Expert Review of Anticancer Therapy

ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20

Neoadjuvant chemotherapy in cervical cancer: an

update

Mariateresa Lapresa, Gabriella Parma, Rosalba Portuesi & Nicoletta

Colombo

To cite this article: Mariateresa Lapresa, Gabriella Parma, Rosalba Portuesi & Nicoletta
Colombo (2015) Neoadjuvant chemotherapy in cervical cancer: an update, Expert Review of
Anticancer Therapy, 15:10, 1171-1181, DOI: 10.1586/14737140.2015.1079777

To link to this article: http://dx.doi.org/10.1586/14737140.2015.1079777

Published online: 07 Sep 2015.

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 Review

Neoadjuvant chemotherapy
in cervical cancer: an update
Expert Rev. Anticancer Ther. 15(10), 1171–1181 (2015)

Mariateresa Lapresa*1, The role of neoadjuvant chemotherapy (NACT) has been investigated in order to improve
Gabriella Parma1, prognosis of patients with locally advanced cervical cancer. According to a meta-analysis,
Rosalba Portuesi2 and NACT followed by radiotherapy may be detrimental with a low dose of cisplatin and longer
cycle intervals. Some meta-analyses showed NACT followed by surgery resulted in a reduction
Nicoletta Colombo1–3
in the risk of death by 35% with a gain of 14% in the 5-year survival compared with
1
European Institute of Oncology,
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radiotherapy. In a Cochrane meta-analysis, overall survival and progression-free survival were

Division of Medical Gynecologic
Oncology, via Giuseppe Ripamonti 435, significantly improved with NACT followed by surgery versus surgery alone (23% reduction in
20141 Milan, Italy the risk of death). The platinum/paclitaxel combination is now the preferred regimen in the
2
Department of Gynaecology and neoadjuvant setting and preliminary data indicate that dose-dense regimens are feasible and
Obstetrics, University Campus Bio
effective (overall response rate: 67.8–87%). A weekly regimen with carboplatin/paclitaxel
Medico, Rome, Italy
3
Department of Translational Surgery before chemoradiation showed promising results and the INTERLACE ongoing trial will
and Medicine, University of Milan help to confirm whether additional short-course chemotherapy given weekly before
Bicocca, Milan, Italy chemoradiation will lead to an improvement in overall survival.
*Author for correspondence:
Tel.: +39 02 943 7954 3222
Fax: +39 02 943 7954 3222
KEYWORDS: emerging therapies . locally advanced cervical cancer . neoadjuvant chemotherapy . radiotherapy
. surgery
maria.lapresa@ieo.it

Cervical cancer is the fourth most common systemic component, are the main cause of
cancer among women worldwide (576,600 esti- treatment failure.
mated new cases) and the fourth cause of can- To improve prognosis, a novel therapeutic
cer death (265,700 deaths) after breast cancer strategy of neoadjuvant chemotherapy
(521,900 deaths), lung cancer (491,200) and (NACT) followed by radical hysterectomy or
colorectal cancer (320,300), while it remains radiotherapy has been investigated.
the second most common cancer in developing The rationale for the use of NACT is: to
regions (444,500 estimated new cases) [1]. reduce the primary tumor size, allowing radical
Based on the results of five randomized clin- operability; to increase the tumor vasculariza-
ical trials [2–7], in 1999, the National Cancer tion and reduce the number of hypoxic cells,
Institute alert strongly recommended that con- improving the radiosensitivity of the tumor
comitant cisplatin-based chemo-radiotherapy and to eradicate micrometastatic disease [9–11].
be considered instead of radiotherapy alone in The use of NACT before radical surgery in
women with invasive cervical cancer for whom cervical cancer patients dates back to the 80s,
radiotherapy was indicated. A recent systematic since the publication of two pilot studies.
review and meta-analysis, derived from 18 trials First, Friedlander et al. [12] showed 66% objec-
carried out in 11 different countries, confirmed tive tumor response and 18% complete remis-
the benefit of concurrent chemoradiation on sions in 33 evaluable patients with advanced
prognosis (absolute improvement of 12% in cervical cancer, receiving 3-weekly cisplatin,
overall survival) and local and distant con- vinblastine and bleomycin (PVB) chemother-
trol [8]. Therefore, concomitant chemo- apy. Similar results were observed by
radiotherapy has become the new standard of Sardi et al., using a more aggressive and inten-
care for locally advanced disease (FIGO stages sive vincristine, bleomycin and cisplatin (VPB)
IB2, IIB, III and IVA). However, the estimated regimen, given at 10-day intervals [10]. Subse-
improvement in 5-year survival was 6% quent trials investigating the role of NACT,
(hazard ratio [HR]: 0.81) with a disease-free despite a wide variability in scheme and sched-
survival rate of 58%. Persistent pelvic disease ule of treatment, have strengthened early data,
and locoregional recurrences, with or without a confirming both feasibility and promising

informahealthcare.com 10.1586/14737140.2015.1079777
2015 Informa UK Ltd ISSN 1473-7140 1171

 Review Lapresa, Parma, Portuesi & Colombo

Table 1. Phase III trials of neoadjuvant chemotherapy + radiotherapy versus radiotherapy [26].

Study (year) Randomized PTS FIGO stage Chemotherapy regimen RT (RTE + IC) Ref.
Souhami et al. (1991) 103 IIIB CDDP-BLM-MMC 50 + 30 Gy [17]
q21 x 3 cycles
Chauvergne et al. (1993) 182 IIB–III CDDP-MTX-CLB-VCR 50 + 18 GY [18]
q21 x 2 cycles
Tattersall et al. (1995) 260 IIB–IVA EPIADM-CDDP 40/50 + 30/35 Gy [19]
q21 x 2-3 cycles
Kumar et al. (1998) 184 IIB–IVA BIP 50 + 30 Gy [20]
Q21 x 2 cycles
Herod et al. (2000) 177 II–IVA BIP NA [21]
Q28 x 2–3 cycles
Symonds et al. (2000) 204 II–IVA CDDP-MTX 40/45 + 24/33.7 Gy [22]
Q14 x 3 cycles
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BIP: Bleomycin, ifosfamide and cisplatin; BLM: Bleomycin; CDDP: Cisplatin; CLB: Clorambucil; EPIADM: Epirubicin; MMC: Mitomycin C; MTX: Methotrexate;
VCR: Vincristine.

results, with overall response rate ranging from 66 to 85%, and recurrence rate and lower 3-year disease-free survival in the che-
a considerable share of pathological complete responses [13–16]. motherapy/radiotherapy group. The randomized trial published
Up to now, several Phase III trials have been conducted in by Kumar et al. [20], using bleomycin, ifosfamide and cisplatin
order to define the true impact of NACT in patients with followed by radiotherapy versus radiotherapy alone in stage
locally advanced cervical cancer. In this review, we will analyze IIB–IVA disease, failed to demonstrate any advantage of the
the main experiences reported in the international literature on sequential arm. Herod et al. [21] showed no difference in
NACT followed by radiotherapy or radical surgery. response rate and overall survival in a randomized multicenter
trial involving 177 patients with inoperable cervical cancer,
NACT followed by radiotherapy versus radiotherapy comparing NACT (BIP) plus radiotherapy with radiotherapy
The use of NACT before radiotherapy could potentially eradi- alone. The trial was prematurely closed: with only 177 patients
cate subclinical distant metastasis, reduce the tumor size and out of 300 originally planned, the study was underpowered to
correct pelvic anatomy distortion, and ultimately allow better detect a benefit of chemotherapy on survival. Symonds et al.
delivery of radiation. There are just over 20 randomized clinical [22] described the results of 204 eligible patients randomized to
trials addressing the role of NACT prior to definitive receive NACT with 3 cycles of methotrexate and cisplatin given
radiotherapy (TABLE 1). every 10 days followed by radiotherapy or radiotherapy alone.
Souhami et al. [17] first reported a randomized trial exploring At the end of treatment, 33% of patients in the radiotherapy
radiotherapy with or without NACT with cisplatin, vincristine, arm and 45% in the combination arm achieved a clinically
mitomycin C and bleomycin. The study, which enrolled stage complete response. The median survival was 111 weeks and
IIIB cervical cancer patients, was early closed due to the evi- 125 weeks. Acute and late radiotherapy toxicity was not
dence of a survival advantage in the control group. The 5-year increased by the addition of chemotherapy. Individual patient
survival was 39 versus 23% (p = 0.02) in favor of radiotherapy data derived from all randomized trials were analyzed by the
alone. However, the higher mortality rate observed in the neo- NACT for Cervical Cancer Meta-analysis Collaboration [23].
adjuvant group was not related to the increased incidence in Data based on 2074 patients from 18 trials showed that cis-
local or distant recurrences but to greater toxicity of the che- platin remains the most frequently used drug, with a planned
motherapy regimen: the mortality due to chemotherapy was total dose ranging from 100 to 320 mg/m2 in 10/28-day
10%. Chauvergne et al. [18] demonstrated similar remission rate cycles. Total dose of radiotherapy (both the external beam
(93 vs 96%), progression-free survival and overall survival radiotherapy and intracavitary radiotherapy) was in the range
(median survival of 42 and 45 months) comparing radiother- of 55–80 Gy. Most of the patients had moderately and poorly
apy alone with radiotherapy after NACT with methotrexate, differentiated stage II–III squamous cervical cancer. Consider-
clorambucil, vincristine and cisplatin in 151 patients with stage ing all trials, the data showed no benefit on survival for the
IIB–III disease. Tattersall et al. [19] reported the results of a ran- NACT group compared with radiotherapy alone. However,
domized study with 260 stage IIB–IVA cervical cancer patients there was a very high level of statistical heterogeneity among
comparing 3 cycles of cisplatin 50 mg/m2 and epirubicin the studies. Some interesting evidences were obtained when the
110 mg/m2 every 3 weeks followed by radiotherapy versus trials were grouped according to chemotherapy schedules
radiotherapy alone. While a high response rate to chemother- (TABLE 2). Trials using chemotherapy cycle length of 14 days and
apy (63%) was observed, there was a significantly higher pelvic shorter had a pooled HR of 0.83 (p = 0.046) with a significant

1172 Expert Rev. Anticancer Ther. 15(10), (2015)

 NACT in cervical cancer Review

17% decrease in the risk of death. With longer chemotherapy Table 2. Overall survival by cycle length and
cycle length, the HR was 1.25, representing a significant cisplatin dose-intensity [26].
(p = 0.005) 25% increase in the risk of death with the experi-
Subgroup analysis No. of study OS (HR)
mental arm. These HRs translate into an absolute reduction in
5-year survival of 8% (from 45 to 37%) with longer treatments Neoadjuvant cycle length
and a 7% absolute improvement in 5-year survival (from 45 to >14 day cycles 11 1.25 (1.07–1.46)
£14 day cycles 7 0.83 (0.69–1.00)
52%) with shorter treatments. Grouping trials by planned cis-
platin dose-intensity, there was a similar difference in survival. Cisplatin dose intensity
The HR was 1.35 for those trials using <25 mg/m2/week, indi- <25 mg/m2/week 7 1.35 (1.11–1.64)
cating a significant 35% increase in the risk of death; in con- ‡25 mg/m2/week 11 0.91 (0.78–1.05)
trast, the HR for trials using more than 25 mg/m2/week was HR: Hazard ratio; OS: Overall survival.

0.91, which suggests a potential 9% decrease in the risk of

death (p = 0.200). Cervical tumors are rapidly proliferating compared with radiotherapy alone (HR: 0.65; p = 0.0004)
with a median doubling time of only 4–4.5 days and high with an absolute improvement of 14% in survival at 5 year,
growth fraction [24,25]. After a few cell divisions, the tumor vol- increasing it from 50 to 64% (TABLE 3). The analysis included
ume may be restored but the tumor cells may be less sensitive data from 872 patients with locally advanced cervical cancer
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to chemotherapy and potentially to conventional radiotherapy, enrolled in five different trials. The largest trial included in the
due to the changed growth kinetics. With these assumptions, meta-analysis, published in 2002 by Benedetti Panici et al. [28],
the schedule of chemotherapy may play an important role: enrolled 441 FIGO stage IB2–III cervical cancer patients and
short and high dose-intense chemotherapy cycle seems optimal compared neoadjuvant platinum-based chemotherapy (recom-
to minimize the tumor repopulation with resistant cells. mended dose >240 mg/m2 for 6–8 weeks) followed by radical
There was no evidence to suggest that chemotherapy was dif- surgery with conventional radiotherapy. The study showed the
ferentially effective in groups of patients stratified by age, stage, superiority of chemotherapy arm both for overall survival
histology or performance status. Data on nodal involvement (58.9 vs 44.5%; p = 0.007) and for disease-free survival
were too sparse to warrant sub-group analysis. Concerning seri- (55.4 vs 41.3%; p = 0.02). A multivariate analysis confirmed
ous late radiotherapy toxicity, data were not sufficient to carry the positive role of NACT in the reduction of relative risk of
out a definitive analysis; therefore, it seems to be similar death (0.63; p = 0.04) and the prognostic value of tumor size
whether chemotherapy was given or not. Last update of this and positive lymph nodes. Both treatments were well tolerated
meta-analysis, published by The Cochrane Collaboration in and no treatment-related deaths were reported. No differences
2004, confirms the data just discussed [26]. were found in terms of relapse rate (40% in neoadjuvant group
vs 50% in the radiation group) and site of recurrences (local and
NACT followed by radical surgery versus radiotherapy distant recurrence rates were similar). Patients with stage III dis-
Some authors have compared the use of NACT followed by ease did not achieve any significant benefit in both overall sur-
radical surgery versus radiation treatment. In 1993, vival and disease-free survival: often these patients require
Sardi et al. [27] showed an interesting overall response rate adjuvant therapy after surgery with associated greater morbidity.
(92%) for neoadjuvant cisplatin-based chemotherapy (3 cycles The main criticism to this study is related to the suboptimal
of PVB) followed by radical surgery or radiotherapy compared radiotherapy administration. Almost 27% of patients did not
with radiotherapy alone in 154 stage IB cervical cancer patients. receive intracavitary RT (due to anatomic limits, refusal, progres-
In the neoadjuvant group, there was a significant reduction in sion disease or toxicity); 11% of patients received less than 60 Gy
size of disease (3 vs 45%; p < 0.0001), in parametrial (3 vs of external pelvic beam radiation total dose at point A and 9%
22%; p < 0.00001) and nodal involvement (7 vs 30%; patients completed the treatment not on time (‡90 days). More-
p < 0.005), and in vascular embolism (15 vs 57%; over, the median total dose delivered was 70 Gy while the opti-
p = 0.00001). Statistically significant differences were observed mal treatment is considered to be between 80 and 90 Gy at point
between the two groups on time to progression: 88% in the A [29]. In contrast, Chang et al. [30], in a randomized clinical trial
neoadjuvant group compared with 67% in the control group evaluating NACT followed by surgery versus radiotherapy alone
(p < 0.03). The study failed to demonstrate a significant in 124 stage IB2–IIA cervical cancer patients, did not observe
improvement on survival when all cases were included in the any difference in the two treatment arm (estimated cumulative
analysis. However, in clinically bulky tumors, with a diameter survival rates at 5 year of 70 and 61%, respectively), despite a
>4 cm, the study showed a statistically significant difference high response rate to chemotherapy (85%).
both in time to progression and in survival (88 vs 60% at The third trial included in this meta-analysis was published
4 years; p = 0.05). These results seem to indicate that this new by Kigawa et al. This is a very small Phase III study in which
therapeutic strategy is particularly effective in patients with the effect of intra-arterial cisplatin and bleomycin followed by
bulky disease. According to a subsequent meta-analysis pub- radical surgery was compared with radiotherapy. Only
lished in 2003 [23], NACT followed by radical surgery showed 50 patients with FIGO stage IIB–IIIB were enrolled into the
a highly significant 35% reduction in the risk of death study. In the experimental arm, the investigators found an

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 Review Lapresa, Parma, Portuesi & Colombo

Table 3. Overall survival Phase III trails of trials of neoadjuvant chemotherapy + surgery versus
radiotherapy [26].
Study (year) Randomized FIGO stage Chemotherapy regimen OS % NACT + RS vs RT Ref.
patients
Kigawa et al. (1996) 50 IIB–IIIB CDDP and bleomycin intra-arterial 0.62 (0.28–1.35) [31]

Sardi et al. (1996) 155 IIIB PVB q10 0.41 (0.25–0.68) [32]
3 cycles
Sardi et al. (1998) 295 IIB PVB q10 0.50 (0.29–0.85) [33]
3 cycles
Chang et al. (2000) 124 IB/IIA PVB q10 1.38 (0.69–2.74) [30]
3 cycles
Benedetti et al. (2002) 441 IB2/III Platinum-based (cycles 2–7) 0.71 (0.54–0.95) [28]

Total (95% CI) 0.65

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CDDP: Cisplatin; NACT: Neoadjuvant chemotherapy; OS: Overall survival; PVB: Cisplatin, vinblastine and bleomycin.

overall response rate of 80% and optimal responders underwent Treatment of Cancer) compared NACT (cisplatin-based chemo-
radical surgery. Their 3-year overall survival was 85.7% com- therapy with a cumulative cisplatin dose at least 225 mg/m2,
pared with 42.9% for patients judged inoperable and 49.5% in equivalent to at least 25 mg/m2 per week) followed by radical
the control arm [31]. Two trials conducted by Sardi et al. were surgery versus concomitant chemoradiation in FIGO stage IB2–
included in this meta-analysis. The first one, published in IIB cervical cancer. The most important limitation of EORTC
1996, is a randomized three-arm trial on 155 patients with trial could be related to the lack of standardized schedule of che-
FIGO stage IIIB. The study design included three arms: radio- motherapy in neoadjuvant arm and the very long accrual period.
therapy alone (= 53 patients); quickly VBP NACT followed by In the concomitant chemoradiation arm, cisplatin was given
radiotherapy (= 52 patients) and VBP NACT followed by radi- weekly at 40 mg/m2 during radiotherapy with a maximum of
cal surgery and adjuvant radiotherapy. Four-year overall survival six administrations, with a total cumulative platinum dose
was respectively 37, 53 and 63%, with statistically significant between 200 and 240 mg/m2. External radiotherapy
differences favoring the neoadjuvant followed by radical surgery (45–50 Gy) combined with external boost or brachytherapy was
group compared with the radiotherapy-alone arm (63 vs 37%; planned; a minimal total dose of 75 Gy to point A was manda-
p = 0.005). The same results were obtained when disease-free tory. The latter study, coordinated by Tata Memorial Hospital,
survival was analyzed: 65 vs 28% (p = 0.005) [32]. The second was activated in September 2003 with a targeted sample size of
trial, published in 1998, was a four-arm randomized trial which 730 patients with FIGO stage IB2–IIB squamous cell carci-
analyzed the impact of neoadjuvant chemotherapy on 259 IIB noma. The study compared 3 cycles of paclitaxel-carboplatin
FIGO stage patients: radiotherapy alone (= 73 patients), sur- NACT followed by radical surgery versus concomitant chemo-
gery followed by radiotherapy (= 75 patients), NACT followed radiotherapy (external radiotherapy followed by intracavitary
by radiotherapy (= 71 patients) and finally NACT followed by brachytherapy concurrently with weekly cisplatin).
radical surgery and adjuvant radiotherapy (= 76 patients). After
7 years follow-up, a statistically significant difference was found NACT followed by radical surgery versus radical
in overall survival between the NACT followed by radical sur- surgery
gery group and radiotherapy control group (65 vs 48%; There are few Phase III trials exploring the role of NACT
p < 0.005) [33]. Unfortunately, both these studies present a before surgery compared with primary surgery and the reported
great bias: 100% of patients received adjuvant radiation treat- results are controversial (TABLE 4).
ment after surgery. In 1997, Sardi et al. [35] first described a randomized study
In all these studies, however, the control arm, radiotherapy comparing quick PVB NACT plus radical surgery with radical
alone without concomitant chemotherapy, does not represent surgery in 205 patients with stage IB squamous cervical cancer.
the current standard of care for locally advanced cervical cancer. Overall survival at 8 years in the NACT group was superior to
In addition, the radiotherapy total dose and the median time of surgery alone (81 vs 66%; p < 0.05). In a subgroup analysis in
radiotherapy administration were sometimes suboptimal. There patients with non-bulky tumors (<4 cm), there was no signifi-
are two randomized Phase III trials which have explored the cant difference in survival between the two groups (82 vs
role of NACT followed by surgery versus chemo-radiotherapy, 77%). Patients with stage IB2 disease, however, demonstrated
but the results are not available as yet. These trials include improved overall survival following NACT (80 vs 61% at
EORTC Protocol 55994 and [34]. The recently closed EORTC 9 years; p < 0.01). This benefit derived from an increase in
55994 trial (European Organization for Research and tumor resectability and improvement of pathological risk

1174 Expert Rev. Anticancer Ther. 15(10), (2015)

 NACT in cervical cancer Review

Table 4. Phase III trials of neoadjuvant chemotherapy + surgery versus surgery [41].

Study (year) Randomized FIGO Chemotherapy OS PFS Ref.

PTS stage regimen NACT + S NACT + S
vs S vs S
Sardi et al. (1997) 210 IB PVB q10 0.53 0.53 [35]
3 cycles (0.31–0.92) (0.31–0.92)
Napolitano et al. 192 IB–IIIB PBV q21 0.84 0.53 [37]
(2003) 3 cycles (0.51–1.40) (0.30–0.94)
Cai et al. (2006) 107 IB CDDP-5-FU q21 0.64 0.63 [36]
2 cycles (0.34–1.21) (0.32–1.22)
Katsumata et al. (2013) 134 IB2–IIB BOMP q21 1.12 1.06 [39]
2–4 cycles (0.56–2.22) (0.60–1.87)
Eddy et al. (2007) 291 IB bulky CDDP-VCR q10 1.01 1 [40]
3 cycles (0.68–1.49) (0.70–1.42)
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Chen et al. (2008) 144 IB2–IIB CDDP-VCR-5-FU q10 0.51 0.57 [38]
2–3 cycles (0.28–0.94) (0.31–1.05)
5-FU: 5-Fluorouracil; CDDP: Cisplatin; NACT: Neoadjuvant chemotherapy; PVB: Cisplatin, vinblastine and bleomycin; VCR: Vincristine.

factors in patients receiving neoadjuvant treatment. While inci- with stage IB2, IIA2 or IIB squamous cervical cancer [39].
dence of high-risk pathological features was similar between Patients were randomized to receive either BOMP (bleomycin
control and non-responders to neoadjuvant treatment, respond- 7 mg on days 1–5; vincristine 0.7 mg/m2 on day 5; mitomycin
ers to chemotherapy had significantly reduced incidence of 7 mg/m2 on day 5; cisplatin 14 mg/m2 on days 1–5) every
nodal metastases, parametrial involvement and vascular space 3 weeks plus radical surgery (type III or IV Okabayashi’s radi-
invasion. Cai et al. [36] showed similar positive results: cal hysterectomy) or radical surgery alone [39]. The study failed
107 patients with stage IB cervical cancer were randomized to to demonstrate a clinical benefit using NACT but it was pre-
receive NACT (cisplatin and 5-fluorouracil) followed by sur- maturely closed at the first planned interim analysis because the
gery versus surgery alone. The NACT group had an improved overall survival in the neoadjuvant arm was inferior to
5-year disease-free survival (83 vs 74%; p = 0.04) and overall the control arm (70 vs 74.4%; p = 0.85). Also the
survival (85 vs 76%; p = 0.01). However, 62% of patients Gynecologic Oncology Group (GOG) 141 trial, published by
receiving NACT underwent adjuvant radiotherapy compared Eddy et al. [40], demonstrated no evidence to support the use of
with 54% of controls. Napolitano et al. [37] published a ran- NACT in locally advanced cervical cancer patients. This multi-
domized trial in 192 stage IB–III squamous cervical cancer center randomized trial comparing NACT with vincristine and
patients, receiving NACT (PVB every 3 weeks for 3 cycles) cisplatin (respectively 1 and 50 mg/m2 every 10 days for
plus radical surgery, radical surgery or radiotherapy alone. The 3 cycles) plus radical hysterectomy and pelvic/para-aortic lym-
5-year disease-free survival was improved in the NACT arm phadenectomy to radical surgery alone in bulky IB cervical can-
only in stage IB–IIA (77.1 vs 64.3%; p < 0.05); no differences cer showed no differences in both progression-free and overall
were observed in stage IIB. However, the 5-year overall survival survival between the two groups. However, the study was
rate was not statistically different between the study groups. closed after randomizing only 70% of the calculated sample
Chen et al. [38] attempted to evaluate whether high-dose short- size, due to slow accrual and the extensive use of off-protocol
term NACT (cisplatin, mitomycin and 5-fluorouracil) prior to adjuvant radiotherapy. It is, then, underpowered to make any
surgery could improve the clinical outcome in 144 stage IB2– definitive conclusions.
IIB cervical cancer. There was a significant difference in 4-year A recent meta-analysis, published on January 2012 by
survival between treatments arms: 71% with neaodjuvant che- Cochrane Collaboration [41], evaluated the above-mentioned
motherapy versus 58% in the control arm (p = 0.04). They 6 randomized trials (1078 women). Cisplatin total dose ranged
also found that responders to NACT had longer survival and from 140 to 300 mg/m2 given in 2–4 courses at 10–21 days
lower recurrence rate than non-responders (p = 0.000 and intervals, with a cisplatin dose intensity of 17–50 mg/m2/week.
p = 0.013). Indeed, in responders a significant reduction in At chemotherapy completion, the surgery performed was radi-
nodal metastases and parametrial infiltration were noted com- cal hysterectomy with lymphadenectomy (pelvic in three trials,
pared with non-responders (16 vs 45.5% for both parameters; pelvic and aortic in two trials, no information about one trial).
p = 0.008). The response to chemotherapy became an indepen- Both overall survival (HR: 0.77; 95% CI: 0.62–0.96;
dent prognostic factor for survival, identifying a subgroup of p = 0.02) and progression-free survival (HR: 0.75; 95% CI:
patients with better prognosis. Conversely, a Japanese Clinical 0.61–0.93; p = 0.008) were significantly improved with NACT
Oncology Group trial (JCOG 0102) evaluated 134 patients with a 23% reduction in the risk of death. There were no

informahealthcare.com 1175
 Review Lapresa, Parma, Portuesi & Colombo

differences on survival according to cisplatin total dose, chemo- benefits of carboplatin-paclitaxel compared with cisplatin-
therapy cycle length or by cervical cancer stage. The estimate paclitaxel combination, in advanced and recurrent cervical can-
for local recurrence was in favor of NACT (odds ratio [OR]: cer. Both regimens were given every 21 days. The trial showed
0.67; 95% CI: 0.45–0.99; p = 0.04); no statistical differences a non-inferiority of the carboplatin-paclitaxel regimen in terms
were found for distant metastases (OR: 0.72; 95% CI: 0.45– of overall survival (17.5 months compared with 18.3 months
1.14; p = 0.16). Exploratory analysis of pathological response in the control arm).
showed a significant decrease in adverse pathological findings In the neoadjuvant setting before surgery, Park et al. [48],
with NACT (OR: 0.54; 95% CI: 0.40–0.73; p < 0.0001 for using a cisplatin-paclitaxel combination given every 10 days for
lymph node status; OR: 0.58; 95% CI: 0.41–0.82; 3 cycles, followed by radical surgery 2 weeks after the comple-
p = 0.002 for parametrial infiltration). While these results tion of chemotherapy, showed an overall response rate of
appear to indicate that NACT may offer a benefit over surgery 90.7% and a 5-year survival of 89.2% in 43 stage IB2–IIB cer-
alone in cervical cancer patients, the widespread use of adjuvant vical cancer women. Initial stage, response to NACT, differen-
radiotherapy given after surgery (36–100%) could obscure its tiation, depth of invasion after chemotherapy and metastasis
real impact on prognosis. were significantly correlated with survival.
Data derived from a recent meta-analysis [42], which included Zanetta et al. [49] described prospectively the results of TIP
5 randomized clinical trials and 4 observational studies involv- regimen (paclitaxel 175 mg/m2, ifosfamide 5 g/m2 and cisplatin
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ing 1784 stage IB1–IIA cervical cancer, indicated that NACT 75 mg/m2 q21) in 38 patients with diagnosis of squamous
significantly reduced the need for adjuvant radiotherapy advanced cervical cancer who underwent 3 cycles of NACT,
(34.5 vs 53%; OR: 0.57; 95% CI: 0.33–0.98) by decreasing achieving an overall clinical response rate of 84%. According to
tumor size, lymph node metastases and distant metastases. the pathology report, the new regimen determined a 34% of
However, it failed to improve survival when compared with optimal response rates (complete response and partial response,
primary surgical treatment alone. Therefore, in early stage cer- defined as cervical residual tumor with stromal invasion
vical cancer, the reduced morbidity associated with a less fre- <3 mm or only in situ carcinoma) with acceptable toxicity
quent use of postoperative radiotherapy should be tempered (grade 3–4 neutropenia = 71%; grade 3–4
with the acute toxicity of NACT. thrombocytopenia = 10.5%). Data on survival showed 76% of
patients alive without evidence of disease at 16 months of
Chemotherapy regimens median follow-up. Based on these encouraging data, the SNAP
The key role of cisplatin is widely accepted in cervical cancer 01 trial was designed, an Italian collaborative randomized
management both in neoadjuvant and salvage treatment and it Phase II study comparing the efficacy of 3-weekly TIP to the
remains the most active single agent [23]. same regimen without paclitaxel (IP: 3-weekly I fosfamide
In advanced and recurrent disease, there are few randomized 5 g/m2 and cisplatin 75 mg/m2) in 219 locally advanced cervi-
trials comparing combinations regimens with cisplatin as single cal cancer patients [50]. The analysis showed a significant superi-
agent. Omura et al. [43] evaluated the efficacy of cisplatin alone, ority of the three-drug regimen in terms of optimal response,
cisplatin plus ifosfamide (IP) or cisplatin plus mitolactol in a which was the primary end point of the study: 48% in TIP
large randomized trial including 454 women with advanced versus 23% in IP arm (OR: 3.22; 95% CI: 1.69–5.88;
cervical cancer. This study showed a significantly higher p = 0.0003). A better overall survival (HR: 0.66) and
response rate (31.1 vs 17.8%; p = 0.004) and a significantly progression-free survival (HR: 0.75) was observed in TIP arm,
longer progression-free survival (p = 0.003) in IP arm com- although not statistically significant (p = 0.11 and 0.20, respec-
pared with cisplatin alone, although the combination regimen tively). In the multivariate analysis, achieving an optimal
was burdened by greater toxicity. In addition, no difference on response was associated with lower risk of death (HR: 5.88;
overall survival was found (8.3 and 8 months, respectively). 95% CI: 2.50–13.84; p < 0.0001). Hematologic toxicity was
Paclitaxel has proven activity in several squamous cell carci- relevant in both arms: however, grade 3 and 4 toxicity was
noma [44] and promising results have been also reported in cer- higher in TIP group (p = 0.02). Four (2%) toxicity-related
vical cancer both in the neodjuvant and salvage setting. In the deaths were recorded: three patients received IP and one patient
GOG study published by Moore et al., in advanced cervical TIP. The results of this trial confirm that TIP is one of the
cancer, the combination of cisplatin and paclitaxel was superior most active neoadjuvant regimens, although its use in clinical
to cisplatin alone with respect to objective response rate (36 vs practice may be limited by the associated severe toxicity. In
19%; p = 0.002), progression-free survival (4.8 vs 2.8 months; order to identify a less toxic regimen, the SNAP02 trial was
p < 0.001) and sustained quality of life, with no improvement designed, which compared TIP with the same regimen without
in overall survival. [45]. The GOG 204 study [46] demonstrated ifosfamide (TP) [51]. Eighty out of 154 enrolled patients
a trend that did not reach a statistically significance, in response received the TP combination, whereas 74 patients received the
rate, progression-free survival and overall survival for cisplatin- TIP regimen. TIP was associated with significantly higher rates
paclitaxel combination compared with other cisplatin doublets of grade 3 and 4 hematological toxicity than TP (78 vs 29%;
containing gemcitabine, topotecan and vinorelbine. More p < 0.0001). The optimal pathologic response (complete
recently, a Japanese GOG study [47] first evaluated the clinical response and partial response, as previously defined) was 43%

1176 Expert Rev. Anticancer Ther. 15(10), (2015)

 NACT in cervical cancer Review

in TIP group and 25% in TP group (OR: 2.3; p = 0.027). CI: 71–94) post-radiotherapy. Overall and progression-free
Based on these results, the trial confirmed the role of TIP as survivals at 3 years were 67% (95% CI: 51–79) and 68%
the most effective neoadjuvant regimen in locally advanced cer- (95% CI: 51–79), respectively. Comparable results were
vical cancer. reported by Singh et al. with a similar therapeutic protocol [62].
Duenas-Gonzales et al. [52] described an overall response rate Following chemotherapy, 67.8% responded. Twenty-three out
of 95% and an optimal pathological response rate of 37%, of 24 patients who underwent chemoradiation were in com-
using neoadjuvant carboplatin-paclitaxel combination as a part plete response at the end of treatment. These promising early
of multimodality treatment for locally advanced cervical cancer. data provided the background for an international multicenter
Similarly, Angioli et al. observed an overall clinical response Phase III trial, INTERLACE (ClinicalTrials.gov [63]), to deter-
rate of 78.3%, including 43.5% complete responses and 34.8% mine whether this new treatment strategy will lead to a signif-
partial responses, in 23 patients with stage IB2–IIB cervical icant improvement in survival compared with standard
cancer, treated with 3-weekly carboplatin-paclitaxel NACT fol- chemoradiation in locally advanced cervical cancer.
lowed by surgery [53]. The carboplatin regimen showed a clearly
improved safety profile with only 8.7% grade 3 and 4 hemato- Rationale of the use of bevacizumab in cervical cancer
logical toxicity and 17.4% of sensory neuropathy; no renal fail- The human papilloma virus is the main carcinogenic driver of
ure was reported. cervical cancer (almost 99% of cases) [64]. Human papilloma
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Based on these results, the combination of carboplatin and virus infection causes inactivation of p53 suppressor gene with
paclitaxel may represent a very active and potentially less toxic consequent stimulation of angiogenesis through VEGF
regimen to be used in the neoadjuvant setting. expression.
A longer exposure to paclitaxel is postulated to enhance its Therefore, based on these biological assumptions the inhibi-
efficacy with reduction in toxicity [54]. Several evidences of bet- tion of neoangiogenesis process represents an attractive target to
ter oncological outcome and/or better toxicity profile observed investigate in order to realize an antitumoral effect.
in breast, non-small-cell lung cancer and ovarian cancer seem Some authors suggest the existence of a synergy between che-
to justify the use of weekly schedule also in cervical cancer motherapy, radiotherapy and anti-VEGF, whereby anti-VEGF
patients [55–58]. In addition, Mori et al. reported that paclitaxel normalizes tumoral vasculature and improves therapeutic
was retained in cervical cancer tissues for 6 days after intrave- efficacy [65].
nous administration of 60 mg/m2 but it could not be detected In preclinical studies, the treatment with anti-VEGF anti-
after 2 weeks, suggesting that a weekly schedule was most effec- body improves tumor oxygenation and presents a synergy with
tive for tumor cell death rather than the standard 3-weekly radiation.
regimen [59]. Bevacizumab, a humanized mAb against VEGF-A, is one of
The same authors published one of the first studies aimed at the new active emerging drugs in several gynecological
determining the role of NACT with carboplatin and paclitaxel malignancies.
on a weekly schedule followed by radical surgery in locally A first Phase II study, conducted in the metastatic cervical
advanced cervical cancer (stage IB2–IIIB) [60]. An objective cancer setting and using bevacizumab as palliative monotherapy
response was observed in 26 out of 30 patients (87%). The (15 mg/kg every 3 weeks) showed an objective tumor regres-
5-year progression-free survival and overall survival were sion in 11% of cases and 24% of patients had stable disease
78.6 and 81.8%, respectively. Lymph node involvement and for at least 6 months [66]. Observed toxicities, in terms of
large tumor size tended to be correlated with inferior outcome; hypertension, thromboembolism and gastroenteritis, were simi-
however, there were no statistically differences because of the lar to those observed in other malignancies.
small number of cases. In advanced cervical cancer, the addition of bevacizumab to
An earlier report by McCormack et al. investigated the fea- standard chemotherapy, as shown by the GOG 240 study [67],
sibility of dose-dense NACT before chemoradiation and revealed a significant improvement in the median overall sur-
assessed the response rate to such a regimen in locally vival in patients with metastatic/recurrent cervical cancer (17 vs
advanced cervical cancer [61]. This single-arm Phase II trial 13.3 months; HR: 0.71; 97% CI: 0.54–0.95; p = 0.0035), and
included 46 patients with stage IB2–IVA, who received an improvement of response rate in the arm with bevacizumab
weekly paclitaxel 80 mg/m2 and carboplatin AUC2, for (48 vs 36%). It is noteworthy that this was the first study to
6 cycles followed by chemoradiation (50.4 Gy plus brachy- demonstrate an improvement in overall survival in gynecologi-
therapy with concomitant cisplatin 40 mg/m2 for 4–6 cycles), cal cancer patients using bevacizumab. However, patients receiv-
began on week 7. The primary end point was response rate ing the anti-angiogenic therapy experienced more side effects
after 12 weeks post-chemoradiation. The dose-dense schedule compared with control. These included grade 3 and 4 bleeding
was feasible as demonstrated by the acceptable toxicity of che- (5 vs 1%), thromboembolism (9 vs 2%) and gastrointestinal/
motherapy (overall 20% grade 3 and 4 toxicities were vaginal fistula (8.3 vs 0%), with nearly 80% of patients requir-
observed) and by the high compliance to radiotherapy (98%). ing unanticipated hospital admission to provide supportive care.
In terms of oncological outcome, complete or partial response Despite the observed toxicity, in consideration of the positive
rate was 70% (95% CI: 54–82) post-NACT and 85% (95% results on overall survival, the drug was approved both in the

informahealthcare.com 1177
 Review Lapresa, Parma, Portuesi & Colombo

USA and in Europe for the treatment of metastatic/recurrent personalized therapy, patient selection for NACT followed by
cervical cancer in combination with chemotherapy. surgery becomes crucial to minimize the need for postoperative
The Radiation Therapy Oncology Group has recently radiotherapy, and avoid the cumulative toxicity associated with
reported the results of a Phase II trial in which bevacizumab a triple treatment modality (chemotherapy, radical surgery and
was associated with chemoradiation with cisplatin in locally radiotherapy). Future studies should therefore focus on how
advanced cervical cancer. In this trial, 49 stage IB–IIIB cervical best to select patients who may derive the greatest benefit from
cancer patients received cisplatin 40 mg/m2 weekly and bevaci- this approach without severe impairment of their quality of life
zumab 10 mg/kg every 2 weeks during the standard external related to short- and long-term sexual, gastrointestinal and uri-
beam pelvic radiation followed by brachytherapy. The treat- nary dysfunctions. Ideally, we should avoid the use of radio-
ment was well tolerated; with a median follow-up of 3.8 years, therapy in young women in order to preserve ovarian and
overall survival rate of 81.3% and disease-free survival of sexual function. They could therefore be treated with a short
68.7% [68]. It should be noticed that in this study, bevacizumab dose-dense regimen followed by clinical evaluation and a lapa-
was used for only three cycles and no maintenance therapy was roscopic assessment of lymph node involvement. Only patients
given. with optimal response and negative nodes will undergo radical
Up to now, no study investigating bevacizumab in neoadju- surgery. This will minimize the need for postoperative chemo-
vant setting are available. Given the promising results shown in radiation and the increased morbidity of this modality added
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metastatic disease, this approach may deserve future research in to radical surgery.
the neoadjuvant setting.
Five-year view
Expert commentary The optimal regimen to be used in the neoadjuvant setting has
Since 1999, after the National Cancer Institute alert, concomi- yet to be defined. Some Phase II studies seem to indicate that
tant chemoradiation has become the new standard of care for carboplatin-based regimens may have similar efficacy compared
locally advanced cervical cancer, with an absolute improvement with cisplatin but with easier administration and less toxicity.
of 12% in overall survival compared with radiotherapy alone. Of particular interest are the weekly regimens with carboplatin
Since a large proportion of cervical cancer deaths are due to and paclitaxel, which demonstrated high activity in Phase II
metastatic disease, this observation points to the need of explor- studies both before surgery and before chemoradiation. This
ing additional systemic approaches in this disease setting. preliminary encouraging data need validation in large prospec-
NACT before definitive radiotherapy has been generally per- tive trials.
ceived as not beneficial or even detrimental. However, recent Targeting the tumor blood supply seems to be a promising
data seem to indicate the importance of cisplatin dose-intensity way to increase the effectiveness of chemotherapy in cervical
and cycle lengths. A Phase II study of a weekly regimen with cancer. No data are so far available on the use of anti-
carboplatin AUC2 and paclitaxel 80/mg/m2 for 6 weeks before angiogenic agents in the neoadjuvant setting. However, bevaci-
definitive chemoradiation was conducted and showed promis- zumab, was recently approved both in the USA and in Europe
ing results. Based on these preliminary encouraging data, the for the treatment of metastatic/recurrent cervical cancer in com-
ongoing INTERLACE trial will help to confirm this observa- bination with chemotherapy. The Radiation Therapy Oncology
tion in a randomized Phase III study. Group has recently reported an overall survival rate of 81.3%
NACT followed by radical surgery improved the clinical and disease-free survival of 68.7%, using bevacizumab associ-
outcome of patients with locally advanced disease when com- ated with chemoradiation [68], but the role of maintenance bev-
pared with surgery alone, with a significant 23% reduction in acizumab after chemoradiation has not been addressed.
the risk of death. NACT was associated with lower incidence Finally, a Phase II study has recently demonstrated that the
of nodal metastases, vascular space invasion and parametrial addition of cediranib to paclitaxel-carboplatin improves
involvement compared with patients who underwent surgery response rate and progression-free survival in recurrent and or
alone. Moreover, responding patients had a better clinical out- metastatic cervical cancer patients [69].
come compared with non-responders. These encouraging preliminary results may justify further
Similarly, NACT followed by radical surgery showed a investigations on the use of anti-angiogenic agents in the
highly significant 35% reduction in the risk of death compared neoadjuvant setting.
with radiotherapy alone (HR: 0.65; p = 0.0004) with an abso-
lute improvement of 14% in 5-year survival, from 50 to 64%. Financial & competing interests disclosure
However, a great proportion of patients still needed adjuvant The authors have no relevant affiliations or financial involvement with
radiotherapy after surgery, making more difficult to assess the any organization or entity with a financial interest in or financial conflict
cost/effective impact of neoadjuvant treatment on clinical out- with the subject matter or materials discussed in the manuscript. This
come. Moreover, we are still missing the comparison of NACT includes employment, consultancies, honoraria, stock ownership or options,
followed by radical surgery with the current standard of care, expert testimony, grants or patents received or pending or royalties.
that is, chemoradiation. The results of EORTC trial No writing assistance was utilized in the production of this
55994 will soon answer this question. In the era of manuscript.

1178 Expert Rev. Anticancer Ther. 15(10), (2015)

 NACT in cervical cancer Review

Key issues
. Cervical cancer is a chemo-responsive tumor.
. Neoadjuvant chemotherapy before surgery improves survival over radiotherapy.
. Neoadjuvant chemotherapy before surgery improves survival over surgery.
. Neoadjuvant chemotherapy before radiotherapy does not improve outcome: possible detrimental effect with the use of prolonged
interval and lower cisplatin dose.
. Optimal regimen to use in the neoadjuvant setting is not yet established.
. Promising preliminary results with dose-dense regimens.

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