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. 2021 Jul 1;16(7):e0253143. doi: 10.1371/journal.pone.0253143

Comparison of the complications between minimally invasive surgery and open surgical treatments for early-stage cervical cancer: A systematic review and meta-analysis

Yilin Li 1,2,#, Qingduo Kong 1,2,#, Hongyi Wei 2, Yongjun Wang 2,*
Editor: Antonio Simone Laganà3
PMCID: PMC8248723  PMID: 34197466

Abstract

Background

This meta-analysis comprehensively compared intraoperative and postoperative complications between minimally invasive surgery (MIS) and laparotomy in the management of cervical cancer. Even though the advantages of laparotomy over MIS in disease-free survival and overall survival for management of gynecological diseases have been cited in the literature, there is a lack of substantial evidence of the advantage of one surgical modality over another, and it is uncertain whether MIS is justifiable in terms of safety and efficacy.

Methods

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 with early-stage (International Federation of Gynecology and Obstetrics classification stage IA1-IIB) cervical cancer. The primary outcomes were intraoperative overall complications, as well as postoperative aggregate complications. Secondary outcomes included the individual complications. Two investigators independently performed the screening and data extraction. All articles that met the eligibility criteria were included in this meta-analysis.

Results

The meta-analysis finally included 39 non-randomized studies and 1 randomized controlled trial (8 studies were conducted on robotic radical hysterectomy (RRH) vs open radical hysterectomy (ORH), 27 studies were conducted on laparoscopic radical hysterectomy (LRH) 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, 95% CI = 1.07–1.86, P<0.05) in comparison with ORH. However, compared to ORH, MIS was associated with significantly lower risk of postoperative aggregate complications (OR = 0.40, 95% CI = 0.34–0.48, P = 0.0143). In terms of individual complications, MIS appeared to have a positive effect in decreasing the complications of transfusion, wound infection, pelvic infection and abscess, lymphedema, intestinal obstruction, pulmonary embolism, deep vein thrombosis, and urinary tract infection. Furthermore, MIS had a negative effect in increasing the complications of cystotomy, bowel injury, subcutaneous emphysema, and fistula.

Conclusions

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 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 disease-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 better 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 surgery has the advantages of providing a three-dimensional perspective and more accurate surgical 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 uncertain 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 hysterectomy (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 are also less than what are seen in laparotomy. Further emphasizing the severity of complications, 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 synonyms 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 classification); (2) Subjects were females who underwent LRH, laparoscopic-assisted vaginal radical hysterectomy (LAVRH), RAH or ORH as primary treatment for cervical cancer; (3) The outcomes 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 chemoradiation therapy) before surgery; (2) The articles were case reports, reviews, meta-analysis, organizational 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, publication year, country, participants’ characteristics, study design, number of study participants, surgical approaches, and FIGO stage. Primary outcomes were intraoperative total complications and postoperative aggregate complication. Secondary outcomes were categorized into two groups (individual intraoperative and postoperative complications). Individual intraoperative 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, lymphocyst, 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 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 subgroup analysis based on the modalities of MIS (LAVRH, total laparoscopic radical hysterectomy (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.

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

Fig 1

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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
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
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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.

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], prospective 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, 54–56], 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 America (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.

Fig 2. Forest plots of intraoperative and postoperative complications between Minimally Invasive Surgical (MIS) and Open Radical Hysterectomy (ORH).

Fig 2

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OR, odds ratio.

Fig 3. Funnel plot of studies evaluating the publication bias of intraoperative and intraoperative complications between MIS and ORH.

Fig 3

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(A). intraoperative complications. (B). postoperative 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, respectively. 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 associated 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), lymphedema (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.

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

3.2 Subgroup analysis

The subgroup analysis compared intraoperative complications and postoperative complications among the three types of MIS, as shown in Table 3. For intraoperative aggregate complications, 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 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 statistically 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 postoperative 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 complications 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.

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

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 complications 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 hysterectomy. Previous studies have shown that the majority of bowel injuries occurred during laparoscopy 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].

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 infection and abscess, lymphedema, intestinal obstruction, pulmonary embolism, and urinary tract infection, whereas the risk of fistula complications was significantly increased, with MIS compared 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 reasons for this result including individual fistula complication had small sample size and 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 complications. Regrettably, this meta-analysis was not able to provide a comparison between surgeons. 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 ligament 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 complications, 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-randomized 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, differences in patients’ characteristics between different surgical cohorts may lead to highly heterogeneous 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 classifying 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 cesarean 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.

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 subcutaneous 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.

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S1 Fig. PRISMA 2009 flow diagram.

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S1 Table. Detailed search strategy.

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Click here for additional data file. (51KB, doc)
S2 Table. Quality assessment of the included studies according to modified NOS score.

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Click here for additional data file. (22.6KB, doc)
S3 Table. Quality assessment of the included studies according to modified Jadad score.

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Click here for additional data file. (15.1KB, doc)
S4 Table. The subgroup analysis of fistula types between MIS and ORH.

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Click here for additional data file. (33KB, doc)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This article was funded by “Capital’s Funds for Health Improvement and Research” (2020-2-8022). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. Epub 2018/09/13. doi: 10.3322/caac.21492 . [DOI] [PubMed] [Google Scholar]
  • 2.Ries E. The operative treatment of cancer of the cervix. JAMA. 1906;XLVII(23):1869–1872. doi: 10.1001/jama.1906.25210230005001b [DOI] [Google Scholar]
  • 3.Wright JD, Herzog TJ, Neugut AI, Burke WM, Lu YS, Lewin SN, et al. Comparative effectiveness of minimally invasive and abdominal radical hysterectomy for cervical cancer. Gynecol Oncol. 2012. Oct;127(1):11–7. doi: 10.1016/j.ygyno.2012.06.031 Epub 2012 Jun 24. . [DOI] [PubMed] [Google Scholar]
  • 4.Ramirez PT, Frumovitz M, Pareja R, Lopez A, Vieira M, Ribeiro R, et al. Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer. N Engl J Med. 2018;379(20):1895–904. Epub 2018/11/01. doi: 10.1056/NEJMoa1806395 . [DOI] [PubMed] [Google Scholar]
  • 5.National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: cervical cancer version 1. Accessed April 1, 2020. https://www.nccn.org/professionals/physician_gls/pdf/cervical_blocks.pdf.
  • 6.Wang YZ, Deng L, Xu HC, Zhang Y, Liang ZQ. Laparoscopy versus laparotomy for the management of early stage cervical cancer. BMC Cancer. 2015;15:928. Epub 2015/11/26. doi: 10.1186/s12885-015-1818-4 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Diver E, Hinchcliff E, Gockley A, Melamed A, Contrino L, Feldman S, et al. Minimally Invasive Radical Hysterectomy for Cervical Cancer Is Associated With Reduced Morbidity and Similar Survival Outcomes Compared With Laparotomy. J Minim Invasive Gynecol. 2017;24(3):402–6. Epub 2016/12/25. doi: 10.1016/j.jmig.2016.12.005 . [DOI] [PubMed] [Google Scholar]
  • 8.Galaal K, Donkers H, Bryant A, Lopes AD. Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev. 2018;10:CD006655. Epub 2018/11/01. doi: 10.1002/14651858.CD006655.pub3 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Maenpaa MM, Nieminen K, Tomas EI, Laurila M, Luukkaala TH, Maenpaa JU. Robotic-assisted vs traditional laparoscopic surgery for endometrial cancer: a randomized controlled trial. Am J Obstet Gynecol. 2016;215(5):588 e1- e7. Epub 2016/10/30. doi: 10.1016/j.ajog.2016.06.005 . [DOI] [PubMed] [Google Scholar]
  • 10.Park DA, Yun JE, Kim SW, Lee SH. Surgical and clinical safety and effectiveness of robot-assisted laparoscopic hysterectomy compared to conventional laparoscopy and laparotomy for cervical cancer: A systematic review and meta-analysis. Eur J Surg Oncol. 2017;43(6):994–1002. Epub 2016/08/23. doi: 10.1016/j.ejso.2016.07.017 . [DOI] [PubMed] [Google Scholar]
  • 11.Gala RB, Margulies R, Steinberg A, Murphy M, Lukban J, Jeppson P, et al. Systematic review of robotic surgery in gynecology: robotic techniques compared with laparoscopy and laparotomy. J Minim Invasive Gynecol. 2014;21(3):353–61. Epub 2013/12/04. doi: 10.1016/j.jmig.2013.11.010 . [DOI] [PubMed] [Google Scholar]
  • 12.Brandt B, Sioulas V, Basaran D, Kuhn T, LaVigne K, Gardner GJ, et al. Minimally invasive surgery versus laparotomy for radical hysterectomy in the management of early-stage cervical cancer: Survival outcomes. Gynecol Oncol. 2020;156(3):591–7. Epub 2020/01/11. doi: 10.1016/j.ygyno.2019.12.038 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Obermair A, Asher R, Pareja R, Frumovitz M, Lopez A, Moretti-Marques R, et al. Incidence of adverse events in minimally invasive vs open radical hysterectomy in early cervical cancer: results of a randomized controlled trial. Am J Obstet Gynecol. 2020;222(3):249 e1- e10. Epub 2019/10/07. doi: 10.1016/j.ajog.2019.09.036 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. (2000). [Google Scholar]
  • 15.Clark HD, Wells GA, Huet C, McAlister FA, Salmi LR, Fergusson D, et al. Assessing the quality of randomized trials: reliability of the Jadad scale. Control Clin Trials. 1999;20(5):448–52. Epub 1999/09/30. doi: 10.1016/s0197-2456(99)00026-4 . [DOI] [PubMed] [Google Scholar]
  • 16.Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58. Epub 2002/07/12. doi: 10.1002/sim.1186 . [DOI] [PubMed] [Google Scholar]
  • 17.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. Epub 2003/09/06. doi: 10.1136/bmj.327.7414.557 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Steed H, Rosen B, Murphy J, Laframboise S, De Petrillo D, Covens A. A comparison of laparascopic-assisted radical vaginal hysterectomy and radical abdominal hysterectomy in the treatment of cervical cancer. Gynecol Oncol. 2004;93(3):588–93. Epub 2004/06/16. doi: 10.1016/j.ygyno.2004.04.003 . [DOI] [PubMed] [Google Scholar]
  • 19.Sharma R, Bailey J, Anderson R, Murdoch J. Laparoscopically assisted radical vaginal hysterectomy (Coelio-Schauta): A comparison with open Wertheim/Meigs hysterectomy. Int J Gynecol Cancer. 2006;16(5):1927–32. Epub 2006/10/03. doi: 10.1111/j.1525-1438.2006.00661.x . [DOI] [PubMed] [Google Scholar]
  • 20.Frumovitz M, dos Reis R, Sun CC, Milam MR, Bevers MW, Brown J, et al. Comparison of total laparoscopic and abdominal radical hysterectomy for patients with early-stage cervical cancer. Obstetrics and Gynecology. 2007;110(1):96–102. doi: 10.1097/01.AOG.0000268798.75353.04 WOS:000247572700016. [DOI] [PubMed] [Google Scholar]
  • 21.Li GY, Yan XJ, Shang HL, Wang G, Chen LS, Han YB. A comparison of laparoscopic radical hysterectomy and pelvic lymphadenectomy and laparotomy in the treatment of Ib-IIa cervical cancer. Gynecologic Oncology. 2007;105(1):176–80. doi: 10.1016/j.ygyno.2006.11.011 WOS:000245559000027. [DOI] [PubMed] [Google Scholar]
  • 22.Uccella S, Laterza R, Ciravolo G, Volpi E, Franchi M, Zefiro F, et al. A comparison of urinary complications following total laparoscopic radical hysterectomy and laparoscopic pelvic lymphadenectomy to open abdominal surgery. Gynecol Oncol. 2007;107(1 Suppl 1):S147–9. Epub 2007/08/28. doi: 10.1016/j.ygyno.2007.07.027 . [DOI] [PubMed] [Google Scholar]
  • 23.Boggess JF, Gehrig PA, Cantrell L, Shafer A, Ridgway M, Skinner EN, et al. A case-control study of robot-assisted type III radical hysterectomy with pelvic lymph node dissection compared with open radical hysterectomy. American Journal of Obstetrics and Gynecology. 2008;199(4):357.e1–.e7. doi: 10.1016/j.ajog.2008.06.058 [DOI] [PubMed] [Google Scholar]
  • 24.Ko EM, Muto MG, Berkowitz RS, Feltmate CM. Robotic versus open radical hysterectomy: a comparative study at a single institution. Gynecol Oncol. 2008;111(3):425–30. Epub 2008/10/22. doi: 10.1016/j.ygyno.2008.08.016 . [DOI] [PubMed] [Google Scholar]
  • 25.Estape R, Lambrou N, Diaz R, Estape E, Dunkin N, Rivera A. A case matched analysis of robotic radical hysterectomy with lymphadenectomy compared with laparoscopy and laparotomy. Gynecol Oncol. 2009;113(3):357–61. Epub 2009/04/07. doi: 10.1016/j.ygyno.2009.03.009 . [DOI] [PubMed] [Google Scholar]
  • 26.Maggioni A, Minig L, Zanagnolo V, Peiretti M, Sanguineti F, Bocciolone L, et al. Robotic approach for cervical cancer: comparison with laparotomy: a case control study. Gynecol Oncol. 2009;115(1):60–4. Epub 2009/07/30. doi: 10.1016/j.ygyno.2009.06.039 . [DOI] [PubMed] [Google Scholar]
  • 27.Malzoni M, Tinelli R, Cosentino F, Fusco A, Malzoni C. Total laparoscopic radical hysterectomy versus abdominal radical hysterectomy with lymphadenectomy in patients with early cervical cancer: our experience. Ann Surg Oncol. 2009;16(5):1316–23. Epub 2009/02/19. doi: 10.1245/s10434-009-0342-7 . [DOI] [PubMed] [Google Scholar]
  • 28.Papacharalabous E, Tailor A, Madhuri T, Giannopoulos T, Butler-Manuel S. Early experience of laparoscopically assisted radical vaginal hysterectomy (Coelio-Schauta) versus abdominal radical hysterectomy for early stage cervical cancer. Gynecological Surgery. 2009;6(2):113–7. doi: 10.1007/s10397-008-0424-8 [DOI] [Google Scholar]
  • 29.Sobiczewski P, Bidzinski M, Derlatka P, Panek G, Danska-Bidzinska A, Gmyrek L, et al. Early cervical cancer managed by laparoscopy and conventional surgery: comparison of treatment results. Int J Gynecol Cancer. 2009;19(8):1390–5. Epub 2009/12/17. doi: 10.1111/IGC.0b013e3181ba5e88 . [DOI] [PubMed] [Google Scholar]
  • 30.Schreuder HW, Zweemer RP, van Baal WM, van de Lande J, Dijkstra JC, Verheijen RH. From open radical hysterectomy to robot-assisted laparoscopic radical hysterectomy for early stage cervical cancer: aspects of a single institution learning curve. Gynecol Surg. 2010;7(3):253–8. Epub 2010/08/12. doi: 10.1007/s10397-010-0572-5 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Lee EJ, Kang H, Kim DH. A comparative study of laparoscopic radical hysterectomy with radical abdominal hysterectomy for early-stage cervical cancer: a long-term follow-up study. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2011;156(1):83–6. doi: 10.1016/j.ejogrb.2010.12.016 WOS:000291715600016. [DOI] [PubMed] [Google Scholar]
  • 32.Sert MB, Abeler V. Robot-assisted laparoscopic radical hysterectomy: comparison with total laparoscopic hysterectomy and abdominal radical hysterectomy; one surgeon’s experience at the Norwegian Radium Hospital. Gynecol Oncol. 2011;121(3):600–4. Epub 2011/03/01. doi: 10.1016/j.ygyno.2011.02.002 . [DOI] [PubMed] [Google Scholar]
  • 33.Taylor SE, McBee WC Jr., Richard SD, Edwards RP. Radical hysterectomy for early stage cervical cancer: laparoscopy versus laparotomy. Jsls. 2011;15(2):213–7. Epub 2011/09/10. doi: 10.4293/108680811X13022985132218 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Gortchev G, Tomov S, Tantchev L, Velkova A, Radionova Z. Robot-assisted radical hysterectomy-perioperative and survival outcomes in patients with cervical cancer compared to laparoscopic and open radical surgery. Gynecological Surgery. 2012;9(1):81–8. doi: 10.1007/s10397-011-0683-7 [DOI] [Google Scholar]
  • 35.Park JY, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH. Laparoscopic compared with open radical hysterectomy in obese women with early-stage cervical cancer. Obstet Gynecol. 2012;119(6):1201–9. Epub 2012/05/24. doi: 10.1097/AOG.0b013e318256ccc5 . [DOI] [PubMed] [Google Scholar]
  • 36.Park JY, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH. Laparoscopic versus open radical hysterectomy in patients with stage IB2 and IIA2 cervical cancer. J Surg Oncol. 2013;108(1):63–9. Epub 2013/06/06. doi: 10.1002/jso.23347 . [DOI] [PubMed] [Google Scholar]
  • 37.Bogani G, Cromi A, Uccella S, Serati M, Casarin J, Pinelli C, et al. Laparoscopic versus open abdominal management of cervical cancer: long-term results from a propensity-matched analysis. J Minim Invasive Gynecol. 2014;21(5):857–62. Epub 2014/04/05. doi: 10.1016/j.jmig.2014.03.018 . [DOI] [PubMed] [Google Scholar]
  • 38.Chen CH, Chiu LH, Chang CW, Yen YK, Huang YH, Liu WM. Comparing robotic surgery with conventional laparoscopy and laparotomy for cervical cancer management. Int J Gynecol Cancer. 2014;24(6):1105–11. Epub 2014/06/14. doi: 10.1097/IGC.0000000000000160 . [DOI] [PubMed] [Google Scholar]
  • 39.Yin XH, Wang ZQ, Yang SZ, Jia HY, Shi M. Clinical observation of laparoscopic radical hysterectomy for cervical cancer. Int J Clin Exp Med. 2014;7(5):1373–7. Epub 2014/07/06.. [PMC free article] [PubMed] [Google Scholar]
  • 40.Asciutto KC, Kalapotharakos G, Löfgren M, Högberg T, Borgfeldt C. Robot-assisted surgery in cervical cancer patients reduces the time to normal activities of daily living. Acta Obstetricia et Gynecologica Scandinavica. 2015;94(3):260–5. doi: 10.1111/aogs.12561 [DOI] [PubMed] [Google Scholar]
  • 41.Xiao M, Zhang Z. Total Laparoscopic Versus Laparotomic Radical Hysterectomy and Lymphadenectomy in Cervical Cancer: An Observational Study of 13-Year Experience. Medicine (Baltimore). 2015;94(30):e1264. Epub 2015/07/30. doi: 10.1097/MD.0000000000001264 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Park JY, Kim D, Suh DS, Kim JH, Kim YM, Kim YT, et al. The Role of Laparoscopic Radical Hysterectomy in Early-Stage Adenocarcinoma of the Uterine Cervix. Ann Surg Oncol. 2016;23(Suppl 5):825–33. Epub 2016/08/10. doi: 10.1245/s10434-016-5489-4 . [DOI] [PubMed] [Google Scholar]
  • 43.Shah CA, Beck T, Liao JB, Giannakopoulos NV, Veljovich D, Paley P. Surgical and oncologic outcomes after robotic radical hysterectomy as compared to open radical hysterectomy in the treatment of early cervical cancer. J Gynecol Oncol. 2017;28(6):e82. Epub 2017/10/14. doi: 10.3802/jgo.2017.28.e82 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Corrado G, Vizza E, Legge F, Pedone Anchora L, Sperduti I, Fagotti A, et al. Comparison of Different Surgical Approaches for Stage IB1 Cervical Cancer Patients: A Multi-institution Study and a Review of the Literature. Int J Gynecol Cancer. 2018;28(5):1020–8. Epub 2018/05/05. doi: 10.1097/IGC.0000000000001254 . [DOI] [PubMed] [Google Scholar]
  • 45.Guo J, Yang L, Cai J, Xu L, Min J, Shen Y, et al. Laparoscopic procedure compared with open radical hysterectomy with pelvic lymphadenectomy in early cervical cancer: a retrospective study. Onco Targets Ther. 2018;11:5903–8. Epub 2018/10/03. doi: 10.2147/OTT.S156064 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Bogani G, Rossetti D, Ditto A, Martinelli F, Chiappa V, Leone C, et al. Minimally invasive surgery improves short-term outcomes of nerve-sparing radical hysterectomy in patients with cervical cancer: a propensity-matched analysis with open abdominal surgery. J Gynecol Oncol. 2019;30(2):e27. Epub 2019/02/12. doi: 10.3802/jgo.2019.30.e27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Matanes E, Abitbol J, Kessous R, Kogan L, Octeau D, Lau S, et al. Oncologic and Surgical Outcomes of Robotic Versus Open Radical Hysterectomy for Cervical Cancer. Journal of Obstetrics and Gynaecology Canada. 2019;41(4):450–8. doi: 10.1016/j.jogc.2018.09.013 [DOI] [PubMed] [Google Scholar]
  • 48.Piedimonte S, Czuzoj-Shulman N, Gotlieb W, Abenhaim HA. Robotic Radical Hysterectomy for Cervical Cancer: A Population-Based Study of Adoption and Immediate Postoperative Outcomes in the United States. J Minim Invasive Gynecol. 2019;26(3):551–7. Epub 2018/09/09. doi: 10.1016/j.jmig.2018.08.012 . [DOI] [PubMed] [Google Scholar]
  • 49.Pahisa J, Martinez-Roman S, Torne A, Fuste P, Alonso I, Lejarcegui JA, et al. Comparative study of laparoscopically assisted radical vaginal hysterectomy and open Wertheim-Meigs in patients with early-stage cervical cancer: eleven years of experience. Int J Gynecol Cancer. 2010;20(1):173–8. Epub 2010/02/05. doi: 10.1111/IGC.0b013e3181bf80ee . [DOI] [PubMed] [Google Scholar]
  • 50.Morgan DJ, Hunter DC, McCracken G, McClelland HR, Price JH, Dobbs SP. Is laparoscopically assisted radical vaginal hysterectomy for cervical carcinoma safe? A case control study with follow up. Bjog. 2007;114(5):537–42. Epub 2007/03/16. doi: 10.1111/j.1471-0528.2007.01291.x . [DOI] [PubMed] [Google Scholar]
  • 51.Zakashansky K, Chuang L, Gretz H, Nagarsheth NP, Rahaman J, Nezhat FR. A case-controlled study of total laparoscopic radical hysterectomy with pelvic lymphadenectomy versus radical abdominal hysterectomy in a fellowship training program. International Journal of Gynecological Cancer. 2007;17(5):1075–82. doi: 10.1111/j.1525-1438.2007.00921.x WOS:000249487500019. [DOI] [PubMed] [Google Scholar]
  • 52.Nam JH, Park JY, Kim DY, Kim JH, Kim YM, Kim YT. Laparoscopic versus open radical hysterectomy in early-stage cervical cancer: long-term survival outcomes in a matched cohort study. Ann Oncol. 2012;23(4):903–11. Epub 2011/08/16. doi: 10.1093/annonc/mdr360 . [DOI] [PubMed] [Google Scholar]
  • 53.Ditto A, Martinelli F, Bogani G, Gasparri ML, Di Donato V, Zanaboni F, et al. Implementation of laparoscopic approach for type B radical hysterectomy: a comparison with open surgical operations. Eur J Surg Oncol. 2015;41(1):34–9. Epub 2014/12/04. doi: 10.1016/j.ejso.2014.10.058 . [DOI] [PubMed] [Google Scholar]
  • 54.Yuan Z, Cao D, Yang J, Yu M, Shen K, Yang J, et al. Laparoscopic vs. Open Abdominal Radical Hysterectomy for Cervical Cancer: A Single-Institution, Propensity Score Matching Study in China. Front Oncol. 2019;9:1107. Epub 2019/11/19. doi: 10.3389/fonc.2019.01107 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Lee CL, Huang KG, Jain S, Lee PS, Soong YK. Comparison of laparoscopic and conventional surgery in the treatment of early cervical cancer. J Am Assoc Gynecol Laparosc. 2002;9(4):481–7. Epub 2002/10/19. doi: 10.1016/s1074-3804(05)60523-3 . [DOI] [PubMed] [Google Scholar]
  • 56.Lim YK, Chia YN, Yam KL. Total laparoscopic Wertheim’s radical hysterectomy versus Wertheim’s radical abdominal hysterectomy in the management of stage I cervical cancer in Singapore: a pilot study. Singapore Med J. 2013;54(12):683–8. Epub 2013/12/21. doi: 10.11622/smedj.2013242 . [DOI] [PubMed] [Google Scholar]
  • 57.Campos LS, Limberger LF, Stein AT, Kalil AN. Postoperative pain and perioperative outcomes after laparoscopic radical hysterectomy and abdominal radical hysterectomy in patients with early cervical cancer: a randomised controlled trial. Trials. 2013;14. doi: 10.1186/1745-6215-14-293 WOS:000325490500001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Llarena NC, Shah AB, Milad MP. Bowel injury in gynecologic laparoscopy: a systematic review. Obstet Gynecol. 2015. Jun;125(6):1407–1417. doi: 10.1097/AOG.0000000000000855 Erratum in: Obstet Gynecol. 2015 Oct;126(4):903. . [DOI] [PubMed] [Google Scholar]
  • 59.van der Voort M, Heijnsdijk EA, Gouma DJ. Bowel injury as a complication of laparoscopy. Br J Surg. 2004. Oct;91(10):1253–8. doi: 10.1002/bjs.4716 . [DOI] [PubMed] [Google Scholar]
  • 60.Ott DE. Subcutaneous emphysema—beyond the pneumoperitoneum. JSLS. 2014. Jan-Mar;18(1):1–7. Erratum in: JSLS. 2016 Apr-Jun;20(2). pii: e2016.00050. doi: 10.4293/108680813X13693422520882 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Liang C, Liu P, Cui Z, Liang Z, Bin X, Lang J, et al. Effect of laparoscopic versus abdominal radical hysterectomy on major surgical complications in women with stage IA-IIB cervical cancer in China, 2004–2015. Gynecol Oncol. 2020;156(1):115–23. Epub 2019/12/07. doi: 10.1016/j.ygyno.2019.10.032 . [DOI] [PubMed] [Google Scholar]
  • 62.Chong GO, Park NY, Hong DG, Cho YL, Park IS, Lee YS. Learning curve of laparoscopic radical hysterectomy with pelvic and/or para-aortic lymphadenectomy in the early and locally advanced cervical cancer: comparison of the first 50 and second 50 cases. Int J Gynecol Cancer. 2009. Nov;19(8):1459–64. doi: 10.1111/IGC.0b013e3181b76640 . [DOI] [PubMed] [Google Scholar]
  • 63.Yim GW, Kim SW, Nam EJ, Kim S, Kim YT. Learning curve analysis of robot-assisted radical hysterectomy for cervical cancer: initial experience at a single institution. J Gynecol Oncol. 2013. Oct;24(4):303–12. doi: 10.3802/jgo.2013.24.4.303 Epub 2013 Oct 2. . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Hwang JH. Urologic complication in laparoscopic radical hysterectomy: meta-analysis of 20 studies. Eur J Cancer. 2012;48(17):3177–85. Epub 2012/07/25. doi: 10.1016/j.ejca.2012.06.006 . [DOI] [PubMed] [Google Scholar]
  • 65.Park DA, Yun JE, Kim SW, Lee SH. Surgical and clinical safety and effectiveness of robot-assisted laparoscopic hysterectomy compared to conventional laparoscopy and laparotomy for cervical cancer: A systematic review and meta-analysis. Eur J Surg Oncol. 2017;43(6):994–1002. Epub 2016/08/23. doi: 10.1016/j.ejso.2016.07.017 . [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Antonio Simone Laganà

26 Feb 2021

PONE-D-20-33497

Complications of surgical treatments for early-stage cervical cancer: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Antonio Simone Laganà, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

The topic of the manuscript is interesting. Nevertheless, the reviewers raised several concerns: considering this point, I invite authors to perform the required major revisions.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I was pleased to revise the manuscript entitled “Complications of surgical treatments for early-stage cervical cancer: a systematic review and meta-analysis” (Manuscript Number: PONE-D-20-33497).

In my honest opinion, the topic is interesting enough to attract the readers’ attention. Nevertheless, authors should clarify different points.

In general, the Manuscript may benefit from some major revisions, as suggested below:

- All the text needs a minor language revision in order to improve readability, some typos and grammatical errors.

- Title. I would suggest revising the title to provide more details regarding the review aim. If you are focusing on a comparison between MIS and open surgery, it have to be clear in the title.

- Abstract. I would suggest improving the method section of the abstract providing the inclusion criteria following the PICO system. The present form is too generic.

- The introduction regarding the surgical approach for cervical cancer is not update. After the LACC trial, it was clearly demonstrated that MIS for cervical cancer is associated with worse overall survival. Therefore, discussing the surgical morbidity have to be done clarifying better the actual role of MIS in cervical cancer.

- Methods. Search strategy and study selection should be improved. Line 99 is conflicting with lines 111-112. I would suggest reporting the study selection following the PICO system.

- Methods. Was a third investigator involved in the case of disagreement.

- Methods. How were the type of complications defined?

- Results, I would suggest providing some data regarding the absolute risk difference and not only the OR. If it is not possible in results. I would suggest discussing this point in the discussion. A change in risk from 10 to 20% and from 0.01 to 0.02 have the same OR but completely different clinical meaning.

- Data regarding the pooled cumulative incidence of complications should be provided.

- Jadad scale in Table 1 is not reported in the study’s methods.

- Lines 314-317. I would suggest provided references supporting the statements.

- Regarding study limitations, how complications were classified and standardized for this review should be clearly reported to allow reproducibility.

- I would suggest discussing better the concept regarding the pooling of studies with completely different study designs.

- The main concern regarding the current review is the background, which is completely out of the more recent literature regarding surgical approach for cervical cancer. This required extensive improvement. Refer to: PMID: 30380365; PMID: 32320800

Reviewer #2: The title of this manuscript does not well represent the topic—this is specifically a comparison of complications between minimally invasive and open surgical treatments for cervical cancer.

Why did the authors choose to focus only on studies that compare the two (or three) surgical methods and exclude case series? Given that only one study was randomized, it seems that they would have had a much larger number of articles without losing substantial rigor.

It would be helpful to ground more general readers into the stage at which women would be candidates for surgical treatment, and how that may differ in LMICs compared to HICs where there are more resources available for radiation.

Line 87: The aim of the meta-analysis was to compare the published rates of common intra-operative and post-operative complications.

Was there a reason that the authors did not abstract the disease stage? Was this not presented in the published studies?

Line 169: What does BMI mean in this context? Do you mean that in some studies, median BMI was reported vs mean vs no BMI description?

Lines 213-217: This needs to be worded more clearly, as the authors are stating that there is an increased odds of aggregate fistula formation, but when disaggregated, the odds of formation of individual fistula types were not increased, likely due to the small numbers in each category. The word “overall” in line 216 is confusing.

Discussion:

The second sentence in the discussion states that the authors aimed to offer new opinions for prognostic indicators in MIS—this was not described in the methods and none of the results would suggest prognostic indicators were evaluated.

Line 281: would change that sentence to read that intestinal obstruction is often related to abdominal adhesions, which are more likely to form after abdominal surgery. I would avoid the phrase “indirectly proved.”

Lines 297-302: There was no difference in fistula rates between ORH and MIS. Given the low numbers of fistulas seen overall, I would avoid making the over-conclusions that the authors may be doing in lines 298-302.

I would suggest that the entire paragraph 284-302 can be combined with the preceding two paragraphs, preferably the urinary complication paragraph. The second sentence, describing the incidence of complications as depending on the surgeon’s skills, is general to all of the complications, not just fistula formation.

Additional limitations that were not described include the lack of data on the surgeon level or years of experience, and additional patient morbidities (in addition to prior surgeries).

Table 2 needs a more descriptive title.

Figure 1: Include the reasons that articles were excluded and the #s per reason at the abstract and full-text stage in the flowchart.

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Reviewer #1: No

Reviewer #2: No

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Decision Letter 1

Antonio Simone Laganà

31 May 2021

Comparison of the complications between minimally invasive surgery and open surgical treatments for early-stage cervical cancer: a systematic review and meta-analysis

PONE-D-20-33497R1

Dear Dr. Wang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Antonio Simone Laganà, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Authors performed the required corrections, which were positively evaluated by the reviewers. I am pleased to accept this paper for publication.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In the new version of the manuscript, authors addressed all recommended revisions, and I appreciated the manuscript improvement.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Acceptance letter

Antonio Simone Laganà

21 Jun 2021

PONE-D-20-33497R1

Comparison of the complications between minimally invasive surgery and open surgical treatments for early-stage cervical cancer: a systematic review and meta-analysis

Dear Dr. Wang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Antonio Simone Laganà

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. PRISMA 2009 checklist.

    (DOC)

    Click here for additional data file. (64.5KB, doc)
    S1 Fig. PRISMA 2009 flow diagram.

    (DOC)

    Click here for additional data file. (57.5KB, doc)
    S1 Table. Detailed search strategy.

    (DOC)

    Click here for additional data file. (51KB, doc)
    S2 Table. Quality assessment of the included studies according to modified NOS score.

    (DOC)

    Click here for additional data file. (22.6KB, doc)
    S3 Table. Quality assessment of the included studies according to modified Jadad score.

    (DOC)

    Click here for additional data file. (15.1KB, doc)
    S4 Table. The subgroup analysis of fistula types between MIS and ORH.

    (DOC)

    Click here for additional data file. (33KB, doc)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (445.7KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

    Articles from PLoS ONE are provided here courtesy of PLOS

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