al. Cost-effectiveness of liquid-based Provides data already
cytology with or without hybrid-capture II HPV test compared with conventional Pap covered in other article
smears: a study by the French Society of Clinical Cytology. Diagn Cytopathol.
2005;33:338-343.
Confortini M, Bulgaresi P, Cariaggi MP et al. Comparing conventional and liquid- Poor reporting
based smears from a consecutive series of 297 subjects referred to colposcopy
assessment. Cytopathology. 2004;15:168-170.
Confortini M, Bulgaresi P, Cariaggi MP et al. Conventional pap smear and liquid- Screening conducted solely in
based cervical cytology smear: comparison from the same patient. Tumori. referred population or does
2002;88:288-290. not report routine and referred
outcomes separately
Corkill MM, Knapp DC, Hutchinson MLM. Improved Accuracy for Cervical Cytology Does not systematically apply
with the ThinPrep Method and the Endocervical Brush-Spatula Collection reference standard
Procedure. Journal of Lower Genital Tract Disease. 1998;2:12-16.

Screening for Cervical Cancer 229 Oregon Evidence-based Practice Center

Appendix D Table 2. Studies Excluded From the Review for KQ2

Key Question 2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?
Reference Reason for exclusion*
Davey E, Barratt A, Irwig L et al. Effect of study design and quality on unsatisfactory Includes studies that do not
rates, cytology classifications, and accuracy in liquid-based versus conventional meet design criteria
cervical cytology: a systematic review. Lancet. 2006;367:122-132.
Davey E, d'Assuncao J, Irwig L et al. Accuracy of reading liquid based cytology Focus on excluded screening
slides using the ThinPrep Imager compared with conventional cytology: prospective methods
study. BMJ. 2007;335:31.
Day SJ, Deszo EL, Freund GG. Dual sampling of the endocervix and its impact on Reported outcomes do not
AutoCyte Prep endocervical adequacy. Am J Clin Pathol. 2002;118:41-46. address a key question
Diaz-Rosario LA, Kabawat SE. Performance of a fluid-based, thin-layer Does not systematically apply
papanicolaou smear method in the clinical setting of an independent laboratory and reference standard
an outpatient screening population in New England. Arch Pathol Lab Med.
1999;123:817-821.
Dupree WB, Suprun HZ, Beckwith DG, Shane JJ, Lucente V. The promise and risk Does not systematically apply
of a new technology: The Lehigh Valley Hospital's experience with liquid-based reference standard
cervical cytology. Cancer. 1998;84:202-207.
Ferenczy A, Franco E, Arseneau J, Wright TC, Richart RM. Diagnostic performance Reported outcomes do not
of Hybrid Capture human papillomavirus deoxyribonucleic acid assay combined with address a key question
liquid-based cytologic study. Am J Obstet Gynecol. 1996;175:651-656.
Ferenczy A, Robitaille J, Franco E, Arseneau J, Richart RM, Wright TC. Screening conducted solely in
Conventional cervical cytologic smears vs. ThinPrep smears. A paired comparison referred population or does
study on cervical cytology. Acta Cytol. 1996;40:1136-1142. not report routine and referred
outcomes separately
Ferreccio C, Bratti MC, Sherman ME et al. A comparison of single and combined Reference standard not
visual, cytologic, and virologic tests as screening strategies in a region at high risk of independent of screening test
cervical cancer. Cancer Epidemiology, Biomarkers & Prevention. 2003;12:815-823.
Ferris DG, Heidemann NL, Litaker MS, Crosby JH, Macfee MS. The efficacy of Does not systematically apply
liquid-based cervical cytology using direct-to-vial sample collection. J Fam Pract. reference standard
2000;49:1005-1011.
Fremont-Smith M, Marino J, Griffin B, Spencer L, Bolick D. Comparison of the Reported outcomes do not
SurePath liquid-based Papanicolaou smear with the conventional Papanicolaou address a key question
smear in a multisite direct-to-vial study. Cancer. 2004;102:269-279.
Genova NJ. Evidence-based medicine--in real time. Comparing methods of cervical Editorials, letters, non-
Ca screening. JAAPA. 2000;13:55-60, 63. systematic review, opinion or
case-control
Geyer JW, Hancock F, Carrico C, Kirkpatrick M. Preliminary evaluation of Cyto-Rich: Does not systematically apply
an improved automated cytology preparation. Diagn Cytopathol. 1993;9:417-422. reference standard
Girianelli VR, Thuler LC, Szklo M et al. Comparison of human papillomavirus DNA Focus on excluded screening
tests, liquid-based cytology and conventional cytology for the early detection of methods
cervix uteri cancer. Eur J Cancer Prev. 2006;15:504-510.
Guidos BJ, Selvaggi SM. Detection of endometrial adenocarcinoma with the Physician choice of cytology
ThinPrep Pap test. Diagn Cytopathol. 2000;23:260-265.
Guidos BJ, Selvaggi SM. Use of the Thin Prep Pap Test in clinical practice. Diagn Physician choice of cytology
Cytopathol. 1999;20:70-73.
Guo M, Hu L, Martin L, Liu S, Baliga M, Hughson MD. Accuracy of liquid-based Pap No comparison to
tests: comparison of concurrent liquid-based tests and cervical biopsies on 782 conventional cytology
women with previously abnormal Pap smears. Acta Cytol. 2005;49:132-138.
Harkness CB, Theofrastous JP, Ibrahim SN, Galvin SL, Lawrence HC. Colposcopy and/or histology
Papanicolaou and thin-layer cervical cytology with colposcopic biopsy control. A only in positives
comparison. J Reprod Med. 2003;48:681-686.
Hartmann KE, Nanda K, Hall S, Myers E. Technologic advances for evaluation of Provides data already
cervical cytology: is newer better? Obstet Gynecol Surv. 2001;56:765-774. covered in other article
Hartmann, KE, Hall, SA, Nanda, K, Boggess, JF, and Zolnoun, D. Screening for Provides data already
Cervical Cancer. ii-74. 2002. Agency for Healthcare Research and Quality. covered in other article
Hatch KD, Sheets E, Kennedy A, Ferris DG, Darragh T, Twiggs L. Multicenter direct Editorials, letters, non-
to vial evaluation of a liquid-based pap test. J Low Genit Tract Dis. 2004;8:308-312. systematic review, opinion or
case-control

Screening for Cervical Cancer 230 Oregon Evidence-based Practice Center

Appendix D Table 2. Studies Excluded From the Review for KQ2

Key Question 2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?
Reference Reason for exclusion*
Hatch, K. D. Multi-site clinical outcome trial to evaluate performance of the ThinPrep Editorials, letters, non-
test. Obstet Gynecol 95[4, Suppl. 1], S51. 2000. systematic review, opinion or
case-control
HAYES and Inc. Thin-layer pap preparations for detecting cervical cancer. 2003. Editorials, letters, non-
systematic review, opinion or
case-control
Health Technology Advisory Committee. Screening for cervical cancer: recent Editorials, letters, non-
advances. 2002. systematic review, opinion or
case-control
Herrero R, Schiffman MH, Bratti C et al. Design and methods of a population-based Reference standard not
natural history study of cervical neoplasia in a rural province of Costa Rica: the independent of screening test
Guanacaste Project. Rev Panam Salud Publica. 1997;1:362-375.
Hessling JJ, Raso DS, Schiffer B, Callicott J, Jr., Husain M, Taylor D. Effectiveness Does not systematically apply
of thin-layer preparations vs. conventional Pap smears in a blinded, split-sample reference standard
study. Extended cytologic evaluation. J Reprod Med. 2001;46:880-886.
Howell LP, Davis RL, Belk TI, Agdigos R, Lowe J. The AutoCyte preparation system Does not systematically apply
for gynecologic cytology. Acta Cytol. 1998;42:171-177. reference standard
Hussein T, Desai M, Tomlinson A, Kitchener HC. The comparative diagnostic Screening conducted solely in
accuracy of conventional and liquid-based cytology in a colposcopic setting. BJOG: referred population or does
An International Journal of Obstetrics & Gynaecology. 2005;112:1542-1546. not report routine and referred
outcomes separately
Hutchinson ML, Agarwal P, Denault T, Berger B, Cibas ES. A new look at cervical Does not systematically apply
cytology. ThinPrep multicenter trial results. Acta Cytol. 1992;36:499-504. reference standard
Hutchinson ML, Cassin CM, Ball HG, III. The efficacy of an automated preparation Does not systematically apply
device for cervical cytology. Am J Clin Pathol. 1991;96:300-305. reference standard
Hutchinson ML, Zahniser DJ, Sherman ME et al. Utility of liquid-based cytology for Reference standard not
cervical carcinoma screening: results of a population-based study conducted in a independent of screening test
region of Costa Rica with a high incidence of cervical carcinoma. Cancer.
1999;87:48-55.
Inhorn SLM, Wilbur DM, Zahniser DP, Linder JM. Validation of the ThinPrep Reported outcomes do not
Papanicolaou Test for Cervical Cancer Diagnosis. Journal of Lower Genital Tract address a key question
Disease. 1998;2:212.
Institute for Clinical Systems Improvement. Liquid-based cervical cytology. 2003. Editorials, letters, non-
systematic review, opinion or
case-control
Kahn JA, Hillard PJ. Cervical cytology screening and management of abnormal Editorials, letters, non-
cytology in adolescent girls. J Pediatr Adolesc Gynecol. 2003;16:167-171. systematic review, opinion or
case-control
Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N. Liquid-based Includes studies that do not
cytology in cervical screening: an updated rapid and systematic review and meet design criteria
economic analysis. Health Technol Assess. 2004;8:iii, 1-iii,78.
Kim HS, Park JS, Park JY et al. Comparison of two preparation methods for Screening conducted solely in
endocervical evaluation. Acta Cytol. 2007;51:742-748. referred population or does
not report routine and referred
outcomes separately
Kim JJ, Leung GM, Woo PP, Goldie SJ. Cost-effectiveness of organized versus Editorials, letters, non-
opportunistic cervical cytology screening in Hong Kong. J Public Health (Oxf). systematic review, opinion or
2004;26:130-137. case-control
Klinkhamer PJ, Meerding WJ, Rosier PF, Hanselaar AG. Liquid-based cervical Precedes search period
cytology. Cancer. 2003;99:263-271.
Kruger J. Randomized pilot study comparing rates of endocervical cell recovery Does not systematically apply
between conventional pap smears and liquid-based cytology in a pregnant reference standard
population. Journal of Lower Genital Tract Disease. 2003;101-103.
Lancaster JM RSB. Evaluation of three cervical cytology screening techniques for Focus on comparison of
use with liquid-based preparations. Adequacy of the endocervical component. cytologic collection tools
Gynecol Oncol. 2001;293-294.
Laverty CR, Farnsworth A, Thurloe JK, Grieves A, Bowditch R. Evaluation of the Does not systematically apply
CytoRich slide preparation process. Anal Quant Cytol Histol. 1997;19:239-245. reference standard

Screening for Cervical Cancer 231 Oregon Evidence-based Practice Center

Appendix D Table 2. Studies Excluded From the Review for KQ2

Key Question 2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?
Reference Reason for exclusion*
Laverty CR, Thurloe JK, Redman NL, Farnsworth A. An Australian trial of ThinPrep: Does not systematically apply
a new cytopreparatory technique. Cytopathology. 1995;6:140-148. reference standard
Lee KR, Ashfaq R, Birdsong GG, Corkill ME, McIntosh KM, Inhorn SL. Comparison Does not systematically apply
of conventional Papanicolaou smears and a fluid-based, thin-layer system for reference standard
cervical cancer screening. Obstet Gynecol. 1997;90:278-284.
Lerma E, Quintana MJ, Quilez M et al. Effectiveness of liquid-based cytology and Colposcopy and/or histology
papanicolaou tests in a low risk population. Acta Cytol. 2007;51:399-406. only in positives
Levine T. ThinPrep LBC cervical sample. Cytopathology. 2007;18:391. Editorials, letters, non-
systematic review, opinion or
case-control
Longatto FA, Pereira SM, Di LC et al. DCS liquid-based system is more effective Focus on excluded screening
than conventional smears to diagnosis of cervical lesions: study in high-risk methods
population with biopsy-based confirmation. Gynecol Oncol. 2005;97:497-500.
Longatto-Filho A, Maeda MY, Erzen M et al. Conventional Pap smear and liquid- Colposcopy and/or histology
based cytology as screening tools in low-resource settings in Latin America: only in positives
experience of the Latin American screening study. Acta Cytol. 2005;49:500-506.
Luthra UK CM. Performance of monolayered cervical smears in a gynecology Does not systematically apply
outpatient setting in Kuwait. Acta Cytol. 2002;303-310. reference standard
Maccallini V, Angeloni C, Caraceni D et al. Comparison of the conventional cervical Colposcopy and/or histology
smear and liquid-based cytology: results of a controlled, prospective study in the only in positives
Abruzzo Region of Italy. SO: Acta Cytologica. 2008;52:568-574.
Malle D, Pateinakis P, Chakka E, Destouni C. Experience with a thin-layer, liquid- Does not systematically apply
based cervical cytologic screening method. Acta Cytol. 2003;47:129-134. reference standard
Marino JF, Fremont-Smith M. Direct-to-vial experience with AutoCyte PREP in a Does not systematically apply
small New England regional cytology practice. J Reprod Med. 2001;46:353-358. reference standard
Masumoto N, Fujii T, Ishikawa M et al. Papanicolaou tests and molecular analyses Poor reporting
using new fluid-based specimen collection technology in 3000 Japanese women. Br
J Cancer. 2003;88:1883-1888.
Mattosinho de Castro Ferraz Mda, Nicolau SM, Stavale JN et al. Cervical biopsy- Focus on excluded screening
based comparison of a new liquid-based thin-layer preparation with conventional methods
Pap smears. Diagn Cytopathol. 2004;30:220-226.
McGoogan E, Reith A. Would monolayers provide more representative samples and Focus on comparison of
improved preparations for cervical screening? Overview and evaluation of systems cytologic collection tools
available. Acta Cytol. 1996;40:107-119.
McGoogan, E. Improved adequacy rates using ThinPrep Pap test for routine Reported outcomes do not
cytopahtology. Cytopathology 10 (Suppl 1), 2. 1999. address a key question
Medical Services Advisory Committee. Liquid based cytology for cervical screening. Includes studies that do not
2002. meet design criteria
Minge L, Fleming M, VanGeem T, Bishop JW. AutoCyte Prep system vs. Does not systematically apply
conventional cervical cytology. Comparison based on 2,156 cases. J Reprod Med. reference standard
2000;45:179-184.
Monsonego J, utillo-Touati A, Bergeron C et al. Liquid-based cytology for primary Does not systematically apply
cervical cancer screening: a multi-centre study. Br J Cancer. 2001;84:360-366. reference standard
Moscicki AB, Cox JT. Practice improvement in cervical screening and management Editorials, letters, non-
(PICSM): symposium on management of cervical abnormalities in adolescents and systematic review, opinion or
young women. Journal of Lower Genital Tract Disease. 2010;14:73-80. case-control
Moseley RP, Paget S. Liquid-based cytology: is this the way forward for cervical Precedes search period
screening? Cytopathology. 2002;13:71-82.
Moss SM, Gray A, Legood R, and Henstock E. Evaluation of hpv/lvc: cervical Reported outcomes do not
screening pilot studies. First report to the Department of Health on LBC. 1-96. address a key question
2003.
Nanda K, McCrory DC, Myers ER et al. Accuracy of the Papanicolaou test in Precedes search period
screening for and follow-up of cervical cytologic abnormalities: a systematic review.
Ann Intern Med. 2000;132:810-819.
NHS, Quality, I. The use of liquid-based cytology for cervical screening (review). Editorials, letters, non-
2003. systematic review, opinion or
case-control

Screening for Cervical Cancer 232 Oregon Evidence-based Practice Center

Appendix D Table 2. Studies Excluded From the Review for KQ2

Key Question 2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?
Reference Reason for exclusion*
Noorani, H. Z., Brown, A., Skidmore, B., and Stuart, G. C. E. Liquid-based cytology Includes studies that do not
and human papillomavirus testing in cervical cancer screening. 2003. meet design criteria
Obwegeser JH BS. Does liquid-based technology really improve detection of Colposcopy and/or histology
cervical neoplasia? A prospective, randomized trial comparing the ThinPrep Pap only in positives
Test with the conventional Pap Test, including follow-up of HSIL cases. Acta Cytol.
2001;709-714.
Pan Q, Belinson JL, Li L et al. A thin-layer, liquid-based pap test for mass screening No comparison to
in an area of China with a high incidence of cervical carcinoma. A cross-sectional, conventional cytology
comparative study. Acta Cytol. 2003;47:45-50.
Papillo JL, Zarka MA, St John TL. Evaluation of the ThinPrep Pap test in clinical Does not systematically apply
practice. A seven-month, 16,314-case experience in northern Vermont. Acta Cytol. reference standard
1998;42:203-208.
Park IA, Lee SN, Chae SW, Park KH, Kim JW, Lee HP. Comparing the accuracy of Colposcopy and/or histology
ThinPrep Pap tests and conventional Papanicolaou smears on the basis of the only in positives
histologic diagnosis: a clinical study of women with cervical abnormalities. Acta
Cytol. 2001;45:525-531.
Partridge EE, bu-Rustum N, Campos S et al. Cervical cancer screening. Journal of Editorials, letters, non-
the National Comprehensive Cancer Network. 2008;6:58-82. systematic review, opinion or
case-control
Payne N, Chilcott J, McGoogan E. Liquid-based cytology in cervical screening: a Precedes search period
rapid and systematic review. Health Technol Assess. 2000;4:1-73.
Pretorius RG, Kim RJ, Belinson JL, Elson P, Qiao YL. Inflation of sensitivity of No comparison to
cervical cancer screening tests secondary to correlated error in colposcopy. Journal conventional cytology
of Lower Genital Tract Disease. 2006;10:5-9.
Ring M, Bolger N, O'Donnell M et al. Evaluation of liquid-based cytology in cervical Does not systematically apply
screening of high-risk populations: a split study of colposcopy and genito-urinary reference standard
medicine populations. Cytopathology. 2002;13:152-159.
Roberts JM, Gurley AM, Thurloe JK, Bowditch R, Laverty CR. Evaluation of the Does not systematically apply
ThinPrep Pap test as an adjunct to the conventional Pap smear. Med J Aust. reference standard
1997;167:466-469.
Roberts JM, Thurloe JK, Bowditch RC et al. A three-armed trial of the ThinPrep Focus on excluded screening
Imaging System. Diagn Cytopathol. 2007;35:96-102. methods
Ronco G, Giorgi RP, Carozzi F et al. Human papillomavirus testing and liquid-based Differential loss to followup
cytology in primary screening of women younger than 35 years: results at and referral criteria
recruitment for a randomised controlled trial. The lancet oncology. 2006;7:547-555.
Rosenthal DL, Geddes S, Trimble CL, Carson KA, Alli PM. The PapSpin: a Focus on excluded screening
reasonable alternative to other, more expensive liquid-based Papanicolaou tests. methods
Cancer. 2006;108:137-143.
Sheets EE, Constantine NM, Dinisco S, Dean B, Cibas ES. Colposcopically Directed Does not systematically apply
Biopsies Provide a Basis for Comparing the Accuracy of ThinPrep and reference standard
Papanicolaou Smears. Obstetrical & Gynecological Survey. 1995;50:659-661.
Sherman M, Schiffman M. Effects of age and human papilloma viral load on Reported outcomes do not
colposcopy triage: data from the randomized Atypical Squamous Cells of address a key question
Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage
Study (ALTS). J Natl Cancer Inst. 2002;102-107.
Sherman ME, Mendoza M, Lee KR et al. Performance of liquid-based, thin-layer Does not systematically apply
cervical cytology: correlation with reference diagnoses and human papillomavirus reference standard
testing. Mod Pathol. 1998;11:837-843.
Sherman ME, Schiffman MH, Lorincz AT et al. Cervical specimens collected in liquid Reported outcomes do not
buffer are suitable for both cytologic screening and ancillary human papillomavirus address a key question
testing. Cancer. 1997;81:89-97.
Shield PW, Nolan GR, Phillips GE, Cummings MC. Improving cervical cytology Does not systematically apply
screening in a remote, high risk population. Med J Aust. 1999;170:255-258. reference standard
Sprenger E, Schwarzmann P, Kirkpatrick M et al. The false negative rate in cervical Does not systematically apply
cytology. Comparison of monolayers to conventional smears. Acta Cytol. reference standard
1996;40:81-89.
Stevens MW, Nespolon WW, Milne AJ, Rowland R. Evaluation of the CytoRich Does not systematically apply
technique for cervical smears. Diagn Cytopathol. 1998;18:236-242. reference standard

Screening for Cervical Cancer 233 Oregon Evidence-based Practice Center

Appendix D Table 2. Studies Excluded From the Review for KQ2

Key Question 2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?
Reference Reason for exclusion*
Strander B, ndersson-Ellstrom A, Milsom I, Radberg T, Ryd W. Liquid-based Does not systematically apply
cytology versus conventional Papanicolaou smear in an organized screening reference standard
program : a prospective randomized study. Cancer. 2007;111:285-291.
Stuart G, Taylor G, Bancej CM et al. Report of the 2003 pan-Canadian forum on Editorials, letters, non-
cervical cancer prevention and control. J Obstet Gynaecol Can. 2004;26:1004-1028. systematic review, opinion or
case-control
Sulik SM, Kroeger K, Schultz JK, Brown JL, Becker LA, Grant WD. Are fluid-based Precedes search period
cytologies superior to the conventional Papanicolaou test? A systematic review. J
Fam Pract. 2001;50:1040-1046.
Syrjanen K, Derchain S, Roteli-Martins C et al. Value of conventional pap smear, Poor reporting
liquid-based cytology, visual inspection and human papillomavirus testing as
optional screening tools among Latin American women <35 and > or =35 years of
age: experience from the Latin American Screening Study. Acta Cytol. 2008;52:641-
653.
Syrjanen K, Naud P, Derchain S et al. Comparing PAP smear cytology, aided visual Reported outcomes do not
inspection, screening colposcopy, cervicography and HPV testing as optional address a key question
screening tools in Latin America. Study design and baseline data of the LAMS
study. Anticancer Res. 2005;25:3469-3480.
Takahashi M, Naito M. Application of the CytoRich monolayer preparation system Does not systematically apply
for cervical cytology. A prelude to automated primary screening. Acta Cytol. reference standard
1997;41:1785-1789.
Tench W. Preliminary assessment of the AutoCyte PREP. Direct-to-vial Does not systematically apply
performance. J Reprod Med. 2000;45:912-916. reference standard
Tezuka F, Oikawa H, Shuki H, Higashiiwai H. Diagnostic efficacy and validity of the Colposcopy and/or histology
ThinPrep method in cervical cytology. Acta Cytol. 1996;40:513-518. only in positives
Tuncer ZS, Baaran M, Sezgin Y, Firat P, Mocan KG. Clinical results of a split Colposcopy and/or histology
sample liquid-based cytology (ThinPrep) study of 4,322 patients in a Turkish only in positives
institution. Eur J Gynaecol Oncol. 2005;26:646-648.
Utagawa ML, Pereira SM, Makabe S et al. Pap test in a high-risk population Focus on excluded screening
comparison of conventional and liquid-base cytology. Diagn Cytopathol. methods
2004;31:169-172.
Vassilakos P, Cossali D, Albe X, Alonso L, Hohener R, Puget E. Efficacy of Reported outcomes do not
monolayer preparations for cervical cytology: emphasis on suboptimal specimens. address a key question
Acta Cytol. 1996;40:496-500.
Vassilakos P, Griffin S, Megevand E, Campana A. CytoRich liquid-based cervical Does not systematically apply
cytologic test. Screening results in a routine cytopathology service. Acta Cytol. reference standard
1998;42:198-202.
Vassilakos P, Saurel J, Rondez R. Direct-to-vial use of the AutoCyte PREP liquid- Does not systematically apply
based preparation for cervical-vaginal specimens in three European laboratories. reference standard
Acta Cytol. 1999;43:65-68.
Wang TY, Chen HS, Yang YC, Tsou MC. Comparison of fluid-based, thin-layer Does not systematically apply
processing and conventional Papanicolaou methods for uterine cervical cytology. J reference standard
Formos Med Assoc. 1999;98:500-505.
Weintraub J, Morabia A. Efficacy of a liquid-based thin layer method for cervical Does not systematically apply
cancer screening in a population with a low incidence of cervical cancer. Diagn reference standard
Cytopathol. 2000;22:52-59.
Weintraub, J. The coming revolution in cervical cytology: a pathologist's guide for Editorials, letters, non-
the clinician. References en Gynecologie Obstetrique 5, 1-6. 1997. systematic review, opinion or
case-control
Wilbur DC, Cibas ES, Merritt S, James LP, Berger BM, Bonfiglio TA. ThinPrep Does not systematically apply
Processor. Clinical trials demonstrate an increased detection rate of abnormal reference standard
cervical cytologic specimens. Am J Clin Pathol. 1994;101:209-214.
Wilbur DC, Dubeshter B, Angel C, Atkison KM. Use of thin-layer preparations for Setting not primary care or
gynecologic smears with emphasis on the cytomorphology of high-grade comparable
intraepithelial lesions and carcinomas. Diagn Cytopathol. 1996;14:201-211.
Wilbur DC, Facik MS, Rutkowski MA, Mulford DK, Atkison KM. Clinical trials of the Does not systematically apply
CytoRich specimen-preparation device for cervical cytology. Preliminary results. reference standard
Acta Cytol. 1997;41:24-29.

Screening for Cervical Cancer 234 Oregon Evidence-based Practice Center

Appendix D Table 2. Studies Excluded From the Review for KQ2

Key Question 2: To what extent does liquid-based cytology improve sensitivity, specificity, and diagnostic
yield and reduce indeterminate results and inadequate samples compared to conventional cervical cytology?
Reference Reason for exclusion*
Yeoh GP, Chan KW, Lauder I, Lam MB. Evaluation of the ThinPrep Papanicolaou Physician choice of cytology
test in clinical practice: 6-month study of 16,541 cases with histological correlation in
220 cases. Hong Kong Med J. 1999;5:233-239.
Yeoh GP, Chan KW. Cell block preparation on residual ThinPrep sample. Diagn Reported outcomes do not
Cytopathol. 1999;21:427-431. address a key question
Zhu J, Norman I, Elfgren K et al. A comparison of liquid-based cytology and Pap Screening conducted solely in
smear as a screening method for cervical cancer. Oncol Rep. 2007;18:157-160. referred population or does
not report routine and referred
outcomes separately
Zielinski SL. Trial quickly changed management of cervical abnormalities. J Natl Editorials, letters, non-
Cancer Inst. 2005;97:479-480. systematic review, opinion or
case-control
* See Appendix B Table 2 for more detailed exclusion criteria
‡
One example of a large study that did not meet criteria for our review is the Guanacaste study, a population-
based study of over 10,000 high-risk women that compared liquid-based to conventional cytology. In this study, the
final histologic diagnosis included the results of the screening tests. Additionally, the reference standard of
colposcopy and biopsy was not systematically applied.

Screening for Cervical Cancer 235 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Adam E, Kaufman RH, Berkova Z, Icenogle J, Reeves WC. Is human papillomavirus Included women with
testing an effective triage method for detection of high-grade (grade 2 or 3) cervical repeated abnormal smears
intraepithelial neoplasia? Am J Obstet Gynecol. 1998;1998:1235-1244. or abnormal smear other
than ASC
Adamopoulou M, Kalkani E, Charvalos E, Avgoustidis D, Haidopoulos D, Yapijakis C. Included women with
Comparison of cytology, colposcopy, HPV typing and biomarker analysis in cervical repeated abnormal smears
neoplasia. Anticancer Res. 2009;29:3401-3409. or abnormal smear other
than ASC
Agorastos T, Dinas K, Lloveras B et al. Human papillomavirus testing for primary Poor reporting
screening in women at low risk of developing cervical cancer. The Greek experience.
Gynecol Oncol. 2005;96:714-720.
Agorastos T, Sotiriadis A, Emmanouilides CJ. Effect of type-specific human Editorial, letter, non-
papillomavirus incidence on screening performance and cost. International Journal of systematic review, opinion,
Gynecological Cancer. 2010;20:276-282. or case-control
Al-Alwan NA. Colposcopy, cervical cytology and human papillomavirus detection as No relevant outcomes
screening tools for cervical cancer. Eastern Mediterranean Health Journal.
2001;7:100-105.
Almonte M, Ferreccio C, Winkler JL et al. Cervical screening by visual inspection, HPV Colposcopy and/or
testing, liquid-based and conventional cytology in Amazonian Peru. Int J Cancer. histology only in positives
2007;121:796-802.
Antonishyn NA, Horsman GB, Kelln RA, Severini A. Human papillomavirus typing and Included women with
viral gene expression analysis for the triage of women with abnormal results from repeated abnormal smears
papanicolaou test smears to colposcopy. Archives of Pathology & Laboratory or abnormal smear other
Medicine. 2009;133:1577-1586. than ASC
Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J. SER includes studies that
Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis do not meet design criteria
of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst.
2004;96:280-293.
Arbyn M, Paraskevaidis E, Martin-Hirsch P, Prendiville W, Dillner J. Clinical utility of SER includes studies that
HPV-DNA detection: triage of minor cervical lesions, follow-up of women treated for do not meet design criteria
high-grade CIN: an update of pooled evidence. Gynecol Oncol. 2005;99:S7-11.
Arbyn M, Ronco G, Meijer CJ, Naucler P. Trials comparing cytology with human Editorial, letter, non-
papillomavirus screening. Lancet Oncology. 2009;10:935-936. systematic review, opinion,
or case-control
Arbyn M, Sankaranarayanan R, Muwonge R et al. Pooled analysis of the accuracy of SER includes studies that
five cervical cancer screening tests assessed in eleven studies in Africa and India. Int do not meet design criteria
J Cancer. 2008;123:153-160.
Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical Editorial, letter, non-
applications of HPV testing: A summary of meta-analyses. Vaccine. 2006;24 Suppl systematic review, opinion,
3:S78-S89. or case-control
Arbyn M., Buntinx F Van Ranst M Corinas Abrahantes J. Triage of women with SER includes studies that
atypical or low-grade cytological abnormalities of the cervix by HPV testing: systematic do not meet design criteria
review and meta-analysis. IPH/EPI-REPORTS Nr.2001-019, 1-240. 2002. Brussels,
Scientific Institute of Public Health.
Arbyn, M. HPV testing in triage of women with equivocal cytology. HPV Today 11, 6-7. SER includes studies that
2007. do not meet design criteria
Arora R, Kumar A, Prusty BK, Kailash U, Batra S, Das BC. Prevalence of high-risk No relevant outcomes
human papillomavirus (HR-HPV) types 16 and 18 in healthy women with cytologically
negative Pap smear. European Journal of Obstetrics, Gynecology, & Reproductive
Biology. 2005;121:104-109.
Atkins KA, Jeronimo J, Stoler MH, ALTS Group. Description of patients with squamous No relevant outcomes
cell carcinoma in the atypical squamous cells of undetermined significance/low-grade
squamous intraepithelial lesion triage study. Cancer. 2006;108:212-221.
Bacon J, Francoeur D, Goldfarb AF, Breech LL. Abnormal pap smears in adolescents. Editorial, letter, non-
J Pediatr Adolesc Gynecol. 2003;16:157-166. systematic review, opinion,
or case-control

Screening for Cervical Cancer 236 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Bais AG, Rebolj M, Snijders PJ et al. Triage using HPV-testing in persistent borderline No comparison to cytology
and mildly dyskaryotic smears: proposal for new guidelines. Int J Cancer.
2005;116:122-129.
Bavin PJ, Giles JA, Deery A et al. Use of semi-quantitative PCR for human No relevant outcomes
papillomavirus DNA type 16 to identify women with high grade cervical disease in a
population presenting with a mildly dyskaryotic smear report. Br J Cancer.
1993;67:602-605.
Belinson JL, Qiao YL, Pretorius RG et al. Shanxi Province cervical cancer screening Focus on excluded
study II: self-sampling for high-risk human papillomavirus compared to direct sampling screening methods
for human papillomavirus and liquid based cervical cytology. International Journal of
Gynecological Cancer. 2003;13:819-826.
Bengtsson E, Lindell M, Wikstrom I, Wilander E. Human papilloma virus tests of Editorial, letter, non-
normal cervical smears collected prior to the development of squamous carcinoma: a systematic review, opinion,
pilot study. Acta Derm Venereol. 2009;89:516-517. or case-control
Bergeron C, Cas F, Fagnani F, iller-Lambert F, Poveda JD. Human papillomavirus Editorial, letter, non-
testing with a liquid-based system: feasibility and comparison with reference systematic review, opinion,
diagnoses. Acta Cytol. 2006;50:16-22. or case-control
Berkhof J, Coupe VM, Bogaards JA et al. The health and economic effects of HPV Editorial, letter, non-
DNA screening in The Netherlands. Int J Cancer. 2010. systematic review, opinion,
or case-control
Bewtra C, Xie Q, Soundararajan S, Gatalica Z, Hatcher L. Genital human Focus on excluded
papillomavirus testing by in situ hybridization in liquid atypical cytologic materials and screening methods
follow-up biopsies. Acta Cytol. 2005;49:127-131.
Bhatla N, Mukhopadhyay A, Kriplani A et al. Evaluation of adjunctive tests for cervical Population not comparable
cancer screening in low resource settings. Indian J Cancer. 2007;44:51-55. to primary care
Blumenthal PD, Gaffikin L, Chirenje ZM, McGrath J, Womack S, Shah K. Adjunctive Population not comparable
testing for cervical cancer in low resource settings with visual inspection, HPV, and the to primary care
Pap smear. International Journal of Gynaecology & Obstetrics. 2001;72:47-53.
Boardman LA, Weitzen S, Stanko C. Atypical squamous cells of undetermined No relevant outcomes
significance, human papillomavirus, and cervical intraepithelial neoplasia 2 or 3 in
adolescents: ASC-US, age, and high-grade cervical neoplasia. Journal of Lower
Genital Tract Disease. 2006;10:140-145.
Bollen LJ, Tjong AHS, van der Velden J et al. Human papillomavirus deoxyribonucleic Included women with
acid detection in mildly or moderately dysplastic smears: a possible method for repeated abnormal smears
selecting patients for colposcopy. Am J Obstet Gynecol. 1997;1997:548-553. or abnormal smear other
than ASC
Bollmann R, Bankfalvi A, Griefingholt H et al. Validity of combined cytology and human Colposcopy and/or
papillomavirus (HPV) genotyping with adjuvant DNA-cytometry in routine cervical histology only in positives
screening: results from 31031 women from the Bonn-region in West Germany. Oncol
Rep. 2005;13:915-922.
Boon ME, Rijkaart DC, Ouwerkerk-Noordam E, Korporaal H. Dutch solutions for liquid- No relevant outcomes
based cytology: analysis of unsatisfactory slides and HPV testing of equivocal
cytology. Diagn Cytopathol. 2006;34:644-648.
Bory JP, Cucherousset J, Lorenzato M et al. Recurrent human papillomavirus infection No relevant outcomes
detected with the hybrid capture II assay selects women with normal cervical smears
at risk for developing high grade cervical lesions: a longitudinal study of 3,091 women.
Int J Cancer. 2002;102:519-525.
Bosch FX, de SS. Human papillomavirus in cervical cancer. Curr Oncol Rep. Editorial, letter, non-
2002;4:175-183. systematic review, opinion,
or case-control
Bozzetti M, Nonnenmacher B, Mielzinska I, I et al. Comparison between hybrid Editorial, letter, non-
capture II and polymerase chain reaction results among women at low risk for cervical systematic review, opinion,
cancer. Ann Epidemiol. 2000;10:466. or case-control
Braganca JF, Derchain SF, Sarian LO, Messias da Silva SM, Labatte S, Zeferino LC. Colposcopy and/or
Aided visual inspection with acetic acid (VIA) and HPV detection as optional screening histology only in positives
tools for cervical cancer and its precursor lesions. Clinical & Experimental Obstetrics &
Gynecology. 2005;32:225-229.

Screening for Cervical Cancer 237 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Bratti MC, Rodriguez AC, Schiffman M et al. Description of a seven-year prospective Reference standard not
study of human papillomavirus infection and cervical neoplasia among 10000 women independent of screening
in Guanacaste, Costa Rica. Rev Panam Salud Publica. 2004;15:75-89. test
Bulk S, Bulkmans NW, Berkhof J et al. Risk of high-grade cervical intra-epithelial Provides no data not
neoplasia based on cytology and high-risk HPV testing at baseline and at 6-months. otherwise covered in other
Int J Cancer. 2007;121:361-367. articles for this study
Bulkmans NW, Bulk S, Ottevanger MS et al. Implementation of human papillomavirus No relevant outcomes
testing in cervical screening without a concomitant decrease in participation rate. J
Clin Pathol. 2006;59:1218-1220.
Bulkmans NW, Rozendaal L, Voorhorst FJ, Snijders PJ, Meijer CJ. Long-term Does not systematically
protective effect of high-risk human papillomavirus testing in population-based cervical apply reference standard of
screening. Br J Cancer. 2005;92:1800-1802. colposcopy and/or histology
Cagle AJ, Hu SY, Sellors JW et al. Use of an expanded gold standard to estimate the Colposcopy and/or
accuracy of colposcopy and visual inspection with acetic acid. Int J Cancer. histology only in positives
2010;126:156-161.
Carozzi F, Bisanzi S, Sani C et al. Agreement between the AMPLICOR Human Colposcopy and/or
Papillomavirus Test and the Hybrid Capture 2 assay in detection of high-risk human histology only in positives
papillomavirus and diagnosis of biopsy-confirmed high-grade cervical disease. J Clin
Microbiol. 2007;45:364-369.
Carozzi FM, Confortini M, Cecchini S et al. Triage with human papillomavirus testing of Poor reporting
women with cytologic abnormalities prompting referral for colposcopy assessment.
Cancer. 2005;105:2-7.
Castle PE, Fetterman B, Poitras N, Lorey T, Shaber R, Kinney W. Five-year No relevant outcomes
experience of human papillomavirus DNA and Papanicolaou test cotesting. Obstetrics
& Gynecology. 2009;113:595-600.
Castle PE, Gravitt PE, Solomon D, Wheeler CM, Schiffman M. Comparison of linear No comparison to cytology
array and line blot assay for detection of human papillomavirus and diagnosis of
cervical precancer and cancer in the atypical squamous cell of undetermined
significance and low-grade squamous intraepithelial lesion triage study. J Clin
Microbiol. 2008;46:109-117.
Castle PE, Schiffman M, Wheeler CM, Wentzensen N, Gravitt PE. Impact of improved No comparison to cytology
classification on the association of human papillomavirus with cervical precancer. Am
J Epidemiol. 2010;171:155-163.
Castle PE, Stoler MH, Solomon D, Schiffman M. The relationship of community No relevant outcomes
biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control
pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2007;127:805-815.
Cattani P, Zannoni GF, Ricci C et al. Clinical performance of human papillomavirus E6 No comparison to cytology
and E7 mRNA testing for high-grade lesions of the cervix. J Clin Microbiol.
2009;47:3895-3901.
Cibas ES, Hong X, Crum CP, Feldman S. Age-specific detection of high risk HPV DNA Does not systematically
in cytologically normal, computer-imaged ThinPrep Pap samples. Gynecol Oncol. apply reference standard of
2007;104:702-706. colposcopy and/or histology
Ciotti M, Sesti F, Paba P et al. Human papillomavirus (HPV) testing in the Poor reporting
management of women with abnormal Pap smears. Experience of a colposcopy
referral clinic. Eur J Gynaecol Oncol. 2004;25:577-584.
Clavel C, Masure M, Bory JP et al. Human papillomavirus testing in primary screening Poor reporting
for the detection of high-grade cervical lesions: a study of 7932 women. Br J Cancer.
2001;84:1616-1623.
Clavel C, Masure M, Levert M et al. Human papillomavirus detection by the hybrid No relevant outcomes
capture II assay: a reliable test to select women with normal cervical smears at risk for
developing cervical lesions. Diagn Mol Pathol. 2000;9:145-150.
Cochand-Priollet B, Cartier I, de Cremoux P et al. Cost-effectiveness of liquid-based Provides no data not
cytology with or without hybrid-capture II HPV test compared with conventional Pap otherwise covered in other
smears: a study by the French Society of Clinical Cytology. Diagn Cytopathol. articles for this study
2005;33:338-343.
Cogliano V, Grosse Y, Baan R, Straif K, Secretan B, El GF. Carcinogenicity of Editorial, letter, non-
combined oestrogen-progestagen contraceptives and menopausal treatment. Lancet systematic review, opinion,
Oncol. 2005;6:552-553. or case-control

Screening for Cervical Cancer 238 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Confortini M, Giorgi RP, Barbarino P, Passarelli AM, Orzella L, Tufi MC. Screening for Colposcopy and/or
cervical cancer with the human papillomavirus test in an area of central Italy with no histology only in positives
previous active cytological screening programme. J Med Screen. 2010;17:79-86.
Contribution of human papillomavirus testing by hybrid capture in the triage of women Editorial, letter, non-
with repeated abnormal pap smears before colposcopy referral. Journal of Lower systematic review, opinion,
Genital Tract Disease. 2001;5:195-196. or case-control
Costa S, Sideri M, Syrjanen K et al. Combined Pap smear, cervicography and HPV Focus on excluded
DNA testing in the detection of cervical intraepithelial neoplasia and cancer. Acta screening methods
Cytol. 2000;44:310-318.
Cotton S, Sharp L, Little J et al. The role of human papillomavirus testing in the No comparison to cytology
management of women with low-grade abnormalities: multicentre randomised
controlled trial. BJOG: An International Journal of Obstetrics & Gynaecology.
2010;117:645-659.
Cotton SC, Sharp L, Little J et al. Trial of management of borderline and other low- No relevant outcomes
grade abnormal smears (TOMBOLA): Trial design. Contemporary Clinical Trials.
2006;27:449-471.
Coupe VM, Berkhof J, Bulkmans NW, Snijders PJ, Meijer CJ. Age-dependent No relevant outcomes
prevalence of 14 high-risk HPV types in the Netherlands: implications for prophylactic
vaccination and screening. Br J Cancer. 2008;98:646-651.
Cox JT, Lorincz AT, Schiffman MH, Sherman ME, Cullen A, Kurman RJ. Human Focus on excluded
papillomavirus testing by hybrid capture appears to be useful in triaging women with a screening methods
cytologic diagnosis of atypical squamous cells of undetermined significance. Am J
Obstet Gynecol. 1995;1995:946-954.
Cox JT. The development of cervical cancer and its precursors: what is the role of Editorial, letter, non-
human papillomavirus infection? Curr Opin Obstet Gynecol. 2006;18 Suppl 1:s5-s13. systematic review, opinion,
or case-control
Cuschieri KS, Cubie HA, Whitley MW et al. Persistent high risk HPV infection No relevant outcomes
associated with development of cervical neoplasia in a prospective population study. J
Clin Pathol. 2005;58:946-950.
Cuschieri KS, Graham C, Moore C, Cubie HA. Human Papillomavirus testing for the Does not systematically
management of low-grade cervical abnormalities in the UK--Influence of age and apply reference standard of
testing strategy. J Clin Virol. 2007;38:14-18. colposcopy and/or histology
Cuzick J, Arbyn M, Sankaranarayanan R et al. Overview of human papillomavirus- SER includes studies that
based and other novel options for cervical cancer screening in developed and do not meet design criteria
developing countries. Vaccine. 2008;26:Suppl-41.
Cuzick J, Beverley E, Ho L et al. HPV testing in primary screening of older women. Br Colposcopy and/or
J Cancer. 1999;81:554-558. histology only in positives
Cuzick J, Clavel C, Petry KU et al. Overview of the European and North American Editorial, letter, non-
studies on HPV testing in primary cervical cancer screening. Int J Cancer. systematic review, opinion,
2006;119:1095-1101. or case-control
Cuzick J, Sasieni P, Davies P et al. A systematic review of the role of human Editorial, letter, non-
papilloma virus (HPV) testing within a cervical screening programme: summary and systematic review, opinion,
conclusions. Br J Cancer. 2000;83:561-565. or case-control
Cuzick J, Sasieni P, Davies P et al. A systematic review of the role of human Precedes search period
papillomavirus testing within a cervical screening programme. Health Technol Assess.
1999;3:i-196.
Cuzick J, Szarewski A, Cubie H et al. Management of women who test positive for Verification bias, lack of
high-risk types of human papillomavirus: the HART study. Lancet. 2003;362:1871- blinding, time to colpo/bx
1876. ‡
not reported
Cuzick J, Szarewski A, Terry G et al. Human papillomavirus testing in primary cervical Colposcopy and/or
screening. Lancet. 1995;1995:1533-1536. histology only in positives
Dalla Palma P, Pojer A, Girlando S. HPV triage of women with atypical squamous cells Colposcopy and/or
of undetermined significance: a 3-year experience in an Italian organized programme. histology only in positives
Cytopathology. 2005;16:22-26.
Davies P, Arbyn M, Dillner J et al. A report on the current status of European research Editorial, letter, non-
on the use of human papillomavirus testing for primary cervical cancer screening. Int J systematic review, opinion,
Cancer. 2006;118:791-796. or case-control

Screening for Cervical Cancer 239 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Dawar M, Deeks S, Dobson S. Human papillomavirus vaccines launch a new era in Editorial, letter, non-
cervical cancer prevention. CMAJ. 2007;2007:456-461. systematic review, opinion,
or case-control
De Francesco MA, Gargiulo F, Schreiber C, Ciravolo G, Salinaro F, Manca N. No comparison to cytology
Comparison of the AMPLICOR human papillomavirus test and the hybrid capture 2
assay for detection of high-risk human papillomavirus in women with abnormal PAP
smear. J Virol Methods. 2008;147:10-17.
de OM, varez-Arguelles ME, Torrents M et al. Prevalence, evolution, and features of No relevant outcomes
infection with human papillomavirus: a 15-year longitudinal study of routine screening
of a women population in the north of Spain. J Med Virol. 2010;82:597-604.
de Vuyst H, Claeys P, Njiru S et al. Comparison of pap smear, visual inspection with Conducted solely in
acetic acid, human papillomavirus DNA-PCR testing and cervicography. International referred population or does
Journal of Gynaecology & Obstetrics. 2005;89:120-126. not report routine and
referred population
outcomes separately
de Vuyst H, Steyaert S, Van Renterghem L et al. Distribution of human papillomavirus No comparison to cytology
in a family planning population in nairobi, kenya. Sex Transm Dis. 2003;30:137-142.
Denny L, Kuhn L, Pollack A, Wainwright H, Wright TC, Jr. Evaluation of alternative Focus on excluded
methods of cervical cancer screening for resource-poor settings. Cancer. screening methods
2000;89:826-833.
Derchain SF, Sarian LO, Naud P et al. Safety of screening with Human papillomavirus Colposcopy and/or
testing for cervical cancer at three-year intervals in a high-risk population: experience histology only in positives
from the LAMS study. J Med Screen. 2008;15:97-104.
Dillner J, Rebolj M, Birembaut P et al. Long term predictive values of cytology and Editorial, letter, non-
human papillomavirus testing in cervical cancer screening: joint European cohort systematic review, opinion,
study. BMJ. 2008;337:a1754. or case-control
Dockter J, Schroder A, Hill C, Guzenski L, Monsonego J, Giachetti C. Clinical No comparison to cytology
performance of the APTIMA HPV Assay for the detection of high-risk HPV and high-
grade cervical lesions. J Clin Virol. 2009;45:Suppl-61.
Dowie R, Stoykova B, Crawford D et al. Liquid-based cytology can improve efficiency No relevant outcomes
of cervical smear readers: evidence from timing surveys in two NHS cytology
laboratories. Cytopathology. 2006;17:65-72.
Ekalaksananan T, Pientong C, Kotimanusvanij D, Kongyingyoes B, Sriamporn S, Colposcopy and/or
Jintakanon D. The relationship of human papillomavirus (HPV) detection to pap smear histology only in positives
classification of cervical-scraped cells in asymptomatic women in northeast Thailand.
Journal of Obstetrics & Gynaecology Research. 2001;27:117-124.
Eltoum IA, Chhieng DC, Roberson J, McMillon D, Partridge EE. Reflex human Editorial, letter, non-
papilloma virus infection testing detects the same proportion of cervical intraepithelial systematic review, opinion,
neoplasia grade 2-3 in young versus elderly women. Cancer. 2005;105:194-198. or case-control
Evans MF, Adamson CS, Papillo JL, St John TL, Leiman G, Cooper K. Distribution of Does not systematically
human papillomavirus types in ThinPrep Papanicolaou tests classified according to the apply reference standard of
Bethesda 2001 terminology and correlations with patient age and biopsy outcomes. colposcopy and/or histology
Cancer. 2006;106:1054-1064.
Fait G, Daniel Y, Kupferminc MJ, Lessing JB, Niv J, Bar-Am A. Does typing of human Focus on excluded
papillomavirus assist in the triage of women with repeated low-grade, cervical screening methods
cytologic abnormalities? Gynecol Oncol. 1998;1998:319-322.
Fait G, Kupferminc MJ, Daniel Y et al. Contribution of human papillomavirus testing by Focus on excluded
hybrid capture in the triage of women with repeated abnormal pap smears before screening methods
colposcopy referral. Gynecol Oncol. 2000;79:177-180.
Farag R, Redline R, bdul-Karim FW. Value of combining HPV-DNA testing with follow- Does not systematically
up Papanicolaou smear in patients with prior atypical squamous cells of undetermined apply reference standard of
significance. Acta Cytol. 2008;52:294-296. colposcopy and/or histology
Ferenczy A, Franco E, Arseneau J, Wright TC, Richart RM. Diagnostic performance of Focus on excluded
Hybrid Capture human papillomavirus deoxyribonucleic acid assay combined with screening methods
liquid-based cytologic study. Am J Obstet Gynecol. 1996;175:651-656.
Ferreccio C, Bratti MC, Sherman ME et al. A comparison of single and combined Reference standard not
visual, cytologic, and virologic tests as screening strategies in a region at high risk of independent of screening
cervical cancer. Cancer Epidemiology, Biomarkers & Prevention. 2003;12:815-823. test

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Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Ferris DG, Schiffman M, Litaker MS. Cervicography for triage of women with mildly Focus on excluded
abnormal cervical cytology results. Am J Obstet Gynecol. 2001;185:939-943. screening methods
Ferris DG, Wright TC, Jr., Litaker MS et al. Comparison of two tests for detecting No comparison to cytology
carcinogenic HPV in women with Papanicolaou smear reports of ASCUS and LSIL. J
Fam Pract. 1998;1998:136-141.
Ferris DG, Wright TC, Jr., Litaker MS et al. Triage of women with ASCUS and LSIL on No comparison to cytology
Pap smear reports: management by repeat Pap smear, HPV DNA testing, or
colposcopy? J Fam Pract. 1998;1998:125-134.
Flores Y, Bishai D, Lazcano E et al. Improving cervical cancer screening in Mexico: Colposcopy and/or
results from the Morelos HPV Study. Salud Publica Mex. 2003;45:Suppl-98. histology only in positives
Flores Y, Shah K, Lazcano E et al. Design and methods of the evaluation of an HPV- No relevant outcomes
based cervical cancer screening strategy in Mexico: The Morelos HPV Study. Salud
Publica Mex. 2002;44:335-344.
Forslund O, Antonsson A, Edlund K et al. Population-based type-specific prevalence No relevant outcomes
of high-risk human papillomavirus infection in middle-aged Swedish women. J Med
Virol. 2002;66:535-541.
Franco EL. A new generation of studies of human papillomavirus DNA testing in Editorial, letter, non-
cervical cancer screening. J Natl Cancer Inst. 2009;101:1600-1601. systematic review, opinion,
or case-control
Franco EL. Randomized controlled trials of HPV testing and Pap cytology: toward Editorial, letter, non-
evidence-based cervical cancer prevention. Int J Cancer. 2004;110:1-2. systematic review, opinion,
or case-control
Genova NJ. Evidence-based medicine--in real time. Comparing methods of cervical Editorial, letter, non-
Ca screening. JAAPA. 2000;13:55-60, 63. systematic review, opinion,
or case-control
Gilbert G. HPV screening more accurate than pap (CCCaST). SO: Journal of the Editorial, letter, non-
National Medical Association. 2008;100:265-266. systematic review, opinion,
or case-control
Giovannelli L, Capra G, Lama A et al. Atypical squamous cells of undetermined No comparison to cytology
significance-favour reactive compared to atypical squamous cells of undetermined
significance-favour dysplasia: association with cervical intraepithelial lesions and
human papillomavirus infection. J Clin Virol. 2005;33:281-286.
Girianelli VR, Thuler LC, Szklo M et al. Comparison of human papillomavirus DNA Poor reporting
tests, liquid-based cytology and conventional cytology for the early detection of cervix
uteri cancer. Eur J Cancer Prev. 2006;15:504-510.
Goff BA, Muntz HG, Bell DA, Wertheim I, Rice LW. Human papillomavirus typing in Focus on excluded
patients with Papanicolaou smears showing squamous atypia. Gynecol Oncol. screening methods
1993;1993:384-388.
Gogola J, Van Dinh T, Lucci JA, III, Smith E, Hannigan EV. Human papillomavirus Included women with
testing for triage in a referral population. Journal of Lower Genital Tract Disease. repeated abnormal smears
2001;5:29-32. or abnormal smear other
than ASC
Gonzalez-Bosquet E, Almagro MM, Mora I, Sunol M, Callejo J, Lailla JM. Prevalence Poor reporting
of human papilloma virus infection of the uterine cervix in women with abnormal
cervical cytology. Eur J Gynaecol Oncol. 2006;27:135-138.
Gravitt PE, Schiffman M, Solomon D, Wheeler CM, Castle PE. A comparison of linear No comparison to cytology
array and hybrid capture 2 for detection of carcinogenic human papillomavirus and
cervical precancer in ASCUS-LSIL triage study. Cancer Epidemiology, Biomarkers &
Prevention. 2008;17:1248-1254.
Guido R, Schiffman M, Solomon D, Burke L. Postcolposcopy management strategies Focus on methods to
for women referred with low-grade squamous intraepithelial lesions or human improve followup of
papillomavirus DNA-positive atypical squamous cells of undetermined significance: a abnormal screening
two-year prospective study. Am J Obstet Gynecol. 2003;188:1401-1405. findings
Guido RS, Jeronimo J, Schiffman M, Solomon D. The distribution of neoplasia arising Does not focus on
on the cervix: results from the ALTS trial. Am J Obstet Gynecol. 2005;193:1331-1337. screening or harms of
screening

Screening for Cervical Cancer 241 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Guillaud M, Benedet JL, Cantor SB, Staerkel G, Follen M, MacAulay C. DNA ploidy Conducted solely in
compared with human papilloma virus testing (Hybrid Capture II) and conventional referred population or does
cervical cytology as a primary screening test for cervical high-grade lesions and not report routine and
cancer in 1555 patients with biopsy confirmation. Cancer. 2006;107:309-318. referred population
outcomes separately
Guyot A, Karim S, Kyi MS, Fox J. Evaluation of adjunctive HPV testing by Hybrid No comparison to cytology
Capture II in women with minor cytological abnormalities for the diagnosis of CIN2/3
and cost comparison with colposcopy. BMC Infectious Diseases. 2003;3:23.
Halfon P, Benmoura D, Khiri H et al. Comparison of the clinical performance of No comparison to cytology
carcinogenic HPV typing of the Linear Array and Papillocheck HPV-screening assay. J
Clin Virol. 2010;47:38-42.
Halfon P, Trepo E, Antoniotti G et al. Prospective evaluation of the Hybrid Capture 2 Does not systematically
and AMPLICOR human papillomavirus (HPV) tests for detection of 13 high-risk HPV apply reference standard of
genotypes in atypical squamous cells of uncertain significance. J Clin Microbiol. colposcopy and/or histology
2007;45:313-316.
Hall S, Lorincz A, Shah F et al. Human papillomavirus DNA detection in cervical Focus on excluded
specimens by hybrid capture: correlation with cytologic and histologic diagnoses of screening methods
squamous intraepithelial lesions of the cervix. Gynecol Oncol. 1996;62:353-359.
Hartmann, KE, Hall, SA, Nanda, K, Boggess, JF, and Zolnoun, D. Screening for Provides no data not
Cervical Cancer. ii-74. 2002. Agency for Healthcare Research and Quality. otherwise covered in other
articles for this study
HAYES and Inc. Hybrid capture HPV testing for cervical cancer. 2004. Editorial, letter, non-
systematic review, opinion,
or case-control
HAYES. HPV Testing Versus Standard Cytology for Primary Screening of Cervical Editorial, letter, non-
Cancer. 2007. systematic review, opinion,
or case-control
Herbert A, Best JM, Chana P et al. Human papillomavirus testing with conventional Colposcopy and/or
Pap smear screening in three inner London community clinics. Journal of Family histology only in positives
Planning & Reproductive Health Care. 2007;33:171-176.
Herrero R, Hildesheim A, Bratti C et al. Population-based study of human No relevant outcomes
papillomavirus infection and cervical neoplasia in rural Costa Rica. J Natl Cancer Inst.
2000;92:464-474.
Herrero R, Schiffman MH, Bratti C et al. Design and methods of a population-based Reference standard not
natural history study of cervical neoplasia in a rural province of Costa Rica: the independent of screening
Guanacaste Project. Rev Panam Salud Publica. 1997;1:362-375. test
Herrington CS, Evans MF, Hallam NF, Charnock FM, Gray W, McGee JD. Human Poor reporting
papillomavirus status in the prediction of high-grade cervical intraepithelial neoplasia in
patients with persistent low-grade cervical cytological abnormalities. Br J Cancer.
1995;1995:206-209.
Hildesheim A, Herrero R, Castle PE et al. HPV co-factors related to the development No relevant outcomes
of cervical cancer: results from a population-based study in Costa Rica. Br J Cancer.
2001;84:1219-1226.
Hillemanns P, Kimmig R, Huttemann U, Dannecker C, Thaler CJ. Screening for Focus on excluded
cervical neoplasia by self-assessment for human papillomavirus DNA. Lancet. screening methods
1999;1999:1970.
Ho L, Terry G, Londesborough P, Cuzick J, Lorenzato F, Singer A. Human No relevant outcomes
papillomavirus DNA detection in the management of women with twice mildly
abnormal cytological smears. J Med Virol. 2003;69:118-121.
Hovland S, Arbyn M, Lie AK et al. A comprehensive evaluation of the accuracy of Conducted solely in
cervical pre-cancer detection methods in a high-risk area in East Congo. Br J Cancer. referred population or does
2010;102:957-965. not report routine and
referred population
outcomes separately
Howard M, Sellors JW, Lytwyn A, Roth P, Mahony JB. Combining human Poor reporting
papillomavirus testing or cervicography with cytology to detect cervical neoplasia.
Archives of Pathology & Laboratory Medicine. 2004;128:1257-1262.

Screening for Cervical Cancer 242 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
HPV DNA Testing in Cervical Cancer Screening: Results From Women in a High-Risk Editorial, letter, non-
Province of Costa Rica. Obstetrical & Gynecological Survey May 2000;55(5):284-286. systematic review, opinion,
2000;284-286. or case-control
Huang S, Erickson B, Tang N et al. Clinical performance of Abbott RealTime High Risk Included women with
HPV test for detection of high-grade cervical intraepithelial neoplasia in women with repeated abnormal smears
abnormal cytology. J Clin Virol. 2009;45:Suppl-23. or abnormal smear other
than ASC
Infantolino C, Fabris P, Infantolino D et al. Usefulness of human papilloma virus testing Editorial, letter, non-
in the screening of cervical cancer precursor lesions: a retrospective study in 314 systematic review, opinion,
cases. European Journal of Obstetrics, Gynecology, & Reproductive Biology. or case-control
2000;93:71-75.
Inoue M, Okamura M, Hashimoto S, Tango M, Ukita T. Adoption of HPV testing as an Colposcopy and/or
adjunct to conventional cytology in cervical cancer screening in Japan. Int J Gynaecol histology only in positives
Obstet. 2010.
Inoue M, Sakaguchi J, Sasagawa T, Tango M. The evaluation of human Colposcopy and/or
papillomavirus DNA testing in primary screening for cervical lesions in a large histology only in positives
Japanese population. International Journal of Gynecological Cancer. 2006;16:1007-
1013.
Institute for Clinical Systems Improvement. HPV DNA Testing for the Screening and Editorial, letter, non-
Monitoring of Cervical Cancer. 2007. systematic review, opinion,
or case-control
Jastania R, Geddie WR, Chapman W, Boerner S. Characteristics of apparently false- No relevant outcomes
negative digene hybrid capture 2 high-risk HPV DNA testing. Am J Clin Pathol.
2006;125:223-228.
Juric D, Mahovlic V, Rajhvajn S et al. Liquid-based cytology--new possibilities in the Does not systematically
diagnosis of cervical lesions. Coll Antropol. 2010;34:19-24. apply reference standard of
colposcopy and/or histology
Kahn JA, Hillard PJ. Cervical cytology screening and management of abnormal Editorial, letter, non-
cytology in adolescent girls. J Pediatr Adolesc Gynecol. 2003;16:167-171. systematic review, opinion,
or case-control
Kahn JA, Slap GB, Bernstein DI et al. Personal meaning of human papillomavirus and No relevant outcomes
Pap test results in adolescent and young adult women. Health Psychology.
2007;26:192-200.
Kaufman RH, Adam E, Icenogle J et al. Relevance of human papillomavirus screening Included women with
in management of cervical intraepithelial neoplasia. Am J Obstet Gynecol. repeated abnormal smears
1997;176:87-92. or abnormal smear other
than ASC
Kaufman RH, Adam E, Icenogle J, Reeves WC. Human papillomavirus testing as Included women with
triage for atypical squamous cells of undetermined significance and low-grade repeated abnormal smears
squamous intraepithelial lesions: sensitivity, specificity, and cost-effectiveness. Am J or abnormal smear other
Obstet Gynecol. 1997;177:930-936. than ASC
Khanna N, Brooks SE, Chen TT, Simsir A, Gordon NJ, Taylor G. Human No comparison to cytology
papillomavirus absence predicts normal cervical histopathologic findings with
abnormal papanicolaou smears: a study of a university-based inner city population. J
Hum Virol. 2001;4:283-287.
Kiatpongsan S, Niruthisard S, Mutirangura A et al. Role of human papillomavirus DNA No comparison to cytology
testing in management of women with atypical squamous cells of undetermined
significance. International Journal of Gynecological Cancer. 2006;16:262-265.
Kitchener HC, Almonte M, Wheeler P et al. HPV testing in routine cervical screening: Provides no data not
cross sectional data from the ARTISTIC trial. Br J Cancer. 2006;95:56-61. otherwise covered in other
articles for this study
Koliopoulos G, Arbyn M, Martin-Hirsch P, Kyrgiou M, Prendiville W, Paraskevaidis E. SER includes studies that
Diagnostic accuracy of human papillomavirus testing in primary cervical screening: A do not meet design criteria
systematic review and meta-analysis of non-randomized studies. Gynecol Oncol.
2007;104:232-246.
Koliopoulos G, Martin-Hirsch P, Paraskevaidis E, Arbyn M. HPV testing versus Editorial, letter, non-
cervical cytology for screening for cancer of the uterine cervix. Cochrane Database of systematic review, opinion,
Systematic Reviews. 2006. or case-control

Screening for Cervical Cancer 243 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Kotaniemi TL, Malila N, Nieminen P et al. Test positivity cutoff level of a high risk Provides no data not
human papillomavirus test could be increased in routine cervical cancer screening. otherwise covered in other
SO: International journal of cancer Journal international du cancer. 2008;123:2902- articles for this study
2906.
Koutsky LA, Harper DM, Breen N et al. Human papillomavirus testing for triage of No relevant outcomes
women with cytologic evidence of low-grade squamous intraepithelial lesions: Baseline
data from a randomized trial. J Natl Cancer Inst. 2000;92:397-402.
Kuhn L, Denny L, Pollack A, Lorincz A, Richart RM, Wright TC. Human papillomavirus Colposcopy and/or
DNA testing for cervical cancer screening in low-resource settings. J Natl Cancer Inst. histology only in positives
2000;92:818-825.
Kulasingam SL, Rajan R, St PY, Atwood CV, Myers ER, Franco EL. Human Editorial, letter, non-
papillomavirus testing with Pap triage for cervical cancer prevention in Canada: a cost- systematic review, opinion,
effectiveness analysis. BMC Medicine. 2009;7:69. or case-control
Kumar K, Iyer VK, Bhatla N, Kriplani A, Verma K. Comparative evaluation of smear Population not comparable
cytology & hybrid capture II for the diagnosis of cervical cancer. Indian J Med Res. to primary care
2007;126:39-44.
Lazcano-Ponce E, Lorincz AT, Salmeron J et al. A pilot study of HPV DNA and Colposcopy and/or
cytology testing in 50,159 women in the routine Mexican Social Security Program. histology only in positives
Cancer Causes Control. 2010.
Lee GY, Kim SM, Rim SY, Choi HS, Park CS, Nam JH. Human papillomavirus (HPV) Included women with
genotyping by HPV DNA chip in cervical cancer and precancerous lesions. repeated abnormal smears
International Journal of Gynecological Cancer. 2005;15:81-87. or abnormal smear other
than ASC
Lee JK, Kim MK, Song SH et al. Comparison of human papillomavirus detection and Poor reporting
typing by hybrid capture 2, linear array, DNA chip, and cycle sequencing in cervical
swab samples. International Journal of Gynecological Cancer. 2009;19:266-272.
Lee KJ, Lee JK, Saw HS. Can human papillomavirus DNA testing substitute for Included women with
cytology in the detection of high-grade cervical lesions? Archives of Pathology & repeated abnormal smears
Laboratory Medicine. 2004;128:298-302. or abnormal smear other
than ASC
Lee NW, Kim D, Park JT, Kim A. Is the human papillomavirus test in combination with Colposcopy and/or
the Papanicolaou test useful for management of patients with diagnoses of atypical histology only in positives
squamous cells of undetermined significance/low-grade squamous intraepithelial
lesions? Archives of Pathology & Laboratory Medicine. 2001;125:1453-1457.
Lepej SZ, Grgic I, Poljak M et al. Detection of human papillomavirus genotypes Focus on excluded
16/18/45 by hybrid capture hybridisation genotyping probe in clinical specimens: the screening methods
first report. J Clin Virol. 2007;40:171-172.
Lerma E, Quintana MJ, Quilez M et al. Effectiveness of liquid-based cytology and Colposcopy and/or
papanicolaou tests in a low risk population. Acta Cytol. 2007;51:399-406. histology only in positives
Li C, Wu M, Wang J et al. A population-based study on the risks of cervical lesion and Does not systematically
human papillomavirus infection among Women in Beijing, People's Republic of China. apply reference standard of
Cancer Epidemiol Biomarkers Prev. 2010. colposcopy and/or histology
Li N, Shi JF, Franceschi S et al. Different cervical cancer screening approaches in a Poor reporting, no
Chinese multicentre study. Br J Cancer. 2009;100:532-537. indeterminate results
provided
Li Y, Ye F, Lu WG, Zeng WJ, Wei LH, Xie X. Detection of human telomerase RNA Poor reporting
gene in cervical cancer and precancerous lesions: comparison with cytological and
human papillomavirus DNA test findings. International Journal of Gynecological
Cancer. 2010;20:631-637.
Lin CT, Tseng CJ, Lai CH, Hsueh S, Huang HJ, Law KS. High-risk HPV DNA detection No comparison to cytology
by Hybrid Capture II. An adjunctive test for mildly abnormal cytologic smears in women
> or = 50 years of age. J Reprod Med. 2000;45:345-350.
Lin HP, Huang YY, Wu HY, Kao JT. Method for testing for human papillomavirus Poor reporting
infection in patients with cervical intraepithelial disease. J Clin Microbiol. 2004;42:366-
368.
Lindh M, Gorander S, Andersson E, Horal P, Mattsby-Balzer I, Ryd W. Real-time Focus on excluded
Taqman PCR targeting 14 human papilloma virus types. J Clin Virol. 2007;40:321-324. screening methods

Screening for Cervical Cancer 244 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Little J. Human papillomavirus testing. Effectiveness of testing for high risk HPV for Editorial, letter, non-
triage of low grade abnormal smears is being assessed in TOMBOLA trial. BMJ. systematic review, opinion,
2001;323:109. or case-control
Longatto-Filho A, Erzen M, Branca M et al. Human papillomavirus testing as an No comparison to cytology
optional screening tool in low-resource settings of Latin America: experience from the
Latin American Screening study. International Journal of Gynecological Cancer.
2006;16:955-962.
Lonky NM, Felix JC, Naidu YM, Wolde-Tsadik G. Triage of atypical squamous cells of No comparison to cytology
undetermined significance with hybrid capture II: colposcopy and histologic human
papillomavirus correlation. Obstetrics & Gynecology. 2003;101:481-489.
Lonky NM, Mahdavi A, Wolde-Tsadik G, Bajamundi K, Felix JC. Evaluation of the Colposcopy and/or
clinical performance of high-risk human papillomavirus testing for primary screening: a histology only in positives
retrospective review of the Southern California Permanente Medical Group
experience. Journal of Lower Genital Tract Disease. 2010;14:200-205.
Lorenzato F, Ho L, Terry G et al. The use of human papillomavirus typing in detection Focus on excluded
of cervical neoplasia in Recife (Brazil). Int J Gynecol Cancer. 2000;10:143-150. screening methods
Lorincz AT, Richart RM. Human papillomavirus DNA testing as an adjunct to cytology Editorial, letter, non-
in cervical screening programs. Archives of Pathology & Laboratory Medicine. systematic review, opinion,
2003;127:959-968. or case-control
Luyten A, Scherbring S, Reinecke-Luthge A et al. Risk-adapted primary HPV cervical Colposcopy and/or
cancer screening project in Wolfsburg, Germany--experience over 3 years. J Clin Virol. histology only in positives
2009;46:Suppl-10.
Lytwyn A, Sellors JW, Mahony JB et al. Adjunctive human papillomavirus testing in the Focus on excluded
2-year follow-up of women with low-grade cervical cytologic abnormalities: a screening methods
randomized trial and economic evaluation. Archives of Pathology & Laboratory
Medicine. 2003;127:1169-1175.
Lytwyn A, Sellors JW, Mahony JB et al. Comparison of human papillomavirus DNA Insufficient sample size,
testing and repeat Papanicolaou test in women with low-grade cervical cytologic poor reporting,
abnormalities: a randomized trial. HPV Effectiveness in Lowgrade Paps (HELP) Study inappropriate exclusions
No. 1 Group. CMAJ. 2000;163:701-707.
MacDonald N, Hebert PC. Human papillomavirus vaccine: waiting for a miracle. Editorial, letter, non-
CMAJ. 2007;2007:433, 435. systematic review, opinion,
or case-control
Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Does not focus on
Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory screening or harms of
Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56:1-24. screening
Masumoto N, Fujii T, Ishikawa M et al. Papanicolaou tests and molecular analyses Poor reporting
using new fluid-based specimen collection technology in 3000 Japanese women. Br J
Cancer. 2003;88:1883-1888.
Medical Services Advisory Committee. Human papillomavirus testing in women with Precedes search period
cytological prediction of low-grade abnormality. 2002.
Medical Services Advisory Committee. Human papillomavirus testing for cervical Precedes search period
screening. 2003.
Monsonego J, Pintos J, Semaille C et al. Human papillomavirus testing improves the Conducted solely in
accuracy of colposcopy in detection of cervical intraepithelial neoplasia. International referred population or does
Journal of Gynecological Cancer. 2006;16:591-598. not report routine and
referred population
outcomes separately
Morin C, Bairati I, Bouchard C et al. Managing atypical squamous cells of Poor reporting
undetermined significance in Papanicolaou smears. J Reprod Med. 2001;46:799-805.
Morin, C. Comparison of the hybrid capture test and polymerase chain reaction in Focus on excluded
identifying women who have an atypical squamous cell of undetermined significance screening methods
Papanicolaou smear and need colposcopy. J Lower Genit Tract Disease 3, 231-238.
1999.
Moscicki AB, Cox JT. Practice improvement in cervical screening and management Editorial, letter, non-
(PICSM): symposium on management of cervical abnormalities in adolescents and systematic review, opinion,
young women. Journal of Lower Genital Tract Disease. 2010;14:73-80. or case-control

Screening for Cervical Cancer 245 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Moscicki AB, Hills N, Shiboski S et al. Risks for incident human papillomavirus No relevant outcomes
infection and low-grade squamous intraepithelial lesion development in young
females. JAMA. 2001;285:2995-3002.
Moscicki AB. Cervical cytology testing in teens. Curr Opin Obstet Gynecol. Editorial, letter, non-
2005;17:471-475. systematic review, opinion,
or case-control
Moss S, Gray A, Legood R et al. Effect of testing for human papillomavirus as a triage No relevant outcomes
during screening for cervical cancer: observational before and after study. BMJ.
2006;332:83-85.
Mould TA, Singer A, Gallivan S. Quantitative detection of oncogenic HPV DNA using Focus on excluded
hybrid capture to triage borderline and mildly dyskaryotic Papanicolaou smears. Eur J screening methods
Gynaecol Oncol. 2000;21:245-248.
Munoz N, Bosch FX, Castellsague X et al. Against which human papillomavirus types Does not focus on
shall we vaccinate and screen? The international perspective. Int J Cancer. screening or harms of
2004;111:278-285. screening
Nene BM, Sankaranaryanan R, Dinshaw KD et al. Comparative efficacy of visual Editorial, letter, non-
inspection with acetic acid, HPV testing and conventional cytology in cervical cancer systematic review, opinion,
screening: a randomised intervention trial in Maharashtra State, India. Int J Cancer. or case-control
2002;98.
Nieminen P, Vuorma S, Viikki M, Hakama M, Anttila A. Comparison of HPV test versus Colposcopy and/or
conventional and automation-assisted Pap screening as potential screening tools for histology only in positives
preventing cervical cancer. BJOG: An International Journal of Obstetrics &
Gynaecology. 2004;111:842-848.
Nobbenhuis MA, Walboomers JM, Helmerhorst TJ et al. Relation of human No relevant outcomes
papillomavirus status to cervical lesions and consequences for cervical-cancer
screening: a prospective study. Lancet. 1999;354:20-25.
Nomelini RS, Barcelos AC, Michelin MA, Adad SJ, Murta EF. Utilization of human No comparison to cytology
papillomavirus testing for cervical cancer prevention in a university hospital. Cad
Saude Publica. 2007;23:1309-1318.
Noorani, H. Z., Brown, A., Skidmore, B., and Stuart, G. C. E. Liquid-based cytology SER includes studies that
and human papillomavirus testing in cervical cancer screening. 2003. do not meet design criteria
Nuovo GJ, Bartholomew D, Jung WW et al. Correlation of Pap smear, cervical biopsy, Does not systematically
and clinical follow-up with an HPV typing microarray system. Diagn Mol Pathol. apply reference standard of
2008;17:107-111. colposcopy and/or histology
Nyirjesy I, Billingsley FS, Forman MR. Evaluation of atypical and low-grade cervical Focus on excluded
cytology in private practice. Obstet Gynecol. 1998;92:601-607. screening methods
Ogilvie G, Krajden M, Maginley J et al. Feasibility of self-collection of specimens for Focus on excluded
human papillomavirus testing in hard-to-reach women. CMAJ. 2007;2007:480-483. screening methods
Ogilvie GS, van Niekerk DJ, Krajden M et al. A randomized controlled trial of Human No relevant outcomes
Papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary
results (HPV FOCAL Trial). BMC Cancer. 2010;10:111.
Oh YL, Shin KJ, Han J, Kim DS. Significance of high-risk human papillomavirus Does not systematically
detection by polymerase chain reaction in primary cervical cancer screening. apply reference standard of
Cytopathology. 2001;12:75-83. colposcopy and/or histology
Ozsaran AA, Dikmen Y, Akercan F et al. The triage of squamous cell abnormalities of Focus on excluded
cervical cytology by human papilloma virus screening. Eur J Gynaecol Oncol. screening methods
2003;24:535-538.
Pajtler M, Milicic-Juhas V, Milojkovic M, Topolovec Z, Curzik D, Mihaljevic I. Does not systematically
Assessment of HPV DNA test value in management women with cytological findings of apply reference standard of
ASC-US, CIN1 and CIN2. Coll Antropol. 2010;34:81-86. colposcopy and/or histology
Pannier-Stockman C, Segard C, Bennamar S et al. Prevalence of HPV genotypes Does not systematically
determined by PCR and DNA sequencing in cervical specimens from French women apply reference standard of
with or without abnormalities. J Clin Virol. 2008;42:353-360. colposcopy and/or histology
Paraskevaidis E, Malamou-Mitsi V, Koliopoulos G et al. Expanded cytological referral Colposcopy and/or
criteria for colposcopy in cervical screening: comparison with human papillomavirus histology only in positives
testing. Gynecol Oncol. 2001;82:355-359.

Screening for Cervical Cancer 246 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Partridge EE, bu-Rustum N, Campos S et al. Cervical cancer screening. Journal of the Editorial, letter, non-
National Comprehensive Cancer Network. 2008;6:58-82. systematic review, opinion,
or case-control
Peto J, Gilham C, Deacon J et al. Cervical HPV infection and neoplasia in a large No relevant outcomes
population-based prospective study: the Manchester cohort. Br J Cancer.
2004;91:942-953.
Petry KU, Bohmer G, Iftner T, Flemming P, Stoll M, Schmidt RE. Human Population not comparable
papillomavirus testing in primary screening for cervical cancer of human to primary care
immunodeficiency virus-infected women, 1990-1998. Gynecol Oncol. 1999;1999:427-
431.
Petry, K. U., Menton, M., Bohmer, G., and Iftner, T. Human papillomavirus DNA- Editorial, letter, non-
testing for primary cervical cancer screening in germany. Anticancer Research 22[1B], systematic review, opinion,
482. 2002. or case-control
Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM, ALTS Group. A No relevant outcomes
2-year prospective study of human papillomavirus persistence among women with a
cytological diagnosis of atypical squamous cells of undetermined significance or low-
grade squamous intraepithelial lesion. J Infect Dis. 2007;195:1582-1589.
Powell N. Single HPV test not useful for predicting CIN2 or worse or for guiding choice Editorial, letter, non-
of further investigations for women aged 20-59 presenting to NHS Cervical Screening systematic review, opinion,
Programme with borderline abnormalities or mild dyskaryosis. Evid Based Med. 2010. or case-control
Pretorius RG, Kim RJ, Belinson JL, Elson P, Qiao YL. Inflation of sensitivity of cervical Provides no data not
cancer screening tests secondary to correlated error in colposcopy. Journal of Lower otherwise covered in other
Genital Tract Disease. 2006;10:5-9. articles for this study
Pretorius RG, Peterson P, Novak S, Azizi F, Sadeghi M, Lorincz AT. Comparison of No comparison to cytology
two signal-amplification DNA tests for high-risk HPV as an aid to colposcopy. J Reprod
Med. 2002;47:290-296.
Prinsen CF, Fles R, Wijnen-Dubbers CW et al. Baseline human papillomavirus status Conducted solely in
of women with abnormal smears in cervical screening: a 5-year follow-up study in The referred population or does
Netherlands. BJOG: An International Journal of Obstetrics & Gynaecology. not report routine and
2007;114:951-957. referred population
outcomes separately
Proca DM, Williams JD, Rofagha S, Tranovich VL, Keyhani-Rofagha S. Improved rate Focus on excluded
of high-grade cervical intraepithelial neoplasia detection in human papillomavirus DNA screening methods
hybrid capture testing. Analytical & Quantitative Cytology & Histology. 2007;29:264-
270.
Ratnam S, Franco EL, Ferenczy A. Human papillomavirus testing for primary Focus on excluded
screening of cervical cancer precursors. Cancer Epidemiol Biomarkers Prev. screening methods
2000;9:945-951.
Rebello G, Hallam N, Smart G, Farquharson D, McCafferty J. Human papillomavirus Poor reporting
testing and the management of women with mildly abnormal cervical smears: an
observational study. BMJ. 2001;322:893-894.
Reuschenbach M, Clad A, von Knebel DC et al. Performance of p16(INK4a)-cytology, No comparison to cytology
HPV mRNA, and HPV DNA testing to identify high grade cervical dysplasia in women
with abnormal screening results. Gynecol Oncol. 2010.
Rijkaart DC, Berkhof J, van Kemenade FJ et al. Comparison of HPV and cytology Colposcopy and/or
triage algorithms for women with borderline or mild dyskaryosis in population-based histology only in positives
cervical screening (VUSA-screen study). Int J Cancer. 2010;126:2175-2181.
Rijkaart DC, Coupe VM, van Kemenade FJ et al. Comparison of Hybrid capture 2 Colposcopy and/or
testing at different thresholds with cytology as primary cervical screening test. Br J histology only in positives
Cancer. 2010.
Rodriguez AC, Schiffman M, Herrero R et al. Longitudinal study of human No comparison to cytology
papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role
of duration of infection. J Natl Cancer Inst. 2010;102:315-324.
Ronnett BM, Manos MM, Ransley JE et al. Atypical glandular cells of undetermined Included women with
significance (AGUS): cytopathologic features, histopathologic results, and human repeated abnormal smears
papillomavirus DNA detection. Hum Pathol. 1999;30:816-825. or abnormal smear other
than ASC

Screening for Cervical Cancer 247 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Rousseau MC, Villa LL, Costa MC, Abrahamowicz M, Rohan TE, Franco E. No relevant outcomes
Occurrence of cervical infection with multiple human papillomavirus types is
associated with age and cytologic abnormalities. Sex Transm Dis. 2003;30:581-587.
Safaeian M, Solomon D, Wacholder S, Schiffman M, Castle P. Risk of precancer and No relevant outcomes
follow-up management strategies for women with human papillomavirus-negative
atypical squamous cells of undetermined significance. Obstetrics & Gynecology.
2007;109:1325-1331.
Salmeron J, Lazcano-Ponce E, Lorincz A et al. Comparison of HPV-based assays with Colposcopy and/or
Papanicolaou smears for cervical cancer screening in Morelos State, Mexico. Cancer histology only in positives
Causes & Control. 2003;14:505-512.
Sandri MT, Lentati P, Benini E et al. Comparison of the Digene HC2 assay and the Does not systematically
Roche AMPLICOR human papillomavirus (HPV) test for detection of high-risk HPV apply reference standard of
genotypes in cervical samples. J Clin Microbiol. 2006;44:2141-2146. colposcopy and/or histology
Sankaranarayanan R, Nene BM, Dinshaw KA et al. A cluster randomized controlled Provides no data not
trial of visual, cytology and human papillomavirus screening for cancer of the cervix in otherwise covered in other
rural India. Int J Cancer. 2005;116:617-623. articles for this study
Sankaranarayanan R, Thara S, Sharma A et al. Accuracy of conventional cytology: Focus on excluded
results from a multicentre screening study in India. J Med Screen. 2004;2004;11:77- screening methods
84.
Santos AL, Derchain SF, Martins MR, Sarian LO, Martinez EZ, Syrjanen KJ. Human Poor reporting
papillomavirus viral load in predicting high-grade CIN in women with cervical smears
showing only atypical squamous cells or low-grade squamous intraepithelial lesion.
Sao Paulo Medical Journal = Revista Paulista de Medicina. 2003;121:238-243.
Sarian LO, Derchain SF, Naud P et al. Evaluation of visual inspection with acetic acid Poor reporting
(VIA), Lugol's iodine (VILI), cervical cytology and HPV testing as cervical screening
tools in Latin America. This report refers to partial results from the LAMS (Latin
AMerican Screening) study. J Med Screen. 2005;12:142-149.
Sarode VR, Werner C, Gander R et al. Reflex human papillomavirus DNA testing on No comparison to cytology
residual liquid-based (TPPT) cervical samples: focus on age-stratified clinical
performance. Cancer. 2003;99:149-155.
Saslow D, Castle PE, Cox JT et al. American Cancer Society Guideline for human Does not focus on
papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA screening or harms of
Cancer J Clin. 2007;57:7-28. screening
Schiffman M, Herrero R, Hildesheim A et al. HPV DNA testing in cervical cancer Reference standard not
screening: results from women in a high-risk province of Costa Rica. JAMA. independent of screening
2000;283:87-93. test
Schiffman M, Khan MJ, Solomon D et al. A study of the impact of adding HPV types to Does not focus on
cervical cancer screening and triage tests. J Natl Cancer Inst. 2005;97:147-150. screening or harms of
screening
Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study Editorial, letter, non-
(ALTS). Arch Pathol Lab Med. 2003;127:946-949. systematic review, opinion,
or case-control
Schlecht NF, Platt RW, Duarte-Franco E et al. Human papillomavirus infection and No relevant outcomes
time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer
Inst. 2003;95:1336-1343.
Schledermann D, Andersen BT, Bisgaard K et al. Are adjunctive markers useful in Does not systematically
routine cervical cancer screening? Application of p16(INK4a) and HPV-PCR on apply reference standard of
ThinPrep samples with histological follow-up. Diagn Cytopathol. 2008;36:453-459. colposcopy and/or histology
Schneede P, Hillemanns P, Ziller F et al. Evaluation of HPV testing by Hybrid Capture No relevant outcomes
II for routine gynecologic screening. Acta Obstet Gynecol Scand. 2001;80:750-752.
Schneider A, Hoyer H, Lotz B et al. Screening for high-grade cervical intra-epithelial Colposcopy and/or
neoplasia and cancer by testing for high-risk HPV, routine cytology or colposcopy. Int J histology only in positives
Cancer. 2000;89:529-534.
Selvaggi SM. ASC-US and high-risk HPV testing: performance in daily clinical Does not systematically
practice. Diagn Cytopathol. 2006;34:731-733. apply reference standard of
colposcopy and/or histology

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Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Sherman ME, Castle PE, Solomon D. Cervical cytology of atypical squamous cells- No relevant outcomes
cannot exclude high-grade squamous intraepithelial lesion (ASC-H): characteristics
and histologic outcomes. Cancer. 2006;108:298-305.
Sherman ME, Lorincz AT, Scott DR et al. Baseline cytology, human papillomavirus No relevant outcomes
testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst.
2003;95:46-52.
Sherman ME, Schiffman MH, Lorincz AT et al. Cervical specimens collected in liquid Focus on excluded
buffer are suitable for both cytologic screening and ancillary human papillomavirus screening methods
testing. Cancer. 1997;81:89-97.
Shi JF, Belinson JL, Zhao FH et al. Human papillomavirus testing for cervical cancer Provides no data not
screening: results from a 6-year prospective study in rural China. Am J Epidemiol. otherwise covered in other
2009;170:708-716. articles for this study
Shin EK, Lee SR, Kim MK et al. Immunocytochemical staining of p16(ink4a) protein as No comparison to cytology
an adjunct test in equivocal liquid-based cytology. Diagn Cytopathol. 2008;36:311-
316.
Shlay JC, Dunn T, Byers T, Baron AE, Douglas JM, Jr. Prediction of cervical No comparison to cytology
intraepithelial neoplasia grade 2-3 using risk assessment and human papillomavirus
testing in women with atypia on papanicolaou smears. Obstetrics & Gynecology.
2000;96:410-416.
Siddiqi A, Spataro M, McIntire H et al. Hybrid capture 2 human papillomavirus DNA Does not systematically
testing for women with atypical squamous cells of undetermined significance apply reference standard of
Papanicolaou results in SurePath and ThinPrep specimens. Cancer Cytopathology. colposcopy and/or histology
2009;117:318-325.
Sideri M, Spinaci L, Schettino F et al. Risk factors for high-grade cervical intraepithelial Focus on excluded
neoplasia in patients with mild cytological dyskaryosis: human papillomavirus testing screening methods
versus multivariate tree analysis of demographic data. Cancer Epidemiol Biomarkers
Prev. 1998;7:237-241.
Sigurdsson K, Arnadottir T, Snorradottir M, Benediktsdottir K, Saemundsson H. Editorial, letter, non-
Human papillomavirus (HPV) in an Icelandic population: the role of HPV DNA testing systematic review, opinion,
based on hybrid capture and PCR assays among women with screen-detected or case-control
abnormal Pap smears. Int J Cancer. 1997;1997:446-452.
Silverloo I, Andrae B, Wilander E. Value of high-risk HPV-DNA testing in the triage of Colposcopy and/or
ASCUS. Acta Obstet Gynecol Scand. 2009;88:1006-1010. histology only in positives
Slawson DC, Bennett JH, Simon LJ, Herman JM. Should all women with cervical Focus on excluded
atypia be referred for colposcopy: a HARNET study. Harrisburgh Area Research screening methods
Network. J Fam Pract. 1994;1994:387-392.
Snijders PJ, Hogewoning CJ, Hesselink AT et al. Determination of viral load thresholds No relevant outcomes
in cervical scrapings to rule out CIN 3 in HPV 16, 18, 31 and 33-positive women with
normal cytology. Int J Cancer. 2006;119:1102-1107.
Sodhani P, Gupta S, Sharma JK et al. Test characteristics of various screening Poor reporting
modalities for cervical cancer: a feasibility study to develop an alternative strategy for
resource-limited settings. Cytopathology. 2006;17:348-352.
Srodon M, Parry DH, Ronnett BM. Atypical squamous cells, cannot exclude high- Does not systematically
grade squamous intraepithelial lesion: diagnostic performance, human papillomavirus apply reference standard of
testing, and follow-up results. Cancer. 2006;108:32-38. colposcopy and/or histology
Stoler MH, Castle PE, Solomon D, Schiffman M, American Society for Colposcopy and Editorial, letter, non-
Cervical Pathology. The expanded use of HPV testing in gynecologic practice per systematic review, opinion,
ASCCP-guided management requires the use of well-validated assays. Am J Clin or case-control
Pathol. 2007;127:335-337.
Stuart G, Taylor G, Bancej CM et al. Report of the 2003 pan-Canadian forum on Editorial, letter, non-
cervical cancer prevention and control. J Obstet Gynaecol Can. 2004;26:1004-1028. systematic review, opinion,
or case-control
Sun XW, Ferenczy A, Johnson D et al. Evaluation of the Hybrid Capture human Focus on excluded
papillomavirus deoxyribonucleic acid detection test. Am J Obstet Gynecol. screening methods
1995;1995:1432-1437.
Suwannarurk K, Tapanadechopol P, Pattaraarchachai J, Bhamarapravati S. Hospital- Colposcopy and/or
based prevalence and sensitivity of high-risk human papillomavirus in Thai urban histology only in positives
population. Cancer Epidemiology. 2009;33:56-60.

Screening for Cervical Cancer 249 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Syrjanen K, Derchain S, Roteli-Martins C et al. Value of conventional pap smear, Poor reporting
liquid-based cytology, visual inspection and human papillomavirus testing as optional
screening tools among Latin American women <35 and > or =35 years of age:
experience from the Latin American Screening Study. Acta Cytol. 2008;52:641-653.
Syrjanen K, Naud P, Derchain S et al. Comparing PAP smear cytology, aided visual Poor reporting
inspection, screening colposcopy, cervicography and HPV testing as optional
screening tools in Latin America. Study design and baseline data of the LAMS study.
Anticancer Res. 2005;25:3469-3480.
Syrjanen S, Shabalova IP, Petrovichev N et al. Human Papillomavirus Testing and Colposcopy and/or
Conventional Pap Smear Cytology as Optional Screening Tools of Women at Different histology only in positives
Risks for Cervical Cancer in the Countries of the Former Soviet Union. J Low Genit
Tract Dis. 2002;6:97-110.
Tarkkanen J, Auvinen E, Nieminen P et al. HPV DNA testing as an adjunct in the Included women with
management of patients with low grade cytological lesions in Finland. Acta Obstet repeated abnormal smears
Gynecol Scand. 2007;86:367-372. or abnormal smear other
than ASC
Terry G, Ho L, Londesborough P, Cuzick J, Mielzynska-Lohnas I, Lorincz A. Detection No relevant outcomes
of high-risk HPV types by the hybrid capture 2 test. J Med Virol. 2001;65:155-162.
Tiews S, Steinberg W, Schneider W, Hanrath C. Determination of the diagnostic Does not systematically
accuracy of testing for high-risk (HR) human papillomavirus (HPV) types 16, 18 and 45 apply reference standard of
in precancerous cervical lesions: preliminary data. J Clin Virol. 2009;46:Suppl-5. colposcopy and/or histology
UK NHS National Coordinating Centre for Health Technology Assessment. A Editorial, letter, non-
randomised trial of human papillomavirus testing in primary cervical screening - systematic review, opinion,
primary research project (ongoing). UK NHS National Coordinating Centre for Health or case-control
Technology Assessment. 2002.
University of Zimbabwe/JHPIEGO Cervical Cancer Project. Visual inspection with Focus on excluded
acetic acid for cervical-cancer screening: test qualities in a primary-care setting. screening methods
University of Zimbabwe/JHPIEGO Cervical Cancer Project. Lancet. 1999;1999:869-
873.
Utagawa ML, Pereira SM, Makabe S et al. Pap test in a high-risk population Focus on excluded
comparison of conventional and liquid-base cytology. Diagn Cytopathol. 2004;31:169- screening methods
172.
van den Akker-van Marie ME, van Ballegooijen M, Rozendaal L, Meijer CJ, Habbema No relevant outcomes
JD. Extended duration of the detectable stage by adding HPV test in cervical cancer
screening. Br J Cancer. 2003;89:1830-1833.
Vassilakos P. Biopsy-based comparison of liquid-based, thin-layer preparations to Colposcopy and/or
conventional Pap smears. The Journal of reproductive medicine. 2000;11-16. histology only in positives
Voss JS, Kipp BR, Campion MB et al. Assessment of fluorescence in situ hybridization No comparison to cytology
and hybrid capture 2 analyses of cervical cytology specimens diagnosed as low grade
squamous intraepithelial lesion for the detection of high grade cervical intraepithelial
neoplasia. Analytical & Quantitative Cytology & Histology. 2010;32:121-130.
Vrtacnik-Bokal E, Rakar S, Jancar N, Mozina A, Poljak M. Role of human No comparison to cytology
papillomavirus testing in reducing the number of surgical treatments for precancerous
cervical lesions. Eur J Gynaecol Oncol. 2005;26:427-430.
Wahlstrom C, Iftner T, Dillner J, Dillner L, Swedescreen Study Group. Population- Conducted solely in
based study of screening test performance indices of three human papillomavirus DNA referred population or does
tests. J Med Virol. 2007;79:1169-1175. not report routine and
referred population
outcomes separately
Walker JL, Wang SS, Schiffman M, Solomon D. Predicting absolute risk of CIN3 Focus on methods to
during post-colposcopic follow-up: results from the ASCUS-LSIL Triage Study (ALTS). improve followup of
Am J Obstet Gynecol. 2006;195:341-348. abnormal screening
findings
Wensveen C, Kagie M, Veldhuizen R et al. Detection of cervical intraepithelial Included women with
neoplasia in women with atypical squamous or glandular cells of undetermined repeated abnormal smears
significance cytology: a prospective study. Acta Obstet Gynecol Scand. 2003;82:883- or abnormal smear other
889. than ASC

Screening for Cervical Cancer 250 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Wentzensen N, Gravitt PE, Solomon D, Wheeler CM, Castle PE. A study of Amplicor No comparison to cytology
human papillomavirus DNA detection in the atypical squamous cells of undetermined
significance-low-grade squamous intraepithelial lesion triage study. Cancer
Epidemiology, Biomarkers & Prevention. 2009;18:1341-1349.
Witt A, Hudelist G, Gregor H, Kucera E, Walchetseder C, Czerwenka K. The detection Focus on excluded
of HPV DNA improves the recognition of cervical intraepithelial lesions. Archives of screening methods
Gynecology & Obstetrics. 2003;268:29-34.
Womack SD, Chirenje ZM, Blumenthal PD et al. Evaluation of a human papillomavirus Population not comparable
assay in cervical screening in Zimbabwe. BJOG: An International Journal of Obstetrics to primary care
& Gynaecology. 2000;107:33-38.
Womack SD, Chirenje ZM, Gaffikin L et al. HPV-based cervical cancer screening in a Population not comparable
population at high risk for HIV infection. Int J Cancer. 2000;85:206-210. to primary care
Wright JD, Rader JS, Davila R et al. Human papillomavirus triage for young women Editorial, letter, non-
with atypical squamous cells of undetermined significance. Obstetrics & Gynecology. systematic review, opinion,
2006;107:822-829. or case-control
Wright TC, Jr. Cervical cancer screening in the 21st century: is it time to retire the PAP Editorial, letter, non-
smear? Clin Obstet Gynecol. 2007;50:313-323. systematic review, opinion,
or case-control
Wright TC, Jr., Denny L, Kuhn L, Pollack A, Lorincz A. HPV DNA testing of self- Colposcopy and/or
collected vaginal samples compared with cytologic screening to detect cervical cancer. histology only in positives
JAMA. 2000;283:81-86.
Wright TC, Jr., Lorincz A, Ferris DG et al. Reflex human papillomavirus No comparison to cytology
deoxyribonucleic acid testing in women with abnormal Papanicolaou smears. Am J
Obstet Gynecol. 1998;178:962-966.
Wright TC, Sun XW, Koulos J. Comparison of management algorithms for the Focus on excluded
evaluation of women with low-grade cytologic abnormalities. Obstet Gynecol. screening methods
1995;1995:202-210.
Wu HH, Allen SL, Kirkpatrick JL, Elsheikh TM. Reflex high-risk human papilloma virus Does not systematically
DNA test is useful in the triage of women with atypical squamous cells cannot exclude apply reference standard of
high-grade squamous intraepithelial lesion. Diagn Cytopathol. 2006;34:707-710. colposcopy and/or histology
Wu S, Meng L, Wang S, Ma D. A comparison of four screening methods for cervical No relevant outcomes
neoplasia. International Journal of Gynaecology & Obstetrics. 2005;91:189-193.
Xiao GQ, Emanuel PO. Cervical parakeratosis/hyperkeratosis as an important cause Does not systematically
for false negative results of Pap smear and human papillomavirus test. Australian & apply reference standard of
New Zealand Journal of Obstetrics & Gynaecology. 2009;49:302-306. colposcopy and/or histology
Yarandi F, Shojaei H, Eftekhar Z, Izadi-Mood N. Comparison of three management Poor reporting
strategies for patients with atypical squamous cells of undetermined significance, after
six months delay: a three-year experience in an Iranian university hospital. Australian
& New Zealand Journal of Obstetrics & Gynaecology. 2009;49:207-210.
Yeoh GP, Tse MP, Chan KW, Lord L. Human papillomavirus DNA and liquid-based Does not systematically
cervical cytology cotesting in screening and follow-up patient groups. Acta Cytol. apply reference standard of
2006;50:627-631. colposcopy and/or histology
Yoon JH, Yoo SC, Kim WY, Chang SJ, Chang KH, Ryu HS. Role of HPV DNA testing No comparison to cytology
for detection of high-grade cervical lesions in women with atypical squamous cells of
undetermined significance: a prospective study in a Korean population. Eur J
Gynaecol Oncol. 2009;30:271-274.
You K, Liang X, Qin F, Guo Y, Geng L. High-risk human papillomavirus DNA testing Focus on excluded
and high-grade cervical intraepithelial lesions. Australian & New Zealand Journal of screening methods
Obstetrics & Gynaecology. 2007;47:141-144.
Zappacosta R, Caraceni D, Ciccocioppo L et al. Is HPV-DNA testing a useful tool in No relevant outcomes
predicting low-grade squamous intraepithelial lesion outcome? A retrospective
longitudinal study. Int J Immunopathol Pharmacol. 2010;23:317-326.
Zdenek, H., Lukac, J., Jabor, A., Chvalova, M., Voracek, J., and Brozkova, M. H. Poor reporting
Human papillomavirus deoxyribonucleic acid testing in screening of high grade
cervical intraepithelial neoplasia. Saudi Medical Journal 20[11], 861-864. 1999.
Zhao C, Zhao S, Heider A, Austin RM. Significance of high-risk human papillomavirus Does not systematically
DNA detection in women 50 years and older with squamous cell papanicolaou test apply reference standard of
abnormalities. Archives of Pathology & Laboratory Medicine. 2010;134:1130-1135. colposcopy and/or histology

Screening for Cervical Cancer 251 Oregon Evidence-based Practice Center

Appendix D Table 3. Studies Excluded From the Review for KQ3

Key Question 3: What are the benefits of using HPV testing as a screening test, either alone or in
combination with cytology, compared with not testing for HPV?
Reference Reason for exclusion*
Zielinski GD, Snijders PJ, Rozendaal L et al. High-risk HPV testing in women with No comparison to cytology
borderline and mild dyskaryosis: long-term follow-up data and clinical relevance. J
Pathol. 2001;195:300-306.
Zielinski SL. Trial quickly changed management of cervical abnormalities. J Natl Editorial, letter, non-
Cancer Inst. 2005;97:479-480. systematic review, opinion,
or case-control
Zuna RE, Wang SS, Rosenthal DL et al. Determinants of human papillomavirus- No relevant outcomes
negative, low-grade squamous intraepithelial lesions in the atypical squamous cells of
undetermined significance/low-grade squamous intraepithelial lesions triage study
(ALTS). Cancer. 2005;105:253-262.

* See Appendix B Table 2 for more detailed exclusion criteria

‡
A large trial that did not meet criteria for inclusion in Key Question 3 was the HPV in Addition to Routine Testing
(HART) study conducted in the UK. In this study, 10,358 women who presented for screening at one of 161 family
practice clinics in the UK received both an HPV test (HC2) and cytology. Women with LSIL or worse went directly to
colposcopy. A 5 percent sample of women negative on both HPV tests and cytology were recalled for colposcopy,
and approximately two-thirds attended. The remaining subset of women who had either ASC-US cytology, HPV
positive test results, or both were randomized to cytology and HPV testing at 6 and 12 months or to immediate
colposcopy. Although the authors report that the specific aims of the study were to compare HPV assays with
conventional cytology in the detection rate and positive predictive value of CIN2+, the results of both tests were used
to determine management of positive screening results after co-testing. Thus, the randomized portion of the HART
study was not designed to determine whether there are benefits of using HPV testing alone or in combination with
cytology compared to not testing for HPV but to evaluate relative merits of management strategies after co-testing or
HPV with cytology triage. Results from HART might be useful to inform future modeling exercises of HPV testing (with
or without cytology co-testing or triage) in women aged 30 to 35 years and older.
The HART study could potentially provide theoretical absolute test results of the sensitivity and specificity of HPV
versus cytology, as they offered colposcopy to a random 5 percent subset of those who were HPV negative and
cytology negative. However, there was 38 percent nonreceipt of colposcopy from that sample, yielding a nonrandom
group of approximately 3 percent of women who were both HPV and cytology negative. Although none of these had
CIN2+, it is a small nonrandom sample (n=283) whose results are assumed to apply to all women who tested
negative on both tests (n=9173) for the purposes of test performance calculations. Relative test performance
(between randomized arms) of HPV versus cytology was not available, as the randomization scheme was performed
in order to determine effective management strategies (immediate colposcopy versus surveillance over 6 to 12
months) for women who were HPV positive but cytology negative or borderline at most. Given other limitations to the
study, we could not be sure that this study could provide unbiased theoretical absolute test performance estimates for
HPV versus cytology. The main limitation is risk of verification bias given that there was differential loss to followup
for colposcopy referral among the study arms (13 to 28%). Although the authors tried to calculate test performance
within strata to “adjust” for differential noncompliance, this assumes that those not lost to followup are representative
of the whole sample, which was shown to not be true using data provided in Table 4 of the Cuzick article. Other
issues include uncertainty as to the timeframe within which colposcopy and biopsy was provided, lack of blinding of
colposcopists to cytology results (with perhaps the ability to guess HPV results), and exclusion of those with
unsatisfactory cytology or incomplete cytology or HPV results (even those with colposcopy).

Screening for Cervical Cancer 252 Oregon Evidence-based Practice Center

Appendix D Table 4. Studies Excluded From the Review for KQ4

Key Question 4: What are the harms of liquid-based cytology?

Reference Reason for exclusion*
Atkins KA, Jeronimo J, Stoler MH, ALTS Group. Description of patients with squamous Reported outcomes do not
cell carcinoma in the atypical squamous cells of undetermined significance/low-grade address a key question
squamous intraepithelial lesion triage study. Cancer. 2006;108:212-221.
Bacon J, Francoeur D, Goldfarb AF, Breech LL. Abnormal pap smears in adolescents. Editorials, letters, non-
J Pediatr Adolesc Gynecol. 2003;16:157-166. systematic review, opinion
or case-control
Genova NJ. Evidence-based medicine--in real time. Comparing methods of cervical Editorials, letters, non-
Ca screening. JAAPA. 2000;13:55-60, 63. systematic review, opinion
or case-control
Hartmann, KE, Hall, SA, Nanda, K, Boggess, JF, and Zolnoun, D. Screening for Provides data covered in
Cervical Cancer. ii-74. 2002. Agency for Healthcare Research and Quality. other articles
Kahn JA, Hillard PJ. Cervical cytology screening and management of abnormal Editorials, letters, non-
cytology in adolescent girls. J Pediatr Adolesc Gynecol. 2003;16:167-171. systematic review, opinion
or case-control
Moseley RP, Paget S. Liquid-based cytology: is this the way forward for cervical Precedes search period
screening? Cytopathology. 2002;13:71-82.
Noorani, H. Z., Brown, A., Skidmore, B., and Stuart, G. C. E. Liquid-based cytology SER includes studies that
and human papillomavirus testing in cervical cancer screening. 2003. do not meet design criteria
Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K. False-negative results in Precedes search period
screening programmes: systematic review of impact and implications. Health Technol
Assess. 2000;4:1-120.
Stuart G, Taylor G, Bancej CM et al. Report of the 2003 pan-Canadian forum on Editorials, letters, non-
cervical cancer prevention and control. J Obstet Gynaecol Can. 2004;26:1004-1028. systematic review, opinion
or case-control
Weintraub, J. The coming revolution in cervical cytology: a pathologist's guide for the Editorials, letters, non-
clinician. References en Gynecologie Obstetrique 5, 1-6. 1997. systematic review, opinion
or case-control
Zielinski SL. Trial quickly changed management of cervical abnormalities. J Natl Editorials, letters, non-
Cancer Inst. 2005;97:479-480. systematic review, opinion
or case-control
* See Appendix B Table 2 for more detailed exclusion criteria

Screening for Cervical Cancer 253 Oregon Evidence-based Practice Center

Appendix D Table 5. Studies Excluded From the Review for KQ5

Key Question 5: What are the harms of using HPV testing as a screening test, either alone or in combination
with cytology?
Reference Reason for exclusion*
Atkins KA, Jeronimo J, Stoler MH, ALTS Group. Description of patients with squamous Reported outcomes do not
cell carcinoma in the atypical squamous cells of undetermined significance/low-grade address a key question
squamous intraepithelial lesion triage study. Cancer. 2006;108:212-221.
Bacon J, Francoeur D, Goldfarb AF, Breech LL. Abnormal pap smears in adolescents. Editorials, letters, non-
J Pediatr Adolesc Gynecol. 2003;16:157-166. systematic review, opinion
or case-control
Bell S, Porter M, Kitchener H, Fraser C, Fisher P, Mann E. Psychological response to Does not focus on
cervical screening. Prev Med. 1995;24:610-616. screening or harms of
screening
Campion MJ, Brown JR, McCance DJ et al. Psychosexual trauma of an abnormal Editorials, letters, non-
cervical smear. Br J Obstet Gynaecol. 1988;95:175-181. systematic review, opinion
or case-control
Castle PE, Katki HA. Benefits and risks of HPV testing in cervical cancer screening. Editorials, letters, non-
Lancet Oncology. 2010;11:214-215. systematic review, opinion
or case-control
Clarke P, Ebel C, Catotti DN, Stewart S. The psychosocial impact of human Editorials, letters, non-
papillomavirus infection: implications for health care providers. Int J STD AIDS. systematic review, opinion
1996;7:197-200. or case-control
Conaglen HM, Hughes R, Conaglen JV, Morgan J. A prospective study of the Population not comparable
psychological impact on patients of first diagnosis of human papillomavirus. to primary care
International Journal of STD & AIDS. 2001;12:651-658.
Daley EM, Perrin KM, McDermott RJ et al. The psychosocial burden of HPV: a mixed- Editorials, letters, non-
method study of knowledge, attitudes and behaviors among HPV+ women. Journal of systematic review, opinion
Health Psychology. 2010;15:279-290. or case-control
Filiberti A, Tamburini M, Stefanon B et al. Psychological aspects of genital human Editorials, letters, non-
papillomavirus infection: a preliminary report. J Psychosom Obstet Gynaecol. systematic review, opinion
1993;14:145-152. or case-control
Genova NJ. Evidence-based medicine--in real time. Comparing methods of cervical Editorials, letters, non-
Ca screening. JAAPA. 2000;13:55-60, 63. systematic review, opinion
or case-control
Graziottin A, Serafini A. HPV infection in women: psychosexual impact of genital warts Editorials, letters, non-
and intraepithelial lesions. Journal of Sexual Medicine. 2009;6:633-645. systematic review, opinion
or case-control
Hartmann, KE, Hall, SA, Nanda, K, Boggess, JF, and Zolnoun, D. Screening for Data covered in other
Cervical Cancer. Rockville (MD): Agency for Healthcare Research and Quality; 2002. articles
Systematic Evidence Review Number 25.
Howlett RI. Acceptability of HPV-DNA testing HPV vaccines and levels of HPV Does not focus on
knowledge. Dissertation Abstracts International: Section B: The Sciences and screening or harms of
Engineering. 2008;Vol.68:4420. screening
Kahn JA, Hillard PJ. Cervical cytology screening and management of abnormal Editorials, letters, non-
cytology in adolescent girls. J Pediatr Adolesc Gynecol. 2003;16:167-171. systematic review, opinion
or case-control
Kahn JA, Slap GB, Bernstein DI et al. Psychological, behavioral, and interpersonal Editorials, letters, non-
impact of human papillomavirus and Pap test results. Journal of Psychiatric Research. systematic review, opinion
2005;14:650-659. or case-control
Keller ML, von S, V, Pankratz B, Hermsen J. Self-disclosure of HPV infection to sexual Reported outcomes do not
partners. West J Nurs Res. 2000;22:285-296. address a key question
Kitchener HC, Almonte M, Gilham C et al. ARTISTIC: a randomised trial of human Data covered in other
papillomavirus (HPV) testing in primary cervical screening. Health technology articles
assessment (Winchester, England). 2009;13:1-150.
Lehr, S. and Lee, M. The psychosocial and sexual trauma of a genital HPV infection. Editorials, letters, non-
Nurse Practitioner Forum 1990; 1, 25-30. systematic review, opinion
or case-control
Linnehan MJ, Groce NE. Psychosocial and educational services for female college Editorials, letters, non-
students with genital human papillomavirus infection. Fam Plann Perspect. systematic review, opinion
1999;31:137-141. or case-control

Screening for Cervical Cancer 254 Oregon Evidence-based Practice Center

Appendix D Table 5. Studies Excluded From the Review for KQ5

Key Question 5: What are the harms of using HPV testing as a screening test, either alone or in combination
with cytology?
Reference Reason for exclusion*
Maggino T, Casadei D, Panontin E et al. Impact of an HPV diagnosis on the quality of Quality issues: small
life in young women. Gynecol Oncol. 2007;107:Suppl-9. sample size, poor reporting,
>6 mos between HPV
diagnosis and
questionnaire in 50% of
sample
Mast TC, Zhu X, muro-Mercon C, Cummings HW, Sings HL, Ferris DG. Development Does not focus on
and psychometric properties of the HPV Impact Profile (HIP) to assess the screening or harms of
psychosocial burden of HPV. Current Medical Research & Opinion. 2009;25:2609- screening
2619.
McCaffery K, Forrest S, Waller J, Desai M, Szarewski A, Wardle J. Attitudes towards Editorials, letters, non-
HPV testing: a qualitative study of beliefs among Indian, Pakistani, African-Caribbean systematic review, opinion
and white British women in the UK. Br J Cancer. 2003;88:42-46. or case-control
McCaffery K, Waller J, Nazroo J, Wardle J. Social and psychological impact of HPV Editorials, letters, non-
testing in cervical screening: a qualitative study. Sex Transm Infect. 2006;82:169-174. systematic review, opinion
or case-control
Monk BJ, Wiley DJ. Human papillomavirus infections: truth or consequences. Cancer. Editorials, letters, non-
2004;100:225-227. systematic review, opinion
or case-control
Newton DC, McCabe MP. Sexually transmitted infections: impact on individuals and Does not focus on
their relationships. Journal of Health Psychology. 2008;13:864-869. screening or harms of
screening
Noorani, H. Z., Brown, A., Skidmore, B., and Stuart, G. C. E. Liquid-based cytology SER includes studies that
and human papillomavirus testing in cervical cancer screening. Ottawa: Canadian do not meet design criteria
Coordinating Office for Health Technology Assessment; 2003. Technology report no
40.
Perrin KK, Daley EM, Naoom SF et al. Women's reactions to HPV diagnosis: insights Editorials, letters, non-
from in-depth interviews. Women & Health. 2006;43:93-110. systematic review, opinion
or case-control
Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K. False-negative results in Precedes search period
screening programmes: systematic review of impact and implications. Health Technol
Assess. 2000;4:1-120.
Philips Z, Johnson S, Avis M, Whynes DK. Human papillomavirus and the value of Does not focus on
screening: young women's knowledge of cervical cancer. Health Educ Res. screening or harms of
2003;18:318-328. screening
Pirotta M, Ung L, Stein A et al. The psychosocial burden of human papillomavirus Does not focus on
related disease and screening interventions. Sex Transm Infect. 2009;85:508-513. screening or harms of
screening
Ramirez JE, Ramos DM, Clayton L, Kanowitz S, Moscicki AB. Genital human Editorials, letters, non-
papillomavirus infections: knowledge, perception of risk, and actual risk in a nonclinic systematic review, opinion
population of young women. J Womens Health. 1997;6:113-121. or case-control
Reed BD, Ruffin MT, Gorenflo DW, Zazove P. The psychosexual impact of human Editorials, letters, non-
papillomavirus cervical infections. J Fam Pract. 1999;48:110-116. systematic review, opinion
or case-control
Rosen NO, Knauper B, Di DP et al. The impact of intolerance of uncertainty on anxiety Does not focus on
after receiving an informational intervention about HPV: A randomised controlled screening or harms of
study. Psychol Health. 2009;1-17. screening
Rosen NO, Knauper B, Page G et al. Brief research report: uncertainty-inducing and Does not focus on
reassuring facts about HPV: a descriptive study of French Canadian women. Health screening or harms of
Care Women Int. 2009;30:892-902. screening
Rubin MM, Tripsas CK. Perceived uncertainty, coping strategies, and adaptation in Does not focus on
women with human papillomavirus on pap smear. Journal of Lower Genital Tract screening or harms of
Disease. 2010;14:81-89. screening
Stuart G, Taylor G, Bancej CM et al. Report of the 2003 pan-Canadian forum on Editorials, letters, non-
cervical cancer prevention and control. J Obstet Gynaecol Can. 2004;26:1004-1028. systematic review, opinion
or case-control

Screening for Cervical Cancer 255 Oregon Evidence-based Practice Center

Appendix D Table 5. Studies Excluded From the Review for KQ5

Key Question 5: What are the harms of using HPV testing as a screening test, either alone or in combination
with cytology?
Reference Reason for exclusion*
Waller J, Marlow LA, Wardle J. The association between knowledge of HPV and Editorials, letters, non-
feelings of stigma, shame and anxiety. Sex Transm Infect. 2007;83:155-159. systematic review, opinion
or case-control
Waller J, McCaffery K, Forrest S, Szarewski A, Cadman L, Wardle J. Awareness of Does not focus on
human papillomavirus among women attending a well woman clinic. Sex Transm screening or harms of
Infect. 2003;79:320-322. screening
Waller J, McCaffery K, Kitchener H, Nazroo J, Wardle J. Women's experiences of Editorials, letters, non-
repeated HPV testing in the context of cervical cancer screening: a qualitative study. systematic review, opinion
Psycho-Oncology. 2007;16:196-204. or case-control
Waller J, McCaffery K, Nazroo J, Wardle J. Making sense of information about HPV in Reported outcomes do not
cervical screening: a qualitative study. Br J Cancer. 2005;92:265-270. address a key question
Waller J, McCaffery KJ, Forrest S, Wardle J. Human papillomavirus and cervical Editorials, letters, non-
cancer: issues for biobehavioral and psychosocial research. Ann Behav Med. systematic review, opinion
2004;27:68-79. or case-control
Wang KL, Jeng CJ, Yang YC et al. The psychological impact of illness among women Does not focus on
experiencing human papillomavirus-related illness or screening interventions. Journal screening or harms of
of Psychosomatic Obstetrics & Gynecology. 2010;31:16-23. screening
Wilkinson C, Jones JM, McBride J. Anxiety caused by abnormal result of cervical Does not focus on
smear test: a controlled trial. BMJ. 1990;300:440. screening or harms of
screening
Zielinski SL. Trial quickly changed management of cervical abnormalities. J Natl Editorials, letters, non-
Cancer Inst. 2005;97:479-480. systematic review, opinion
or case-control
*See Appendix B Table 2 for more detailed exclusion criteria

Screening for Cervical Cancer 256 Oregon Evidence-based Practice Center

Appendix E. Screening Benefit Considerations Illustrated by NTCC
Phase II Trial113
The recently reported NTCC Phase II trial of primary HPV screening (compared with cytology) illustrates
the tricky and complicated considerations when trying to determine screening benefit, much less net
impact (screening benefit minus harms), for alternative approaches in a program of cervical cancer
screening. After a single round of HPV screening, disease detection was relatively greater (2-4 times
greater, depending on age and whether defined as CIN3+ or CIN2+) compared with cytology alone,
although cancers were uncommon in both arms. However, colposcopies were also relatively elevated, at
least 2-4 times, with a much higher burden in younger women undergoing primary HPV screening
(13.1% in those under 35 vs. 5.8% in women 35 and older) and as compared to younger and older
women undergoing conventional cytology (3.6% and 2.4% respectively). This trial also reported a relative
decrease in CIN3+ in the HPV arm compared with cytology at the second screening round 3.5 years later
which consisted of both groups receiving conventional cytology. While this finding has been interpreted as
indicating preventive benefit, since the same test was used in both arms, it is unfortunate that this
approach renders the trial non-informative about repeat HPV screening. Experts have suggested that
reduced CIN3+ detection in subsequent screening rounds may be a surrogate measure of screening
program benefit, by signaling earlier disease detection and treatment. However, CIN3+ is a combined
outcome (CIN3, CIS, ICC) that includes some potentially regressive disease. And in NTCC Phase II (as
with most trials to date) no impact on cancers was detected. Also, even if one accepts this trial as
evidence of HPV screening benefit, net impact cannot be determined as cumulative colposcopy burden is
not reported yet for this study. Colposcopy burden could conceivably be improved in the HPV screening
arm relative to cytology if early treatment has prevented disease, but whether this is true and how much
remains to be demonstrated. And, the potential harms from diagnosis and treatment of non-progressive
disease cannot even be estimated due to incomplete reporting. Longer term follow-up and more complete
reporting of all screening-related activities and results, including colposcopies, are needed to fully
interpret this trial. However, this trial provides several take-away messages as presented. First, given the
greatly increased colposcopy requirement and relatively diminished cancer burden in younger women,
HPV screening alone in women under 35 is not promising. Second, unless future reporting confirms an
ongoing reduction in CIN3+ (and ideally cervical cancers) after one-time HPV screening in older women,
careful weighing of benefits with harms from additional colposcopy requirements will be necessary even
for modeling an ongoing program of repeat cervical cancer screening. Finally, modeling will also need to
adjust for the difference between the trial colposcopy referral threshold (ASC-US+) and US practice.

ASC-US: atypical squamous cells of undetermined significance; CIN: cervical intraepithelial neoplasia; CIS:
carcinoma in situ; HPV: human papillomavirus; ICC: invasive cervical cancer; NTCC: New Technologies for Cervical
Cancer ; US: United States

Screening for Cervical Cancer 257 Oregon Evidence-based Practice Center

Appendix F. Ongoing and Pending Trials
Principal Approximate Status
Location Population Investigations Outcomes
investigators size as of 2010
KQ1: Age to begin screening

KQ2: Liquid-based cytology

KQ3: HPV testing

Trial
Routine HPV DNA testing ≥CIN2
* Vancouver, expected to
Coldman screening 33,000 with cytology ≥CIN3
BC finish March
Age 25-69 triage Cost analysis
2014
Trial
HPV testing alone ≥CIN2
Routine expected to
* Toronto, or in combination ≥CIN3
Murphy screening 1712 finish
ON with conventional Rate of
Aged ≥18 January
cytology colposcopies
2011
HPV cotesting Trial
with conventional expected to
Routine ≥CIN2
* cytology finish
Ngan Hong Kong screening 12,000 ≥CIN3
compared to January
Age 30-60
conventional 2017
cytology alone
KQ4: Harms of liquid-based cytology

KQ5: Harms of HPV testing

*
Available at: www.clinicaltrials.gov. Accessed September 29, 2010.

Screening for Cervical Cancer 258 Oregon Evidence-based Practice Center

Appendix G. Recommendations of Other Groups

Age to start Interval for

Organization Screening interval Definition of high risk Age to stop screening
screening high risk
American College of Age 21 Under age 30: 2 years HIV infection Annual 65 or 70 years with 3 normal screenings and no
Obstetricians and abnormalities within past 10 years. Assess risk
Gynecologists, 2009
1 Age 30+ with three Immunosuppressed HIV: twice in factors annually.
consecutive normal the first year
screenings: every 3 years Diethylstilbestrol exposure
in utero of diagnosis After total hysterectomy if no prior high-grade CIN
and annually
Women previously treated after If had CIN 2 or 3, then continue screening
for CIN 2, CIN 3, or cancer
in the past
American College of At onset of At least 2 initial screening Not mentioned Not mentioned Age 65, if no abnormal smears
Preventive Medicine, sexual activity tests 1 year apart; then
Practice Guidelines or age 18 if interval lengthened at
2
Committee, 1996 sexual history discretion of patient and
is unknown doctor, but not to exceed >3
“Although the research on year interval
which this statement was
based is out of date, the
position/ recommendations
contained in this policy
were reaffirmed by the
ACPM Board of Regents
on 1/31/2005 until the
evidence can be
reevaluated.”
American Academy of Onset of Once a year until at least 3 Starting to have sex early Not mentioned Throughout life even after menopause; discuss with
3
Family Physicians, 2008 sexual activity normal smears (before age 20) physician if > 65 years
or age 18
After this, you should have a Having had many sexual
Pap smear at least every 3 partners
years
Being infected with an STD
or having had a sex
partner who has an STD
Smoking
Using birth control pills
and/or giving birth to many
children when also infected
with HPV

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Appendix G. Recommendations of Other Groups

Age to start Interval for

Organization Screening interval Definition of high risk Age to stop screening
screening high risk
Canadian Task Force on Women > age Two annual screens, then Early onset of sexual More Until age 69
Preventive Health Care, 18 who have every three years intercourse frequently
4
1994 had sexual than 3 years
intercourse Many sexual partners
Is on priority list for update Sexual partner with many
sexual partners
American Cancer Society, Three years Testing should be done every HPV Infection Yearly Women 70 years of age or older who have had 3 or
5
2009 after year with the regular Pap test more normal Pap tests in a row and no abnormal
beginning to or every 2 years using the Smoking Pap test results in the last 10 years may choose to
have vaginal newer liquid-based Pap test HIV infection/ stop having cervical cancer testing
intercourse, Immunosupressed
but no later Beginning at age 30, women Women with a history of cervical cancer, DES
than age 21 who have had 3 normal Pap Chlamydia infection exposure before birth, HIV infection, or a weakened
years test results in a row may get immune system should continue to have annual
tested every 2 to 3 years with Diet (overweight, low in
fruits/veggies) screening
either the conventional
(regular) or liquid-based Pap Oral contraceptives Women who have had a total hysterectomy
test or every 3 years with (removal of the uterus and cervix) may also choose
HPV testing >2 full-term pregnancies
to stop having cervical cancer testing, unless the
Low SES surgery was done as a treatment for cervical cancer
or pre-cancer
First full-term pregnancy at
<17 yrs
Diethylstilbestrol (DES)
Family history of cervical
cancer
Institute for Clinical Three years Every 3 years after 3 Not mentioned Not mentioned No age recommended for screening to stop
Systems Improvement, post-onset of consecutive normal smears
6
2009 sexual activity over 5 years. Women with total hysterectomy for benign disease
or by age 21 - and no history of CIN 2 or 3 can stop screening.

UK National Health Service Age 25 Age 25-49: every 3 years Not mentioned Not mentioned Age 65+: Only screen those who have not been
Cervical Screening screened since age 50 or have had recent abnormal
Programme, 2009
7 Age 50-65: every 5 years tests
Age 65+: Only screen those
who have not been screened
since age 50 or have had
recent abnormal tests

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Appendix G. Recommendations of Other Groups

Age to start Interval for

Organization Screening interval Definition of high risk Age to stop screening
screening high risk
Australian National 18-20 years or Every 2 years “check with Age 70 if two normal Pap smears in last 5 years.
Cervical Screening 1-2 yrs within your doctor”
8
Program, 2009 first sexual
intercourse
whichever is
later
New Zealand National Age 20 for all If first cervical smear test, or Immunosuppressed Annual Age 70
Cervical Screening women who if haven’t had a test for over 5
9
Programme, 2008 have had years, have a second cervical
sexual smear test at 1 year
intercourse
Otherwise, every three years
for most women

European guidelines for Age 20 to 30 3-5-year intervals until Special attention should be The upper limit should not be lower than 60 years.
quality assurance in yrs paid to the problem of Stopping screening in older women is probably
cervical cancer screening, the age of 60 older women who have appropriate among women who have had three or
10
2008 never attended screening, more consecutive previous (recent) normal cytology
as they exhibit increased results.
risk for cervical cancer.

References

1. ACOG Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 109: cervical cytology screening. Obstet Gynecol. 2009;114(6):1409-1419.
2. Hawkes AP, Kronenberger CB, MacKenzie TD, et al. Cervical cancer screening: American College of Preventive Medicine practice policy statement. Am J Prev Med.
1996;12(5):342-344.
3. American Academy of Family Physicians. Pap Smears. Leawood, KS: American Academy of Family Physicians; 2008. Accessed at
http://familydoctor.org/online/famdocen/home/women/reproductive/gynecologic/138.html on 11 May 2011.
4. Canadian Task Force on Preventive Health Care. Screening for Cervical Cancer. Ottawa, Ontario: Canadian Task Force on Preventive Health Care; 1994. Accessed at
http://www.canadiantaskforce.ca/_archive/index.html on 11 May 2011.
5. American Cancer Society Guidelines for the Early Detection of Cancer. Atlanta, GA: American Cancer Society; 2010. Accessed at
http://www.cancer.org/Healthy/FindCancerEarly/CancerScreeningGuidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer on 11 May 2011.
6. Institute for Clinical Systems Improvement. Health Care Guideline: Preventive Services for Adults. Bloomington, MN: Institute for Clinical Systems Improvement; 2010.
Accessed at http://www.icsi.org/preventive_services_for_adults/preventive_services_for_adults_4.html on 11 May 2011.
7. NHS Cervical Screening Programme. About Cervical Screening. London: National Health Service; 2011. Accessed at http://www.cancerscreening.nhs.uk/cervical/about-
cervical-screening.html on 11 May 2011.
8. Australia Department of Health and Ageing. National Cervical Screening Program. Canberra, Australia: Australia Department of Health and Ageing; 2009. Accessed at
http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/cervical-about on 11 May 2011.
9. New Zealand National Cervical Screening Programme. Guidelines for Cervical Screening in New Zealand. Wellington, New Zealand: National Screening Unit, Ministry of Health;
2008. Accessed at http://www.nsu.govt.nz/files/NCSP/NCSP_Guidelines_ALL_small(1).pdf on 11 May 2011.
10. Arbyn M, Anttila A, Jordan J, et al. European Guidelines for Quality Assurance in Cervical Cancer Screening: second edition—summary document. Ann Oncol. 2010;21(3):448-
458.

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Appendix H. Cervical Cancer and HPV: Prevalence, Incidence and Mortality Rates

HPV
Prevalence among Adjusted Prevalence Crude age-specific prevalence among women with normal cytology Prevalence of HPV
Country women with normal among women with normal (general population) % (95% CI) types 16 and 18
cytology cytology (general (Estimated from Figure 24) among cervical
(general population) population), by region,* % cancer cases
< 25y 25-34y 35-44y 45-54y 55+y
% (95% CI) (95% CI)† % (95% CI)
9.9 North America: 26 27.5 14 12 12.5 74.3
Canada
(9.5-10.4) 11.3 (10.6-12.1) (22.5-32.5) (22.5-34) (6.3-25) (4.4-24) (5.0-25) (67.0-80.6)

12.2 Eastern Asia: 9 10 13.5 12.5 10 71.0

China
(11.8-12.6) 13.6 (12.5-14.9) (6-14) (8-12.5) (12-15.5) (10-15) (7.5-14) (69.8-72.2)

8.9 Northern Europe: 22 14 7 6 6 79.1

England (UK)
(8.6-9.1) 7.9 (7.4-8.4) (21.5-23) (13.5-15) (6-7.5) (5-6.5) (5.0-6.4) (74.4-83.2)
7.5 No data 18.5 8.5 4.3 4 88.5
Finland NR
(7.1-7.9) available (17-20) (7.5-9) (3.9-5.0) (3.5-5) (85.2-91.2)

12.8 Western Europe: 43 31.5 19 21 13 75.6

France
(12.3-13.4) 8.4 (8.0-8.8) (35-51) (26.5-38.5) (16-24) (16-26.5) (8-18.5) (73.3-77.8)

6.3 Western Europe: 76.8

Germany No data available
(5.9-6.8) 8.4 (8.0-8.8) (65.1-86.1)

7.9 South-Central Asia: 15.5 14 14 14 14.5 82.5

India
(7.5-8.2) 7.5 (7.0-8.0) (14-18) (13-15) (11-15) (10-16) (9.5-19) (79.5-85.1)

9.0 Southern Europe: 22 10 11.5 9.5 9 72.1

Italy
(8.7-9.3) 6.8 (5.7-7.7) (19-25) (9.5-10.5) (8.5-15) (7-13) (7-12) (67.6-76.4)
3.9 Western Europe: 16.5 8 5 3.5 2.5 87.9
Netherlands
(3.6-4.1) 8.4 (8.0-8.8) (5-35) (7.5-9) (NR) (NR) (NR) (84.6-90.7)
5.5 Northern Europe: 7 7.5 5 5.5 No data 68.5
Sweden
(4.9-6.0) 7.9 (7.4-8.4) (3.5-11) (6-8) (4.5-6.5) (1-16) available (64.7-72.2)
6.3 17.1 7.8 6.4 5.3 5.7 78.7
Switzerland NR
(5.9-6.7) (11.5-25.0) (6.4-8.5) (5.7-7.4) (4.7-6.4) (5.0-6.4) (77.0-80.3)‡

13.3 North America: 27 12 6 4.5 3 76.6

United States
(13.0-13.6) 11.3 (10.6-12.1) (26.5-27.5) (11-12.5) (5.5-6.5) (3.5-5) (2.5-3.5) (74.3-78.8)

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Appendix H. Cervical Cancer and HPV: Prevalence, Incidence and Mortality Rates

Cervical Cancer

Age-specific incidence rates (per Age-specific mortality rates

Age- Age-
Crude 100,000 women per year) (per 100,000 women per year)
standardized Crude standardized
Country Incidence Rate (Estimated from Figure 17) (Estimated from Figure 17)
Incidence Rate Mortality Rate Mortality Rate
(per 100,000
(per 100,000 (per 100,000 (per 100,000
women per
women per women per year) women per
year)
year) 15-44y 45-54y 55-64y 65+y year) 15-44y 45-54y 55-64y 65+y

Canada 8.5 6.6 8.5 12 12 11 3.2 1.9 1 4 5.5 10

China 11.7 9.6 11 21 22 15 5.2 4.2 2 8.5 13 21.5

England (UK) 9.3 7.2 10 12 10.5 13 3.6 2.0 1 4.5 5 10

Finland 5.2 3.7 4.5 6 6 9.5 1.9 0.9 0.5 1 2.5 6

France 9.1 7.1 9 16 11.5 11 3.1 1.8 1 5 5 7

Germany 10.6 6.9 6 20 15 15.5 4.8 2.3 1 5.5 7 12.5

India 23.5 27.0 15.5 72 90 68 12.8 15.2 6 33 53 63

Italy 9.4 6.7 7.5 16.5 15 11 3.0 1.5 1 4 4 6.5

Netherlands 7.1 5.4 7 10 8 11 2.8 1.5 1 3 3.5 9.5

Sweden 9.7 7.4 10 13 13 13.5 3.8 1.8 1 4 5 11.5

Switzerland 5.7 4.0 5 7 7 10.5 1.9 0.9 0.5 1.5 2.5 6

United States 7.0 5.7 7 11 10 10 2.4 1.7 1.5 4 4.5 6

Unless otherwise specified, all data from WHO/ICO Information Center on HPV and Cervical Cancer, 2008;
http://apps.who.int/hpvcentre/statistics/dynamic/ico/SummaryReportsSelect.cfm (updated September 15, 2010)
* Data from de Sanjose S, Diaz M, Castellsague X, et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus
DNA in women with normal cytology: a meta-analysis. Lancet. 2007;7:453-459.
† Adjusted for region, study type, study design, publication year, sampling collection device, cell storage medium, HPV assay, primer used,
study youngest age included, and study oldest age included
‡ Western Europe regional estimated used instead as specific data unavailable

Screening for Cervical Cancer 263 Oregon Evidence-based Practice Center