PLOS ONE

RESEARCH ARTICLE

Comparison of the complications between

minimally invasive surgery and open surgical
treatments for early-stage cervical cancer: A
systematic review and meta-analysis
Yilin Li1,2☯, Qingduo Kong1,2☯, Hongyi Wei2, Yongjun Wang ID2*

1 Clinical Medical College, Weifang Medical University, Weicheng District, Weifang, Shandong, China,
2 Division of Gynecology and Obstetrics, Life Science Park of Zhongguancun, Peking University International
a1111111111 Hospital, Changping District, Beijing, China
a1111111111
a1111111111 ☯ These authors contributed equally to this work.
a1111111111 * wyongjunhys@sina.com
a1111111111

Abstract

OPEN ACCESS
Background
Citation: Li Y, Kong Q, Wei H, Wang Y (2021)
Comparison of the complications between This meta-analysis comprehensively compared intraoperative and postoperative complica-
minimally invasive surgery and open surgical tions between minimally invasive surgery (MIS) and laparotomy in the management of cervi-
treatments for early-stage cervical cancer: A cal cancer. Even though the advantages of laparotomy over MIS in disease-free survival
systematic review and meta-analysis. PLoS ONE
16(7): e0253143. https://doi.org/10.1371/journal.
and overall survival for management of gynecological diseases have been cited in the litera-
pone.0253143 ture, there is a lack of substantial evidence of the advantage of one surgical modality over
Editor: Antonio Simone Laganà, University of
another, and it is uncertain whether MIS is justifiable in terms of safety and efficacy.
Insubria, ITALY

Received: November 6, 2020 Methods

Accepted: May 29, 2021 In this meta-analysis, the studies were abstracted that the outcomes of complications to
compare MIS (laparoscopic or robot-assisted) and open radical hysterectomy in patients
Published: July 1, 2021
with early-stage (International Federation of Gynecology and Obstetrics classification stage
Peer Review History: PLOS recognizes the
IA1-IIB) cervical cancer. The primary outcomes were intraoperative overall complications,
benefits of transparency in the peer review
process; therefore, we enable the publication of as well as postoperative aggregate complications. Secondary outcomes included the indi-
all of the content of peer review and author vidual complications. Two investigators independently performed the screening and data
responses alongside final, published articles. The extraction. All articles that met the eligibility criteria were included in this meta-analysis.
editorial history of this article is available here:
https://doi.org/10.1371/journal.pone.0253143
Results
Copyright: © 2021 Li et al. This is an open access
article distributed under the terms of the Creative The meta-analysis finally included 39 non-randomized studies and 1 randomized controlled
Commons Attribution License, which permits trial (8 studies were conducted on robotic radical hysterectomy (RRH) vs open radical hys-
unrestricted use, distribution, and reproduction in
terectomy (ORH), 27 studies were conducted on laparoscopic radical hysterectomy (LRH)
any medium, provided the original author and
source are credited. vs ORH, and 5 studies were conducted on all three approaches). Pooled analyses showed
that MIS was associated with higher risk of intraoperative overall complications (OR = 1.41,
Data Availability Statement: All relevant data are
within the paper and its Supporting Information 95% CI = 1.07–1.86, P<0.05) in comparison with ORH. However, compared to ORH, MIS
files. was associated with significantly lower risk of postoperative aggregate complications (OR =

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PLOS ONE Complications of surgical treatments for early-stage cervical cancer

Funding: This article was funded by “Capital’s 0.40, 95% CI = 0.34–0.48, P = 0.0143). In terms of individual complications, MIS appeared
Funds for Health Improvement and Research” to have a positive effect in decreasing the complications of transfusion, wound infection, pel-
(2020-2-8022). The funders had no role in study
design, data collection and analysis, decision to
vic infection and abscess, lymphedema, intestinal obstruction, pulmonary embolism, deep
publish, or preparation of the manuscript. vein thrombosis, and urinary tract infection. Furthermore, MIS had a negative effect in
Competing interests: The authors have declared
increasing the complications of cystotomy, bowel injury, subcutaneous emphysema, and
that no competing interests exist. fistula.

Conclusions
Our meta-analysis demonstrates that MIS is superior to laparotomy, with fewer postopera-
tive overall complications (wound infection, pelvic infection and abscess, lymphedema,
intestinal obstruction, pulmonary embolism, and urinary tract infection). However, MIS is
associated with a higher risk of intraoperative aggregate complications (cystotomy, bowel
injury, and subcutaneous emphysema) and postoperative fistula complications.

1. Introduction
Being the fourth most common cancer among women, it has been estimated that there were
approximately 528, 000 new cases of cervical cancer with 266, 000 deaths annually [1]. Until
now, radical hysterectomy with an open abdominal approach was the predominant modality
for the treatment of early cervical cancer [2]. After 1992, with the development of laparoscopic
approach, minimally invasive surgery (MIS, i.e., laparoscopy or robotic surgery) for radical
hysterectomy to treat cervical cancer has been accepted widely as a standard treatment for
early-stage cervical cancer [3].
Surprisingly, the results of Laparoscopic Approach of the Cervix (LACC) clinical trial
showed that minimally invasive radical hysterectomy was associated with lower rates of dis-
ease-free survival and overall survival compared with open surgery in 2018 [4]. After that, the
open abdominal approach was defined as the “standard and recommended approach to radical
hysterectomy” for cervical cancer by the National Comprehensive Cancer Network (NCCN)
guidelines [5]. Therefore, discussing the surgical complications have to be done clarifying bet-
ter the actual role of MIS and laparotomy in cervical cancer.
Till date, the advantages of MIS over laparotomy for management of gynecological diseases
have been cited in the literature to included less blood loss, shorter hospital stay, and faster
recovery [6–8]. Similarly, most previous studies on this subject also showed that robotic sur-
gery has the advantages of providing a three-dimensional perspective and more accurate surgi-
cal positioning than laparotomy [9–11]. However, MIS was also associated with its complexity
of operation, longer learning curve, and higher cost than laparotomy. Therefore, there is no
good evidence of the overall advantage of one surgical modality over another, and it is uncer-
tain whether MIS is justifiable in terms of safety and efficacy, due to the small sample sizes, the
low-quality of previous studies, and the limited number of randomized controlled trials
(RCTs).
As for complications, many previous studies showed that MIS and open radical hysterec-
tomy (ORH) have no difference in terms of intraoperative and postoperative complications
[12]. With further development of instruments and skills, several studies found that MIS was
associated with lower rate of intraoperative and postoperative complications than laparotomy
[13]. Unfortunately, till date, it is unclear whether the rates of individual complications in MIS

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are also less than what are seen in laparotomy. Further emphasizing the severity of complica-
tions, which are a key factor in the evaluation of cervical cancer.
The aim of this meta-analysis was to compare the published rates of common intraoperative
and postoperative complications between ORH and MIS in order to provide valid evidence for
evaluating the advantages of different surgical procedures for managing cervical cancer.

2. Methods
2.1. Search strategy
A comprehensive, systemic search for articles was performed using the databases of PubMed,
Embase, Cochrane library, and Web of science. We searched the articles in each database from
the data of its inception until—February 2020. Search terms included a combination of syno-
nyms and abbreviations relating to cervical cancer, laparoscopy, laparotomy, robotic surgery,
and complication. All articles that met the eligibility criteria were assessed. The details of the
search strategy are shown in S1 Table.

2.2. Selection criteria

Studies were included if they met the following criteria: (1) Patients were classified as stage
IA-IIB (according to the 2018 International Federation of Gynecology and Obstetrics classifi-
cation); (2) Subjects were females who underwent LRH, laparoscopic-assisted vaginal radical
hysterectomy (LAVRH), RAH or ORH as primary treatment for cervical cancer; (3) The out-
comes of complications in MIS and ORH were reported. Articles were excluded if they met the
following criteria: (1) Patients received other treatments (radiation or concurrent chemoradia-
tion therapy) before surgery; (2) The articles were case reports, reviews, meta-analysis, organi-
zational guidelines, letters, expert opinions, or conference abstracts; (3) The studies had
inadequate data for outcome assessment; (4) The articles had no outcomes of interest. (5) The
published Articles were not in English.

2.3. Data extraction and quality assessment

Data were extracted into a standard form, and included information on the first author, publi-
cation year, country, participants’ characteristics, study design, number of study participants,
surgical approaches, and FIGO stage. Primary outcomes were intraoperative total complica-
tions and postoperative aggregate complication. Secondary outcomes were categorized into
two groups (individual intraoperative and postoperative complications). Individual intrao-
perative complications included bladder damage, cystotomy, bowel injury, subcutaneous
emphysema, nerve injury, ureteral injury, and vessel injury. Postoperative complications
included wound infection, incisional hernia, pelvic infection and abscess, lymphedema, lym-
phocyst, intestinal obstruction, pulmonary embolism, deep vein thrombosis, and fistula. In
this meta-analysis, we used the Newcastle-Ottawa scale to evaluate 39 studies and the Jadad
scale to evaluate 1 study S2 and S3 Tables [14, 15]. Two reviewers independently evaluated and
cross-checked the qualities of the included studies, as well as assessed the bias of the studies.
Disagreements were discussed between two evaluators in order to reach a consensus and the
third reviewer also provided the opinion.

2.4. Data synthesis and meta-analysis

This meta-analysis was conducted using Stata SE version 12.0 software (StataCorp, College
Station, TX). We analyzed heterogeneity with the chi-square test, and P-value < 0.10 was used
to establish statistical significance with I2 test [16]. I2 values > 50% were considered substantial

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evidence of statistical heterogeneity. To estimate pooled odds ratio (OR) with 95% confidence
interval (CI), a fixed-effects model was used in the absence of significant heterogeneity; the
random-effects model was used in the presence of significant heterogeneity [17]. We evaluated
the publication bias for each of the pooled study groups with a funnel plot. We carried out sub-
group analysis based on the modalities of MIS (LAVRH, total laparoscopic radical hysterec-
tomy (TLRH), and RRH) to assess the outcomes of different subgroups.

3. Results
A total of 40 studies were included in this analysis. The flowchart of the selection process is
shown in Fig 1. The initial search retrieved 3,673 articles from the four databases. All articles
were imported into Endnote for screening. After excluding duplicates, 1,887 articles were
identified for the next step of screening. By reviewing titles and abstracts, 1,798 articles were
removed for not meeting the selection criteria, and 89 articles were identified to be assessed
for eligibility. Eventually, 40 studies were identified in the final analysis, and all of them were
screened after reviewing the full text. We used the Newcastle-Ottawa scale to assess the quality
of 39 studies and Jadad scale to assess 1 RCT, Table 1 shows the results of included studies.
The main characteristics of the 40 studies are shown in Table 1. The study designs were as
follow: retrospective study (n = 31) [18–48], retrospective matched study (n = 6) [49–54], pro-
spective cohort study (n = 2) [55, 56], and RCT (n = 1) [57]. Thirteen studies were conducted
in Asia (China, Israel, Korea, Singapore, and Taiwan) [21, 35, 36, 38, 39, 41, 42, 45, 47, 52, 54–

Fig 1. Flow chart of study selection in this meta-analysis.

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Table 1. Characteristics of the 40 studies included in the meta-analysis.

Study cohort Year Country Study design Approach Number(N) FIGO stage (N) BMIa Agea(years) Scoreb
Lee et al. 2002 China, Taiwan prospective LAVRH 30 IA-IB 30 54.4 ± 12.6 46.2(32–64) 6
ORH 30 IA-IB 30 56.3 ± 10.4 48.0(34–68)
Steed et al. 2004 Canada retrospective LAVRH 71 IA-IB 71 - 43 (30–69) 6
ORH 205 IA-IB 205 - 44 (24–86)
Sharma et al. 2006 England retrospective LAVRH 35 IA2–IIB 35 - 43.4(28–60) 8
ORH 32 IA2–IIB 32 - 42.8(28–66)
Frumovitz et al. 2007 USA retrospective LRH 35 IA-IB 35 28.1(18.4–40.8) 40.8(28.4–63.4) 8
ORH 54 IA-IB 54 28.2(17.4–46.4) 42.5(27.3–68.3)
Li et al. 2007 China retrospective LRH 90 IB-IIA 90 - 42 ± 9 6
ORH 35 IB-IIA 35 - 44 ± 11
Morgan et al. 2007 Ireland retrospective matched LAVRH 30 IA–IB 30 25 (18.6–47) 35 (25–54) 6
ORH 30 IA–IIB 30 24 (19.8–29.5) 38 (20–63)
Uccella et al. 2007 Italy retrospective LRH 50 IA2–IIA 50 23 (17.4–35) 47 (24–78) 7
ORH 48 IA2–IIA 48 25 (19–43) 53 (28–75)
Zakashansky et al. 2007 USA retrospective matched LRH 30 IA1–IIA 30 - 48.3 ± 12.25 7
ORH 30 IA1–IIA 30 - 46.6 ± 11.75
Boggess et al.c 2008 USA retrospective RRH 51 IA1–IIA 47 28.6 ± 7.2 47.4 ± 12.9 6
ORH 49 IA2–IIA 49 26.1 ± 5.1 41.9 ± 11.2
Ko et al. 2008 USA retrospective RRH 16 IA1–IB1 16 27.6 ± 6.4 42.3 ± 7.9 5
ORH 32 IA1–IIA 32 26.6 ± 5.9 41.7 ± 8.1
Estape et al. 2009 USA retrospective RRH 32 IB1-IB2 32 29.7 ± 3.2 55.0(33–83) 7
LRH 17 IA2-IB2 17 28.1 ± 4.8 52.8(37–83)
ORH 14 IB1-IB2 14 29.5 ± 6.4 42.0(27–71)
Maggioni et al. 2009 USA retrospective RRH 40 IA2–IIA 40 24.1 ± 5.5 44.1 ± 9.1 7
ORH 40 IA2–IIA 40 23.6 ± 5.0 49.8 ± 14.1
Malzoni et al. 2009 Italy retrospective TLRH 65 IA1–IB1 65 26(19–35) 40.5 ± 7.7 9
ORH 62 IA1–IB1 62 29(19–35) 42.7 ± 8.6
Papacharalabous et al. 2009 UK retrospective LAVRH 14 IA2–IB 14 - 38.6 ± 3.6 8
ORH 12 IA2–IB 12 - 43.5 ± 12.9
Sobiczewski et al. 2009 Poland retrospective LRH 22 IA1–IB1 22 - 45.44 ± 9 8
ORH 58 IA1–IIA 58 - 51.19 ± 12
Schreuder et al. c 2010 Netherlands retrospective RRH 13 IB1-IIB 13 - 43 (31–78) 7
ORH 14 IB1-IB2 14 - 46 (32–68)
Lee et al. 2011 ROK retrospective LRH 24 IA2–IIa 24 23.4±3.55 48.4 ± 7.25 9
ORH 48 IA2–IIa 48 23.9±4.7 50.2 ± 8.25
Sert et al. 2011 Norway retrospective RRH 35 IA1–IB1 35 25.4±4.36 44.1 ± 10.5 9
LRH 7 IA1–IB1 7 22.5±1.84 45.0 ± 12.9
ORH 26 IA1–IB1 26 25±3.0 44.8 ± 11.8
Taylor et al. 2011 USA retrospective LAVRH 9 IA2–IB1 9 26.3 (20.6–36.1) 41.4 (31–60) 7
ORH 18 IA2–IB1 18 26.9 (17–38.3) 41.1 (25–61)
Gortchev et al. 2012 Bulgaria retrospective RRH 73 - - 46.0 ± 11.2 8
LAVRH 46 - - 42.5 ± 9.9
ORH 175 - - 49.0 ± 11.0
Nam et al. 2012 Korea retrospective matched LRH 263 IA2–IIA 263 - - 8
ORH 263 IA2–IIA 263 - -
Park et al. 2012 Korea retrospective LRH 54 IA2–IIA2 54 31.8 ± 1.39 49.4 ± 11.5 7
ORH 112 IA2–IIA2 112 31.7 ± 1.5 52.1 ± 11.8
(Continued )

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Table 1. (Continued)

Study cohort Year Country Study design Approach Number(N) FIGO stage (N) BMIa Agea(years) Scoreb
Lim et al. 2013 Singapore prospective LRH 18 IA1-IIA 18 22.9 (16.0–33.7) 48 (30–65) 9
ORH 30 IA1-IIA 30 22.4 (17.9–33.9) 47 (33–67)
Park et al. 2013 Korea retrospective LRH 115 IB2-IIA2 115 23.1 (15.6–34.8) 48.5 (25–77) 8
ORH 188 IB2-IIA2 188 23.7 (17.6–34.7) 48.1 (25–84)
BoganI et al. 2014 Italy retrospective LRH 65 IA2-IIB 65 25.1 ± 5.2 48.9 ±13.5 9
ORH 65 IA2-IIB 65 25.9 ± 6.1 50.9 ± 14
Chen et al. 2014 Taiwan retrospective RRH 24 IA-IIB 24 24.4 ± 4.9 53.7 ± 15.3 8
LRH 32 IA-IIB 32 23.2 ± 3.4 51.2 ± 11.9
ORH 44 IA-IIB 44 24.9 ± 4.6 51.9 ± 11.3
Yin et al. 2014 China retrospective LRH 22 IA2–IIA 22 - 44 ± 1.5 6
ORH 23 IA2–IIA 23 - 46 ± 2.3
Asciutto et al. 2015 Sweden retrospective RRH 64 IA2–IIA 64 27.0 ± 6.1 45.4 ± 13.6 6
ORH 185 IA2–IIA 178 25.7 ± 4.7 45.7 ± 13.0
Ditto et al. 2015 Italy retrospective matched LRH 60 IA2–IB1 60 24.3 ± 2.9 46 (29–79) 9
ORH 60 IA2–IB1 60 24.0 ± 4.3 45.5 (15–78)
Xiao et al. 2015 China retrospective LRH 106 IA-IIB 106 23.8 ± 3.9 43.7 ± 9.3 8
ORH 48 IA-IIB 48 24.7 ± 3.8 45.7 ± 11.3
Park et al. 2016 Korea retrospective LRH 186 IA2–IIA1 186 23.69 (17.1–34.9) 45.3 (27–71) 7
ORH 107 IA2–IIA1 107 23.58 (17.1–35.9) 47.3 (28–73)
Shah et al. 2017 USA retrospective RRH 109 IA1-IB2 109 27.9 (17.6–51.6) 45.2 (25–84) 7
ORH 202 IA1-IB2 202 29.1 (18.3–55.7) 45.4 (19–88)
Corrado et al. 2018 Italy retrospective RRH 88 IB1 88 23.3 (18–47.6) 46 (27–77) 8
LRH 152 IB1 152 23.5 (17–35) 45 (23–78)
ORH 101 IB1 101 24.8 (18–51) 50 (28–76)
Guo et al. 2018 China retrospective LRH 412 IA-IIA 412 22.81 (14.3–35.6) 44.19 (25–76) 7
ORH 139 IA-IIA 139 23.19 (13.8–36.6) 40.52 (23–62)
Bogani et al. c 2019 Italy Retrospective matched LRH 35 IB1-IIA 23 22.9 ± 4.0 41.1 ± 6.9 7
ORH 35 IB1-IIA 24 20.1 ± 9.3 44.1 ± 12.7
Matanes et al. 2019 Israel retrospective RRH 74 IA1-IIA 74 26.4(18.2–42.1) 48(29–77) 8
ORH 24 IA1-IIA 24 26.2(20.6–38.5) 47(24–69)
Piedimonte et al. 2019 Canada Retrospective RRH 749 - - - 6
ORH 2584 - - -
Yuan et al. 2019 China Retrospective matched LRH 99 IIA2-IIA2 99 44.56 ± 7.60 43.58 ± 8.86 9
ORH 99 IIA2-IIA2 99 24.56 ± 1.50 44.56 ± 7.60
Pahisa et al. 2010 Spain Retrospective LAVRH 67 IA2-IIA 67 25.4 ± 1.1 51 (29–75) 7
ORH 23 IA2-IIA 23 27.2 ± 2.5 48 (31–67)
Campos et al. 2013 Brazil RCT LRH 16 IA2–IB 16 - 36.19 ± 9.78 5
ORH 14 IA2–IB 14 - 39.64 ± 6.23

ORH: Open radical hysterectomy, LRH: Laparoscopic radical hysterectomy, RRH: Robotic radical hysterectomy, LAVRH: Laparoscopic-assisted vaginal radical
hysterectomy, RCT: Randomized controlled trial
a: Mean, median or unknow.
b: Jadad scale: score: 1~3, indicating low quality study; score: 4~7, indicating high quality study. Newcastle-Ottawa scale: score�5, indicating high risk of bias; score>5,
indicating low risk of bias.
c: These studies including other FIGO stages of cervical cancer.

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56], ten in North America (Canada, and USA) [18, 20, 23–26, 33, 43, 48, 51], sixteen in Europe
(UK, Ireland, Poland, Netherlands, Federal Republic of Germany, Norway, Bulgaria, Italy,
Sweden, and Spain) [19, 22, 27–32, 34, 37, 40, 44, 46, 49, 50, 53], and one study in South Amer-
ica (Brazil) [57]. In all, we identified 9003 patients in the pooled analysis: 2277 patients had
LRH, 1,368 patients had RRH and 5358 patients had ORH (we compared 1,368 patients who
underwent RRH vs 3,490 patients who underwent ORH, and 2277 patients who underwent
LRH vs 2,228 patients who underwent ORH). As shown in Table 1, 8 studies compared RRH
with ORH [23, 24, 26, 29, 39, 42, 46, 47], 25 studies compared LRH with ORH [18–22, 27, 28,
30, 32, 34–36, 38, 40, 41, 44, 45, 48–57], and 5 studies compared all 3 surgical approaches [25,
31, 33, 37, 43].

3.1 MIS vs ORH

3.1.1 Primary outcomes. We show the results of intraoperative aggregate complications
and postoperative overall complications between MIS and ORH in Fig 2, respectively. For
intraoperative complications, the incidence of intraoperative complications in MIS (121/3459)
were statistically higher than ORH (102/5174), and the risk of intraoperative complications
(OR = 1.41, 95% CI = 1.07–1.86, P<0.05) in MIS was higher compared with ORH. In terms of
postoperative complications, MIS was associated with significantly lower risk of postoperative
complications (OR = 0.40, 95% CI = 0.34–0.48, P = 0.0143) compared with ORH. There was
no heterogeneity in studies of intraoperative aggregate complications (I2 = 0%, P = 0.748).
However, we found that the studies of postoperative overall complications were associated
with high heterogeneity (I2 = 51%, P<0.01). The result of publication bias was shown in Fig 3,
the funnel plot was nearly symmetric on both sides, so there was no publication bias in the
results of intraoperative aggregate complications and postoperative overall complications.
3.1.2 Secondary outcomes. In order to determine the source of difference, we analyzed
the results of individual intraoperative and postoperative complications in Table 2, respec-
tively. For intraoperative complications, there were no significant differences between MIS
and ORH in the bladder damage, nerve injury, ureteral injury, or vessel injury, with ORs of
1.28 (95% CI = 0.75–2.19, P = 0.3), 0.51 (95% CI = 0.14–1.93, P = 0.343), 1.05 (95% CI = 0.61–
1.76, P = 0.959), 1.01 (95% CI = 0.59–1.73, P = 0.753), respectively. However, MIS was associ-
ated with increased risk of cystotomy (OR = 2.27, 95% CI = 1.23–4.20), bowel injury
(OR = 2.15, 95% CI = 0.95–4.89), subcutaneous emphysema (OR = 4.36, 95% CI = 0.94–20.29)
in comparison with ORH. In terms of postoperative complications, there were comparable in
the risk of incisional hernia (OR = 0.93, 95% CI = 0.34–2.51, P = 0.803) and lymphocyst
(OR = 0.73, 95% CI = 0.46–1.15, P = 0.123) between MIS and ORH. Comparing to ORH, MIS
was associated with significantly lower risks of wound-infection (OR = 0.15, 95% CI = 0.08–
0.28, P<0.01), pelvic infection and abscess (OR = 0.40, 95% CI = 0.26–0.63, P<0.01), lymph-
edema (OR = 0.48, 95% CI = 0.24–0.98, P = 0.03), intestinal obstruction (OR = 0.30, 95%
CI = 0.21–0.43, P<0.01), pulmonary embolism (OR = 0.36, 95% CI = 0.09–1.48, P = 0.025),
deep vein thrombosis (OR = 0.56, 95% CI = 0.35–0.88, P = 0.01), and urinary tract infection
(OR = 0.56, 95% CI = 0.34–0.91, P = 0.013). However, the risk of fistula (OR = 1.69, 95%
CI = 0.02–2.79, P = 0.011) was significant increased in the MIS group than in ORH.

3.2 Subgroup analysis

The subgroup analysis compared intraoperative complications and postoperative complica-
tions among the three types of MIS, as shown in Table 3. For intraoperative aggregate compli-
cations, compared to ORH, the risks of complications were not increased in RRH (OR = 1.11,
95% CI = 0.62–2.01, P = 0.11) and TLRH (OR = 1.34, 95%CI = 0.94–1.93, P = 0.722), whereas

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Fig 2. Forest plots of intraoperative and postoperative complications between Minimally Invasive Surgical (MIS)
and Open Radical Hysterectomy (ORH). OR, odds ratio.
https://doi.org/10.1371/journal.pone.0253143.g002

it was higher in LAVRH (OR = 2.27, 95%CI = 1.02–5.04, P = 0.044). For postoperative overall
complication, the risk in LAVRH (OR = 0.71, 95%CI = 0.26–1.93, P = 0.506) was not statisti-
cally different from that of ORH. However, RRH (OR = 0.42, 95%CI = 0.26–0.68, P<0.01) and
TLRH (OR = 0.58, 95%CI = 0.45–0.74, P<0.01) was associated with a reduced risk of postop-
erative complication when compared with ORH. In a stratified analysis (S4 Table), in an
attempt to further determine the difference in fistula complications, we also analyzed compli-
cations with different types of fistula, including vesicovaginal, rectovaginal, ureterovaginal and
urinary fistula, with ORs of 1.55 (95%CI = 0.59–4.06, P = 0.376), 2.88 (95%CI = 0.44–18.70,
P = 0.269), 1.60 (95%CI = 0.59–4.34, P = 0.353), and 1.25 (95%CI = 0.53–2.97, P = 0.612)
respectively. Interestingly, there was no significant difference in risk of the individual fistula
types between MIS and ORH.

4. Discussion
This study assessed most comprehensive results of complications of cervical cancer surgeries
and evaluated the safety of different surgical strategies. The rates of perioperative complica-
tions will become a key factor of importance in comparing surgical modalities for managing
cervical cancer. We aimed to provide a basis for the selection of optimal surgical methods, as
well as offer new opinions for actual role of MIS in cervical cancer.
Our meta-analysis indicated that the overall risk of intraoperative complications was
increased with MIS than with ORH. Patients accepted to MIS experienced almost 2 times the
risk of intraoperative complications compared with patients accepted to ORH. There were no
significant differences in risk for intraoperative complications including bladder damage,
nerve injury, ureteral injury, and vessel injury among individual intraoperative complications.
However, MIS group was associated with higher risk in complications of cystotomy, bowel
injury, and subcutaneous emphysema in comparison to ORH. This finding was consistent
with previous studies. The differences in bowel injury between MIS and ORH can be explained
by the use of surgical instruments such as a trocar and Veress needle during radical hysterec-
tomy. Previous studies have shown that the majority of bowel injuries occurred during lapa-
roscopy using a Veress needle or trocar placement [58, 59]. The subcutaneous emphysema was
the unique complications in MIS, many risk factors will lead to it during MIS including
increased intra-abdominal pressure, total gas volume, and gas flow rate [60].

Fig 3. Funnel plot of studies evaluating the publication bias of intraoperative and intraoperative complications
between MIS and ORH. (A). intraoperative complications. (B). postoperative complications.
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PLOS ONE Complications of surgical treatments for early-stage cervical cancer

Table 2. Meta-analysis estimates of individual complications between MIS and ORH.

Category MIS ORH OR (95% CI) P value I2(%)
Transfusion 301/2490 494/4408 0.34[0.22,0.53] <0.001 72.3
Intraoperative complications
Bladder damage 25/2279 24/4009 1.28[0.75,2.19] 0.3 0
Cystotomy 32/586 14/677 2.27[1.23,4.20] 0.002 0
Bowel injury 12/1479 8/3449 2.15[0.95,4.89] 0.041 0
Subcutaneous emphysema 7/246 0/207 4.36[0.94,20.29] 0.008 0
Nerve injury 2/1181 5/802 0.51[0.14,1.93] 0.343 0
Ureteral injury 22/2519 24/4520 1.05[0.61,1.76] 0.959 0
Vessel injury 21/2328 27/4112 1.01[0.59,1.73] 0.753 0
Postoperative complications
Wound infection 5/1380 104/3277 0.15[0.08,0.28] <0.001 0
Incisional hernia 7/898 7/811 0.93[0.34,2.51] 0.803 0
Pelvic infection and abscess 30/1713 78/3396 0.40[0.26,0.63] <0.001 39.9
Lymphedema 13/791 19/619 0.48[0.24,0.98] 0.03 0
Lymphocyst 40/1614 35/1194 0.73[0.46,1.15] 0.123 8.4
Intestinal obstruction 37/2490 281/4070 0.30[0.21,0.43] <0.001 0
Pulmonary embolism 0/508 7/558 0.36[0.09,1.48] 0.025 0
Deep vein thrombosis 31/2289 78/3886 0.56[0.35,0.88] 0.01 0
Fistula 38/2203 17/1904 1.69[0.02,2.79] 0.011 0
Urinary tract infection 33/764 44/799 0.56[0.34,0.91] 0.013 3

OR: Odds ratio; CI: Confidence interval; MIS: Minimally invasive surgery; ORH: Open radical hysterectomy

https://doi.org/10.1371/journal.pone.0253143.t002

Regarding postoperative complications, our meta-analysis found that MIS was associated
with significantly lower risk of postoperative overall complications compared with ORH. In
individual postoperative complications, incisional hernia and lymphocyst had no differences
between MIS and ORH. MIS was superior to ORH in terms of wound infection, pelvic infec-
tion and abscess, lymphedema, intestinal obstruction, pulmonary embolism, and urinary tract
infection, whereas the risk of fistula complications was significantly increased, with MIS com-
pared to ORH. Interestingly, in a stratified analysis of fistula complications, we found that
there were no significant differences in risk for four types of fistula complications. Possible rea-
sons for this result including individual fistula complication had small sample size and

Table 3. The subgroup analysis of laparoscopic types between MIS and ORH in intraoperative and postoperative overall complications.
Category Laparoscopic type Study OR (95% CI) P value I2(%)
Intraoperative complications
TLRH 23 1.34[0.94,1.93] 0.11 0
LAVRH 5 2.27[1.02,5.04] 0.044 0
RRH 13 1.11[0.62,2.01] 0.722 0
Postoperative complications
TLRH 25 0.58[0.45,0.74] <0.01 0
LAVRH 7 0.71[0.26,1.93] 0.506 58.5
RRH 11 0.42[0.26,0.68] <0.01 45.3

OR: Odds ratio; CI: Confidence interval; TLRH: Total laparoscopic radical hysterectomy; RRH: Robotic radical hysterectomy; LARVH: Laparoscopic assisted
radical vaginal hysterectomy.

https://doi.org/10.1371/journal.pone.0253143.t003

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PLOS ONE Complications of surgical treatments for early-stage cervical cancer

excessive weight of included studies biased the results [61]. Although there were no significant
differences in the risks of vesicovaginal, rectovaginal, ureterovaginal, and urinary fistula
between MIS and ORH, the incidence rates of these four types of fistula complications in MIS
were higher than that of ORH. This finding was worthy of our attention.
Taken together, the surgeon proficiency may be a factor in determining the rates of compli-
cations. Regrettably, this meta-analysis was not able to provide a comparison between sur-
geons. Furthermore, the learning curve could play an important role in complications between
different surgical modalities, and MIS was associated with a longer learning curve than ORH
because of the complexity of surgical procedure, and also might have influenced complication
rates [62, 63]. The use of surgical instruments was related to viscus injuries, which may be
caused by thermal injury, due to the high temperature of the surgical instruments resulting in
the damage of submucosal or deeper tissues of the bladder, intestines, and bowel. Previous
studies have evaluated the thermal injury of bowel in laparoscopic approach [62]. It must be
taken that thermal injury was an inherent risk of the technique during radical hysterectomy,
and therefore surgeon should pay attention to this issue. Overall, these factors were associated
with the incidence of intraoperative and postoperative complications.
Concerning the subgroup meta-analysis of surgical modalities, intraoperative complication
rate increased in the course of LAVRH, as well as there were no differences in TLRH and
RRH. This finding is consistent with that of previous meta-analyses. The requirement for
refinement of LAVRH is very high due to the complex pelvic floor anatomy in females. In the
vaginal approach, the ureters and bladder are identified by traction on the uterus after the liga-
ment around the uterus is isolated and cut [64], and urinary tract trauma is a clear risk during
LAVRH. With time, laparoscopy is continually evolving with the improvement in surgical
skills, instruments, and learning curve, and these improvements may be partly responsible for
reduction in intraoperative complication over time [63]. For postoperative aggregate compli-
cations, both RRH and TLRH were associated with lower risk compared to ORH. These results
were validated in previous studies, Park et al. compared the complications of three approaches,
RRH had a positive effect in reducing overall complications than ORH for cervical cancer
patients [65]. For LAVRH group, the high heterogeneity and the small sample size could bias
the results of postoperative complications. In the future, we need more high-quality cohort
studies to evaluate and compare the risk of postoperative complications between MIS and
ORH.
There are limitations to this meta-analysis. First, included studies were primarily non-ran-
domized studies, which could not provide high-quality evidence. Furthermore, our study did
not include single-arm studies, which can lead to the bias of the result. Additionally, differ-
ences in patients’ characteristics between different surgical cohorts may lead to highly hetero-
geneous outcomes in studies and affect the results of the pooled analysis. The statistical
methods could not fully diminish these differences. Second, the difference of surgeons in these
articles were not reported including the level of experience in surgeons and types of surgeons,
these factors could affect the surgical outcomes as time went by. The additional morbidities of
patients in these studies were not involved, these factors could contribute to the bias of results.
Third, most studies included in this meta-analysis did not use standardized methods of classi-
fying complications, such as the Clavien-Dindo classification system, and the final results may
be affected by these differences in the reporting of complications. Among all included studies,
only one adopted the Clavien-Dindo classification system of complications [39]. Forth, during
the extraction of complication data, many studies revealed that patients had undergone cesar-
ean section or previous abdominal surgery and had severe adhesions in the past, alluding to
the fact that the success of laparoscopy will be affected by adhesions. Therefore, the incidence
of complications ultimately may interfere with the results and may be a cause of bias.

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PLOS ONE Complications of surgical treatments for early-stage cervical cancer

5. Conclusion
Our meta-analysis demonstrates that MIS is superior to laparotomy, with fewer postoperative
overall complications (wound infection, pelvic infection and abscess, lymphedema, intestinal
obstruction, pulmonary embolism, and urinary tract infection). However, MIS is associated
with a higher risk of intraoperative aggregate complications (cystotomy, bowel injury, and sub-
cutaneous emphysema) and postoperative fistula complications. In the future, high-quality
prospective studies and RCTs are needed to provide sufficient evidence for evaluating the pros
and cons of using MIS to treat cervical cancer.

Supporting information
S1 Checklist. PRISMA 2009 checklist.
(DOC)
S1 Fig. PRISMA 2009 flow diagram.
(DOC)
S1 Table. Detailed search strategy.
(DOC)
S2 Table. Quality assessment of the included studies according to modified NOS score.
(DOC)
S3 Table. Quality assessment of the included studies according to modified Jadad score.
(DOC)
S4 Table. The subgroup analysis of fistula types between MIS and ORH.
(DOC)

Author Contributions
Conceptualization: Yongjun Wang.
Data curation: Yilin Li.
Funding acquisition: Yongjun Wang.
Investigation: Qingduo Kong, Hongyi Wei.
Methodology: Yilin Li, Yongjun Wang.
Supervision: Hongyi Wei.
Visualization: Qingduo Kong.
Writing – original draft: Yilin Li.
Writing – review & editing: Yilin Li, Yongjun Wang.

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