Choosing the most appropriate minimally invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: Insights from a comprehensive cancer center.

OBJECTIVE: The aim of the study was to compare the characteristics of procedures for gynecologic cancers conducted with conventional laparoscopy (CL) or robotically assisted laparoscopy (RAL) in the context of an enhanced recovery program (ERP).
METHODS: This is a secondary analysis of prospectively collected data from a cohort study conducted between 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) and 2018. We included patients who had undergone minimally invasive surgery for gynecological cancers and followed our ERP. The endpoints were the analysis of postoperative complications, the length of postoperative hospitalization (LPO), and the proportion of combined procedures depending on the approach (RAL or CL). Combined procedures were defined by the association of at least two of the following operative items: hysterectomy, pelvic lymphadenectomy, and para-aortic lymphadenectomy.
RESULTS: A total of 362 women underwent either CL (n = 187) or RAL (n = 175) for gynecologic cancers and followed our ERP. The proportion of combined procedures performed by RAL was significantly higher (85/175 [48.6%]) than that performed by CL (23/187 [12.3%]; p < 0.001). The proportions of postoperative complications were similar between the two groups (19.4% versus 17.1%; p = 0.59). Logistic regression analysis revealed a statistically insignificant trend in the association of RAL with a reduced likelihood of an LPO > 3 days after adjusting for predictors of prolonged hospitalization (adjusted OR = 0.573 [0.236-1.388]; p = 0.217).
CONCLUSION: Experts from our cancer center preferentially choose RAL to perform gynecologic oncological procedures that present elements of complexity. More studies are needed to determine whether this strategy is efficient in managing complex procedures in the framework of an ERP.

Introduction

Over the past two decades, the implementation of enhanced recovery programs (ERPs) worldwide has allowed physicians to re-evaluate and improve the management of patients who undergo surgery [1,2]. The main goal of an ERP is to create an optimal, standardized environment for surgery to improve patient recovery. Decreasing hospitalization length without increasing the complication and readmission rates is the primary goal of this improvement [1,3]. The benefit of ERPs is well established for many types of surgeries [2], including gynecologic oncological surgery [4-6].

Minimally invasive surgery (MIS) has been the most important surgical innovation in the past three decades. Its widespread implementation has allowed drastic reductions in length of stay and postoperative morbidity compared with that of open surgery for many procedures, including those related to gynecologic cancers [7-9]. Robotic-assisted laparoscopy (RAL) enables a greater adoption of MIS by supporting the ability to perform complex procedures that were previously restricted to surgeons with advanced laparoscopic skills. However, the benefits of RAL in improving surgical quality and patient health in comparison to conventional laparoscopy (CL) are still debated for most procedures [9]. In addition, RAL generates higher costs, and many MIS expert centers are still compelled to use both CL and RAL to manage hospital expenditures. There are no studies in the scientific literature that specifically assess the value of RAL in comparison to CL in the context of an ERP.

In a previous study, we determined predictors of successful early hospital discharge in the context of our ERP [10]. Combined procedures (e.g., the association of at least two procedures) and overweight were found to be associated with a prolonged length of postoperative hospitalization (LPO). The aim of the present study was to describe and compare the characteristics of procedures for gynecologic cancers that were performed with either CL or RAL in our unit in the context of an ERP.

Materials and methods

Study design

This was a secondary analysis of prospectively collected data from a cohort study conducted between January 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) and September 2018. All women over 18 years of age who required gynecologic surgery at the Institut Paoli-Calmette during the study period followed our ERP. They were informed of the study during their first consultation and were asked to provide written consent for the storage and use of their data. The study was approved by our ethical committee (Paoli-Calmettes Institute’s review board, RAAC-IPC-2016-011/NCT03950011). All data were prospectively and anonymously collected in the Database for Data Collection in the Context of an Enhanced Recovery After Surgery Program in Oncology Surgery (BDD RAAC).

Our institutional ERP was published in 2017 [4] and is in accordance with the latest published recommendations [5,11-14]. The main pathways of the ERP are summarized in Fig 1. Consecutive patients undergoing minimally invasive procedures (hysterectomy and/or pelvic or para-aortic lymphadenectomy) either by RAL or CL for gynecologic cancers (cervical, endometrial or ovarian cancer) were identified. We excluded patients who underwent surgery for benign indications and patients for whom a laparotomy was indicated. RALs were performed either with a da Vinci Xi® or a da Vinci Si® surgical system (Intuitive Surgical Inc. Sunnyvale, California, United States), and CLs were performed with a basic IMAGE1 S™ set (Karl Storz Endoskope SE & Co. KG, Tuttlingen, Germany).

Fig 1

Summary of the Institut Paoli-Calmettes enhanced recovery program.

All procedures were performed by four senior surgeons. In the context of the ERP, the choice of MIS was determined for each case according to what was feasible with consideration of the type of cancer, tumor stage and patient’s comorbidities. As access to the robotic platform was limited, the choice between RAL and CL also took into consideration the availability of the platform.

The following parameters were analyzed: age, BMI, American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index score [15], oncological indication, surgical procedure, surgical approaches and LPO (defined as nights spent at hospital after surgery, excluding the night before the surgery). The exclusion criteria were surgery for benign indications and open surgery procedures. After discharge, a postoperative nurse coordinator conducted phone call interviews on days 1, 7 and 30 to record all occurrences of readmission to other hospitals and/or long-term postoperative complications. Per- and postoperative complications were collected according to the Clavien-Dindo classification [16].

All procedures in this study involving human participants were performed in accordance with the French ethical standards and with the 2008 Helsinki declaration. All included patients provided written informed consent before surgery. This work was approved by the institutional review board of the hospital (Institut Paoli-Calmettes Comité d'Orientation Stratégique).

Statistical analysis

Categorical variables are described using counts and frequencies, and quantitative variables are described using medians and 95% confidence intervals (95% CIs). The characteristics of patients who underwent CL or RAL were compared using χ2 tests for discrete variables and two-sample t-tests for continuous variables. To compare the likelihood of a prolonged hospitalization (LPO > 3 days) between the RAL and CL procedures, we conducted a logistic regression analysis, integrating predictors that were previously established by our team [10]: age > 70 years, overweight and obesity, ASA score > 2, combined procedures and radical hysterectomies. The results were reported as adjusted odds ratios (ORs) with 95% confident intervals (95% CIs) and p values.

Procedures were categorized as ‘isolated’ (hysterectomy [± omentectomy] or pelvic lymphadenectomy or para-aortic lymphadenectomy) or ‘combined’ (association of two or more different procedures).

The level of statistical significance was set at α = 0.05. Statistical analyses were carried out using SPSS® software version 24. We followed the reporting recommendations specified in the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) Statement.

Results

Characteristics of the study population

A total of 540 patients underwent surgery and followed our ERP during the study period (Fig 2). We excluded 178 patients who either underwent laparotomy (n = 97, including 12 for benign indications) and/or had surgery for benign indications (n = 93). Thus, a total of 362 patients were included in the final analysis (that is, 362/447 [81%] of patients with malignant indications underwent MIS). A total of 187 patients underwent CL, and 175 patients underwent RAL. The percentage of procedures performed using RAL over time is presented in Fig 3. Baseline characteristics are summarized in Table 1. The overall compliance rate with the ERP criteria was 90% (previously published data [4]). The populations of patients who underwent CL and RAL were comparable in terms of Charlson Comorbidity Index score (p = 0.126), ASA score (p = 0.216) and oncological indication (p = 0.216). Patients who underwent RAL were significantly older (61.0 years [58.7–62.9] vs. 57 years [54.8–58.8]; p = 0.006) and had a higher median BMI (25.0 kg/m2 [25.9–28.1] vs. 24.1 kg/m2 [24.6–26.4]; p = 0.044) than patients who underwent CL. The proportion of combined procedures performed by RAL was significantly higher than that performed by CL (RAL: 85/175 [48.6%]; CL: 23/187 [12.3%]; p < 0.001).

Fig 2

Subject disposition (CONSORT flow diagram).

a Overall population was represented by those women who followed the enhanced recovery program between January 2016 and September 2018 b 12 Women underwent laparotomy for benign indications.

Fig 3

Percentage of minimally invasive procedures performed by conventional laparoscopy and robotically assisted laparoscopy over time.

Table 1

Patient characteristics at baseline and surgical procedures.

Characteristics		Total N = 362	Conventional Laparoscopy N = 187	Robotically assisted laparoscopy N = 175	p-value
Age, years, median (95% CI)		59.0 (57.3–60.2)	57.0 (54.8–58.8)	61.0 (58.7–62.9)	0.006**
BMI, kg/m2, median (95% CI)		24.6 (25.5–27.0)	24.1 (24.6–26.4)	25.0 (25.9–28.1)	0.044*
ASA score, median (95% CI)		2.0 (1.9–2.0)	2.0 (1.8–2.0)	2.0 (1.9–2.0)	0.216
Charlson score, median (95% CI)		0.0 (0.3–0.5)	0.0 (0.2–0.5)	0.0 (0.3–0.7)	0.126
Isolated procedures, n (%)		254 (70.2%)	164 (87.7%)	90 (51.4%)	< 0.001**
	Total Hysterectomy (± omentectomy)	133 (36.7%)	71 (38.0%)	62 (35.4%)	0.663
	Pelvic lymphadenectomy	24 (6.6%)	15 (8.0%)	9 (5.1%)	0.187
	Para-aortic lymphadenectomy	97 (26.8%)	78 (41.7%)	19 (10.9%)	<0.001**
Combined proceduresa, n (%)		108 (29.8%)	23 (12.3%)	85 (48.6%)	< 0.001**
	Total hysterectomy and pelvic lymphadenectomy	55 (15.2%)	10 (5.3%)	45 (25.7%)	< 0.001**
	Radical hysterectomy and pelvic lymphadenectomy	13 (3.6%)	1 (0.5%)	12 (6.9%)	0.001**
	Pelvic and para-aortic lymphadenectomy	6 (1.7%)	2 (1.1%)	4 (2.3%)	0.312
	Hysterectomy, pelvic and para-aortic lymphadenectomy	9 (2.5%)	1 (0.5%)	8 (4.6%)	0.014*
	Hysterectomy, pelvic and para-aortic lymphadenectomy and omentectomy	25 (6.9%)	9 (4.8%)	16 (9.1%)	0.078
Oncological indication, n (%)					0.216
	Cervical cancer	176 (49.0%)	99 (53.5%)	77 (44.3%)	0.055
	Endometrial cancer	153 (42.6%)	69 (37.3%)	84 (48.3%)	0.021
	Ovarian cancer	28 (7.8%)	16 (8.6%)	12 (6.9%)	0.343
	Uterine sarcoma	2 (0.6%)	1 (0.5%)	1 (0.6%)	0.743

*p-value<0.05

**p-value<0.01

aCombined procedures: association among two or more different procedures.

Abbreviations: BMI = Body Mass Index; ASA = American Society of Anesthesiologists; 95% CI = 95% Confidence Interval

Peri- and postoperative outcomes

The median operative time was longer for RAL (163 minutes [95% CI 170.9–193.5]) than for CL (137 minutes [140.2–161.6]; p < 0.001). The overall proportion of perioperative complications was 0.8% and was similar for both surgical approaches (p = 0.612) (Table 2). The rate of conversions to laparotomy was similar for the two approaches (1.1% for RAL vs. 4.3% for CL; p = 0.069). The median LPO was higher after RAL (2.0 days [1.8–2.2]) than after CL (1.0 day [1.4–1.9]; p = 0.027).

Table 2

Operative time, length of hospitalization, complications and readmissions.

Characteristics			Total N = 362	Conventional Laparoscopy N = 187	Robotically assisted laparoscopy N = 175	p-value
Operative time, minutes, median (95% CI)			150.0 (158.2–173.9)	137.0 (140.2–161.6)	163.0 (170.9–193.5)	< 0.001**
Conversions to laparotomy, n (%)			10 (2.8%)	8 (4.3%)	2 (1.1%)	0.069
Perioperative complications, n (%)			3 (0.8%)	1 (0.5%)	2 (1.1%)	0.612
Length of hospitalization after the operation, days, median (95% CI)			1.0 (1.7–2.0)	1.0 (1.4–1.9)	2.0 (1.8–2.2)	0.027*
Intensive care unit hospitalizations, n (%)			5 (1.4%)	2 (1.1%)	3 (1.7%)	0.676
Postoperative complications, n (%)			66 (18.2%)	32 (17.1%)	34 (19.4%)	0.588
	Hospital Readmissions		30 (8.3%)	15 (8.0%)	15 (8.6%)	0.851
	Complication severity (Clavien-Dindo classification), n (%)					0.577
		Stage I	15 (22.7%)	8 (25.0%)	7 (20.6%)	-
		Stage II	27 (40.9%)	11 (34.4%)	16 (47.1%)	-
		Stage III	23 (34.8%)	12 (37.5%)	11 (32.4%)	-
		Stage IV	1 (1.5%)	1 (3.1%)	0 (0.0%)	-
	Type of complication, n (%)					0.411
		Infectious	10 (15.2%)	3 (9.4%)	7 (20.6%)	-
		Scar complications	2 (3.0%)	2 (6.3%)	0 (0.0%)	-
		Digestive	6 (9.1%)	2 (6.3%)	4 (11.8%)	-
		Bleeding	10 (15.2%)	4 (12.5%)	6 (17.6%)	-
		Lymphatic	25 (37.9%)	15 (46.9%)	10 (29.4%)	-
		Neurologic	3 (4.5%)	1 (2.9%)	2 (6.3%)	-
		Urinary	7 (10.6%)	2 (6.3%)	5 (14.7%)	-
		Thromboembolic	1 (1.5%)	1 (3.1%)	0 (0.0%)	-
		Others	2 (3.0%)	1 (3.1%)	1 (2.9%)	-

95% CI = 95% Confidence Interval

* p-value < 0.05

** p-value < 0.01

Operative time

The operative time analyzed according to subgroups of procedures is shown in Table 3. Combined procedures were performed faster with RAL than with CL (229.0 minutes [213.2–245.3] vs. 269.0 minutes [234.2–331.4]; p = 0.008). The operative times were similar for isolated procedures for the two approaches (131.0 minutes [128.8–146.7] for RAL vs. 130.0 minutes [125.9–138.9] for CL; p = 0.338). There was no statistically significant difference for any of the procedures when analyzed individually.

Table 3

Operative time (minutes, median (95% CI)), analyzed by subgroups of procedures.

		Conventional laparoscopy	Robotically assisted laparoscopy	p-value
Isolated procedures		130.0 (125.9–138.9)	131.0 (128.8–146.7)	0.338
	Total hysterectomy	117.0 (115.9–136.0)	131.0 (124.3–147.3)	0.197
	Pelvic lymphadenectomy	130.0 (116.9–157.9)	147.0 (130.0–191.5)	0.160
	Para-aortic lymphadenectomy	139.0 (127.8–147.0)	129.0 (117.7–148.7)	0.689
Combined proceduresa		269.0 (234.2–331.4)	229.0 (213.2–245.3)	0.008**
	Total hysterectomy and pelvic lymphadenectomy	190.5 (158.7–246.9)	186.0 (177.1–210.2)	0.644
	Radical hysterectomy and pelvic lymphadenectomy	534.0	250.5 (236.8–277.1)	NS
	Pelvic and para-aortic lymphadenectomy	237.0	259.0 (175.0–342.0)	NS
	Hysterectomy, pelvic and para-aortic lymphadenectomy	248.0	236.5 (148.7–279.5)	NS
	Hysterectomy, pelvic and para-aortic lymphadenectomy and omentectomy	353.0 (291.6–424.2)	282.5 (266.3–351.3)	0.165

* p-value < 0.05

**p-value < 0.01

a Combined procedures: association among two or more different procedures. NS = Not statistically significant

Length of postoperative hospitalization

The LPO analyzed according to subgroups of procedures is shown in Table 4. For combined procedures, the median LPOs were similar for both approaches (2.0 days [1.7–5.0] for CL vs. 2.0 days [1.9–2.5] for RAL; p = 0.114). For isolated procedures (i.e., total hysterectomy, pelvic lymphadenectomy or para-aortic lymphadenectomy), the median LPO was significantly higher for RAL (2.0 days [1.6–2.1]) compared with CL (1.0 day [1.3–1.7]; p = 0.045). The median LPOs were similar in both groups for total hysterectomies (p = 0.391), pelvic lymphadenectomies (p = 0.105) and para-aortic lymphadenectomies (p = 0.661). For total hysterectomies with pelvic lymphadenectomies, LPO was significantly lower in the RAL group (2.0 days [1.4–1.9]) than in the CL group (2.0 days [1.3–4.0]; p = 0.007). The number of observations for the other combined procedures was too low to allow any reliable comparison of the LPO.

Table 4

Length of postoperative hospitalization (median (95% CI)), analyzed by subgroups of procedures.

		Conventional laparoscopy	Robotically assisted laparoscopy	p-value
Isolated procedures		1.0 (1.3–1.7)	2.0 (1.6–2.1)	0.045*
	Total hysterectomy	1.0 (1.4–2.0)	2.0 (1.5–2.2)	0.391
	Pelvic lymphadenectomy	1.0 (1.2–1.9)	2.0 (0.9–3.9)	0.105
	Para-aortic lymphadenectomy	1.0 (1.0–1.7)	1.0 (1.2–1.7)	0.661
Combined proceduresa		2.0 (1.7–5.0)	2.0 (1.9–2.5)	0.114
	Total hysterectomy and pelvic lymphadenectomy	2.0 (1.3–4.0)	2.0 (1.4–1.9)	0.007**
	Radical hysterectomy and pelvic lymphadenectomy	2.0	2.0 (1.9–3.2)	NS
	Pelvic and para-aortic lymphadenectomy	1.5	2.5 (1.2–4.3)	NS
	Hysterectomy, pelvic and para-aortic lymphadenectomy	2.0	1.5 (0.9–3.1)	NS
	Hysterectomy, pelvic and para-aortic lymphadenectomy and omentectomy	2.0 (0.7–6.4)	2.0 (2.0–4.7)	0.886

* p-value < 0.05

a Combined procedures: association among two or more different procedures. 95% CI = 95% confidence interval; NS = non-statistically significant.

Logistic regression analysis showed a statistically insignificant trend of RAL reducing the likelihood of an LPO > 3 days after adjusting for predictors of prolonged hospitalization (age > 70 years, overweight and obesity, ASA score > 2, combined versus isolated procedures and radical hysterectomies) (adjusted OR = 0.573 [0.236–1.388]; p = 0.217).

Discussion

In a previous study, we determined predictors of increased hospital stay in the context of an ERP [10]. The present study describes and compares the procedures that were performed by CL or by RAL over three years in our unit after the implementation of our ERP. Our results show that when expert surgeons from our unit have to choose between CL and RAL to treat gynecological cancers, they more frequently choose RAL to perform procedures that present elements of complexity (i.e., higher age, higher BMI and/or combined procedures). Consequently, the two groups (RAL and CL) are too different to allow a reliable comparison. This prevents us from firmly forming a conclusion on the effect of this strategy of choosing the surgical route on the LPO. Despite this major impediment, our study provides a hint on the value of RAL in managing complex patients and procedures. Indeed, the results of the logistic regression analysis, which took into account predictors of prolonged hospitalization, showed a statistically insignificant trend in the association of RAL with a reduced likelihood of an LPO greater than 3 days. Without statistical adjustment, the only subgroup that showed a significant reduction in the LPO for RAL compared to that for CL was the total hysterectomies with pelvic lymphadenectomies subgroup. The number of observations for the other combined procedures was too low to draw any reliable conclusions. Conversely, when used for isolated procedures, RAL seems to be significantly associated with an increased LPO compared to CL. These results, while broadly limited by the weak comparability of the groups, seem to support the idea that RAL is more profitable when used for more complex procedures and patients. The interpretation of the operative time is subject to the same limitations since we cannot take into account all the possible confounders related to the differences between the two populations. The operative time was decreased for combined procedures performed by RAL. For isolated procedures, however, the operative time was similar between the two approaches, suggesting that the increased LPO in patients that underwent isolated procedures could be attributable to other features of RAL (such as the number and width of incisions), or to other confounders (age, BMI).

Over three years, 81% of the gynecologic oncological procedures at our center were performed by minimally invasive techniques. Maintaining this high proportion of procedures performed by MIS is one of the key objectives of our ERP, as it allows drastic reductions in LPO. As with many MIS expert centers, we are compelled to use both CL and RAL to address both hospital expenditures and surgical equipment availability. Therefore, for each procedure, the surgical approach has to be carefully determined to safely reduce length of stay and morbidity and improve return to the intended oncological treatment.

There is abundant literature comparing RAL and CL for the management of gynecologic cancer [17]. However, the vast majority of studies are retrospective or historical control studies and report on a limited number of observations. The most robust evidence in favor of RAL concerns the surgical treatment of endometrial cancers, with several meta-analyses showing reduced rates of conversion to laparotomy and estimated blood loss but overall similar lengths of stay, operative times, complications and oncologic outcomes [18]. One randomized controlled trial with 101 patients compared RAL to CL for surgery related to endometrial cancer and found reduced operative time and rate of conversions to laparotomy with RAL. Length of stay and postoperative pain were similar between the two groups [19]. Studies investigating the surgical treatments of cervical and ovarian cancers are less consistent and have not demonstrated the superiority of RAL over CL [20-22]. Overall, the only consensus with regard to the management of gynecologic cancers using MIS is that MIS is superior to open surgery for peri- and early postoperative outcomes, although the noninferiority of MIS has recently been questioned with regard to long-term oncological outcomes, in particular for early-stage cervical cancers [23]. Furthermore, the literature tends to show that RAL can increase the utilization of MIS by improving learning curves compared with CL but is more costly than CL or open surgery [17,24-26].

The current literature evidence is weak, and randomized controlled studies should be conducted to set recommendations on the profitability of RAL for gynecologic oncological procedures.

The main strengths of our study are its prospective data collection, the standardized ERP that assures similar management for every patient, the thorough reporting of postoperative complications and the subgroup analysis by type of procedure rather than by type of cancer.

Our primary objective was to describe and compare the characteristics of procedures for gynecologic cancers that were performed with either CL or RAL in our unit. Although we determined that surgeons from our unit preferentially choose to use RAL to perform complex procedures, two major impediments prevented us from concluding whether this strategy is effective in reducing LPO. First, surgical approaches are clearly chosen by surgeons with the a priori belief of a better profitability of RAL for more complex procedures and patients. Consequently, we obtained two groups with very different features, which makes it difficult to compare outcomes. We attempted to overcome this bias by conducting a subgroup analysis and a logistic regression analysis. These analyses must be interpreted with the utmost precaution and cannot provide sufficient evidence for the recommendation of one surgical approach over the other regardless of complexity. Second, our study population presents with a high degree of heterogeneity since it includes patients suffering from different gynecological cancers. We chose to conduct our subgroup analysis by regrouping patients who underwent similar procedures rather than those with the same cancer localization. Although this method is suitable for analyzing the surgical complexity, it does not account for the specific difficulties associated with the surgical treatment of each cancer. Furthermore, our study focused mainly on the LPO, which is the easiest way to assess the efficiency of an ERP. However, it does not render the whole complexity of the treatment of gynecological cancers. Indeed, we did not reported data on oncological outcomes, such as relapse-free survival. The long-term quality of life is also missing from our reported data. In particular, we did not report any data on fertility preservation, which is strongly linked to the well-being of young patients suffering from gynecological cancers [27-31]. Thus, we cannot formally make conclusions on the profitability of each surgical approach and can only describe the elements that we used to decide which MIS technique will be used. Finally, the reproducibility of our findings is limited to MIS expert centers where surgeons have advanced skills in both RAL and CL.

In conclusion, experts from our cancer center preferentially choose RAL to perform gynecologic oncological procedures that present elements of complexity. With regard to technical and financial concerns, these results may suggest a dedicated role for RAL and CL in these clinical pathways. Additional studies are needed to confirm the value of this approach.

Clinical and surgical data.

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20 Feb 2020

PONE-D-20-01006

Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center

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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.

In addition, authors may consider the following comments:

- In light of the advanced techniques to detect early stage disease, to date it is mandatory to consider even the possibility of fertility-sparing approaches in order to preserve reproductive potential of women affected by gynecological cancers. I invite authors to discuss this point, referring to: PMID: 28868252; PMID: 28840513; PMID: 28188573.

- The management of women affected by gynecological cancers needs a particular attention even to the preservation of an appropriate quality of life and sexual function, which risk to be severely impaired by surgical/chemo/radio treatments. I would discuss this point, at least briefly, referring to: PMID: 28625095; PMID: 28275393.

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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: Yes

Reviewer #2: No

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

**********

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: Yes

Reviewer #2: No

**********

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: PONE-D-20-01006

In this article the authors tried to compare the characteristics of procedures for gynecologic cancers conducted with laparoscopy or robotic-assisted laparoscopy. Results showed that expert surgeons from the center preferentially choose robotic-assisted laparoscopy to perform complex gynecologic oncological procedures. The topic of this manuscript is interesting and falls within the scope of the journal. Moreover, the study methodology is well described, and the results are precisely presented.

Reviewer #2: I was pleased to revise the manuscript entitled “Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center” (Manuscript Number: PONE-D-20-01006).

The study was approved by the local Institutional Review Board and written informed consent was obtained from all patients enrolled in this study.

In general, this manuscript was aimed to compare the characteristics of procedures for gynecologic cancers conducted with conventional laparoscopy (CL) or robotic-assisted laparoscopy (RAL) in the context of an enhanced recovery program (ERP). In my honest opinion, the topic is interesting enough to attract the readers’ attention. Nevertheless, there are different methodological limits that impede conclusions. The manuscript presents different limits as reported below:

• All the text needs a language revision by a native English speaker person, in order to improve its readability.

• I would suggest checking the use of abbreviation, which should be reported in the extended form at the first use both in the abstract and manuscript and avoid abbreviation explanation.

• Abstract. Based on the abstract it is unclear the role of enhanced recovery program in the manuscript.

• Methods. I would suggest better clarifying the inclusion and exclusion criteria. Both for the prospective study and both for the population included in the analysis. It is unclear who was collected in the database.

• The results are a description of the population underwent minimally invasive surgery for gynecologic oncological disease at the Institut Paoli-Calmettes. The comparison between CL and RAL is strongly limited by the differences between women underwent one or the other surgical technique based primarily on the surgeon choice, which is based on the patient characteristics and required surgical procedure. More than a description of population characteristics is not possible considering these differences. The logistic regression shows this point, clarifying that other factors instead of the minimally invasive approach are actually cause of the observed differences.

• Discussion. Lines 218-223. This interpretation is unclear, particularly about the compliance with ERP. No comparison between before and after the introduction of ERP is provided. The results of logistic regression show how the observed differences between the two population are not related to the surgical approach but to other confounders.

• The interpretation of operative time is questionable if not corrected for all the possible confounders related to the difference between the two population.

• Line 259. Why should the observational design be a weakness?

• Study limits should be improved and better reported.

**********

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Reviewer #1: No

Reviewer #2: No

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29 Mar 2020

Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer

Response to reviewers

Dear Editor,

Please find below our answers to each reviewers’ questions and comments regarding the manuscript of our latest article entitled ‘Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center’. We are grateful to have the opportunity to submit this new and corrected version of the manuscript. Although we are fully aware that our study does not provide an absolute proof that robotic-assisted laparoscopy is superior to conventional laparoscopy to perform complex procedures, we are confident that our results will at the very least give new insights on this matter in the particular setting of an enhanced recovery program. We advocate that this study be seen as a kind of experience sharing well supported by figures. Our impression is that the use of robotic-assisted laparoscopy allows us to perform increasingly complex procedures while maintaining acceptable length of hospitalization and complication rates. Awareness of the respective profitability of conventional laparoscopy and robotic-assisted laparoscopy could allow surgeons to make an educated decision for the surgical route they will use for their patients.

Sincerely yours,

The Authors

Editor’s comments

PONE-D-20-01006

Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center

PLOS ONE

Dear Dr. Netter,

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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Antonio Simone Laganà, M.D., Ph.D.

Academic Editor

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Additional Editor Comments (if provided):

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.

In addition, authors may consider the following comments:

- In light of the advanced techniques to detect early stage disease, to date it is mandatory to consider even the possibility of fertility-sparing approaches in order to preserve reproductive potential of women affected by gynecological cancers. I invite authors to discuss this point, referring to: PMID: 28868252; PMID: 28840513; PMID: 28188573.

- The management of women affected by gynecological cancers needs a particular attention even to the preservation of an appropriate quality of life and sexual function, which risk to be severely impaired by surgical/chemo/radio treatments. I would discuss this point, at least briefly, referring to: PMID: 28625095; PMID: 28275393.

Response to the Editor: Editor is right, fertility preservation is now one of the major challenges in the management of women’s cancers. Our unit always discuss these issues for women of reproductive age and we consistently refer these patients to a fertility specialist prior to surgery. Obviously, it is always difficult to address the vast variety of topics linked to the field of gynecological cancers. Nevertheless, we acknowledge that this interesting point was missing from the discussion section. We modified the paragraph regarding the limitations of our study in the discussion:

Original sentence: Furthermore, we have not reported data on estimated blood loss, post-operative pain or oncological outcomes, as our report focused on the main objectives of the ERP (morbidity and length of stay).

Modified Sentence: Furthermore, our study focused mainly on the LPO which is the easiest way to assess the efficiency of an ERP. However, it does not render the whole complexity of the treatment of gynecological cancers. Indeed, we have not reported data on the oncological outcomes such as the relapse-free survival. The long-term quality of life is also missing from our reported data. In particular, we did not report any data on the fertility preservation which is strongly linked to the well-being of young patients suffering from gynecological cancers [27-31]. Thus, we cannot formally conclude on the profitability of each surgical approach, and can only describe the elements that we use to decide which MIS technique will be used.

27. Chiofalo B, Palmara V, Laganà AS, Triolo O, Vitale SG, Conway F, et al. Fertility Sparing Strategies in Patients Affected by Placental Site Trophoblastic Tumor. Curr Treat Options Oncol. 2017;18: 58. doi:10.1007/s11864-017-0502-0

28. Laganà AS, La Rosa VL, Rapisarda AMC, Platania A, Vitale SG. Psychological impact of fertility preservation techniques in women with gynaecological cancer. Ecancermedicalscience. 2017;11: ed62. doi:10.3332/ecancer.2017.ed62

29. Vitale SG, La Rosa VL, Rapisarda AMC, Laganà AS. The Importance of Fertility Preservation Counseling in Patients with Gynecologic Cancer. J Reprod Infertil. 2017;18: 261–263.

30. Vitale SG, Rossetti D, Tropea A, Biondi A, Laganà AS. Fertility sparing surgery for stage IA type I and G2 endometrial cancer in reproductive-aged patients: evidence-based approach and future perspectives. Updat Surg. 2017;69: 29–34. doi:10.1007/s13304-017-0419-y

31. Vitale SG, La Rosa VL, Rapisarda AMC, Laganà AS. Fertility preservation in women with gynaecologic cancer: the impact on quality of life and psychological well-being. Hum Fertil Camb Engl. 2018;21: 35–38. doi:10.1080/14647273.2017.1339365

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We ensured that our manuscript meets PLOS ONE’s style requirements, including for file naming.

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We added our IRB in the materials and methods section (RAAC-IPC-2016-011)

3. In your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a) the recruitment date range (month and year), b) a description of how participants were recruited, and c) descriptions of where participants were recruited and where the research took place.

We ensured that we provided the aforementioned details:

a) The recruitment date range was already written: “study from January 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) to September 2018.”

b and c) We modified the description of our recruitment methods:

Original sentence: All the patients who followed the ERP signed an informed consent form and the study was approved by our ethical committee

Modified sentence: All women over 18 years of age who required gynecologic surgery at the Institut Paoli-Calmette during the study period followed our ERP. They were informed of the study during their first consultation and were asked to provide written consent for the storage and use of their data. The study was approved by our ethical committee.

4. Thank you for stating the following in the Competing Interests section:

"I have read the journal's policy and the authors of this manuscript have the following competing interests:

Eric Lambaudie and Gilles Houvenaeghel are proctors for Intuitive Surgical.

Other authors have nothing to disclose."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

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We included our updated Competing Interests statement in our cover letter: “We have read the journal's policy and the authors of this manuscript have the following competing interests: Eric Lambaudie and Gilles Houvenaeghel are proctors for Intuitive Surgical. Other authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

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We ensured that we referred to Figure 3 in the manuscript: “The percentage of procedures performed using RAL over time is presented in Figure 3.”

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We included captions for our Supporting Information files at the end of the manuscript before the references:

Supporting information

S1 Dataset. Clinical and surgical data.

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: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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

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: Yes

Reviewer #2: No

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: PONE-D-20-01006

In this article the authors tried to compare the characteristics of procedures for gynecologic cancers conducted with laparoscopy or robotic-assisted laparoscopy. Results showed that expert surgeons from the center preferentially choose robotic-assisted laparoscopy to perform complex gynecologic oncological procedures. The topic of this manuscript is interesting and falls within the scope of the journal. Moreover, the study methodology is well described, and the results are precisely presented.

We thank Reviewer #1 for his kind remarks.

Reviewer #2: I was pleased to revise the manuscript entitled “Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center” (Manuscript Number: PONE-D-20-01006).

The study was approved by the local Institutional Review Board and written informed consent was obtained from all patients enrolled in this study.

In general, this manuscript was aimed to compare the characteristics of procedures for gynecologic cancers conducted with conventional laparoscopy (CL) or robotic-assisted laparoscopy (RAL) in the context of an enhanced recovery program (ERP). In my honest opinion, the topic is interesting enough to attract the readers’ attention. Nevertheless, there are different methodological limits that impede conclusions. The manuscript presents different limits as reported below:

1. All the text needs a language revision by a native English speaker person, in order to improve its readability.

At your request, we had the manuscript proofread by AJE scholar, we attach the certificate to the submission.

2. I would suggest checking the use of abbreviation, which should be reported in the extended form at the first use both in the abstract and manuscript and avoid abbreviation explanation.

Abbreviations:

CL = conventional laparoscopy

RAL = robotic-assisted laparoscopy

ERP = enhanced recovery program

LPO = post-operative length of hospitalization

MIS = minimally invasive surgery

We checked the use of abbreviation throughout the manuscript and did the required corrections.

3. Abstract. Based on the abstract it is unclear the role of enhanced recovery program in the manuscript.

We agree with Reviewer #2 this was insufficiently explained in the abstract. We modified accordingly:

Original sentence: This is a secondary analysis of prospectively collected data at a comprehensive cancer center between 2016 and 2018. We included patients that underwent minimally-invasive surgery for gynecological cancers.

Modified sentence: This is a secondary analysis of prospectively collected data from a cohort study conducted between 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) and 2018. We included patients that underwent minimally-invasive surgery for gynecological cancers and followed our ERP.

4. Methods. I would suggest better clarifying the inclusion and exclusion criteria. Both for the prospective study and both for the population included in the analysis. It is unclear who was collected in the database.

Reviewer #2 is right, our recruitment method was insufficiently explained. We actually conducted a secondary analysis of prospectively collected data (as mentioned in the abstract) from a prospective cohort study in which every patient undergoing surgery for a gynecological cancer is included within the framework of our ERP since January 2016. We modified the “study design” section accordingly:

Original sentences: We conducted a prospective observational study from January 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) to September 2018. All the patients who followed the ERP signed an informed consent form and the study was approved by our ethical committee

Modified sentences: This was a secondary analysis of prospectively collected data from a cohort study conducted between January 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) and September 2018. All women over 18 years of age who required gynecologic surgery at the Institut Paoli-Calmette during the study period followed our ERP. They were informed of the study during their first consultation and were asked to provide written consent for the storage and use of their data. The study was approved by our ethical committee

Original sentence: Consecutive patients undergoing minimally invasive procedures (hysterectomy and/or pelvic or para-aortic lymphadenectomy), either by RAL or CL, for gynecologic cancers (cervical, endometrial or ovarian cancer) were identified.

Modified sentence: Consecutive patients undergoing minimally invasive procedures (hysterectomy and/or pelvic or para-aortic lymphadenectomy), either by RAL or CL, for gynecologic cancers (cervical, endometrial or ovarian cancer) were identified. We excluded patients who underwent surgery for benign indications and patients for whom a laparotomy was indicated.

5. The results are a description of the population underwent minimally invasive surgery for gynecologic oncological disease at the Institut Paoli-Calmettes. The comparison between CL and RAL is strongly limited by the differences between women underwent one or the other surgical technique based primarily on the surgeon choice, which is based on the patient characteristics and required surgical procedure. More than a description of population characteristics is not possible considering these differences. The logistic regression shows this point, clarifying that other factors instead of the minimally invasive approach are actually cause of the observed differences.

Reviewer #2 is right. Our study is only a description of our current surgical practice and an attempt to determine if it is efficient in the context of our ERP. Our conclusion is that the surgeons from our unit preferentially choose RAL over CL to perform more complex procedures. Although this conclusion is well supported by our results, we acknowledge that we were somehow too liberal when suggesting in the discussion that RAL was superior to CL too perform complex procedure. Therefore we tried to attenuate the interpretation of our results throughout the manuscript to clarify that we cannot conclude on the superiority of one route or the other for complex procedures.

Abstract:

Original sentence: The logistic regression analysis that adjusted for predictors of prolonged hospitalization suggested that the use of RAL reduced the likelihood of a LPO > 3 days (Adjusted OR = 0.573 [0.236–1.388]; p = 0.217).

Modified sentence: The logistic regression analysis that adjusted for predictors of prolonged hospitalization revealed a non-statistically significant trend in favor of RAL being associated to a reduced likelihood of a LPO > 3 days (Adjusted OR = 0.573 [0.236–1.388]; p = 0.217).

Original sentence: This seems to be efficient, in the context of our ERP, to maintain acceptable LPO and complication rate even for more complex procedures.

Modified sentence: More studies are needed to determine whether this strategy is efficient to manage complex procedures in the framework of an ERP.

Discussion:

Original paragraph: Although their choice is more intuitive and experienced-based than properly supported by scientific evidences, it seems to comply with the objectives of our ERP. Indeed, the results of the logistic regression analysis taking into account predictors of a prolonged hospitalization showed a non-statistically significant trend in favor of RAL reducing the likelihood of a LPO superior to 3 days. Conversely, when used for isolated procedures RAL significantly increases the LPO compared to CL. The operative time for isolated procedures was, however, similar for the two approaches, suggesting that the increased LPO is attributable to other features of RAL, such as the number and width of incisions. For combined procedures, there was a non-significant statistical trend in favor of RAL reducing LPO. Operative time was also decreased for combined procedures performed by RAL. Subgroup analysis of total hysterectomies with pelvic lymphadenectomies showed a significant reduction of LPO for RAL compared to CL. The number of observations for the other combined procedures were too low to draw any reliable conclusions.

Modified paragraph: As a consequence, the two groups (RAL and CL) are too different to allow a reliable comparison. This prevents us from firmly concluding on the influence of this strategy of choosing the surgical route on the LPO. Despite this major impediment, our study gives us a hint on the value of RAL to manage complex patients and procedures. Indeed, the results of the logistic regression analysis taking into account predictors of a prolonged hospitalization showed a non-statistically significant trend in favor of RAL being associated to a reduced likelihood of a LPO superior to 3 days. Without statistical adjustment, the only subgroup that showed a significant reduction of LPO for RAL compared to CL was the total hysterectomies with pelvic lymphadenectomies subgroup. The number of observations for the other combined procedures were too low to draw any reliable conclusions. Conversely, when used for isolated procedures RAL seems to be significantly associated with an increased LPO compared to CL. These results brought together, while broadly limited by the weak comparability of the groups, seem to support the fact that RAL is more profitable when used for more complex procedures and patients. The interpretation of the operative time is subject to the same limitations since we cannot take into account all the possible confounders related to the differences between the two populations. The operative time was decreased for combined procedures performed by RAL. For isolated procedures it was, however, similar for the two approaches, suggesting that the increased LPO in this subgroup could be attributable to other features of RAL (such as the number and width of incisions). or to other confounders (age, BMI).

Conclusion

Sentence deleted: This seems to be efficient, in the context of our ERP, to maintain acceptable LPO and complication rate even for more complex procedures.

6. Discussion. Lines 218-223. This interpretation is unclear, particularly about the compliance with ERP. No comparison between before and after the introduction of ERP is provided. The results of logistic regression show how the observed differences between the two population are not related to the surgical approach but to other confounders.

Reviwer #2 is right, with this study design we cannot conclude on whether RAL is of any help for our ERP. We modified accordingly:

Original sentence: Although their choice is more intuitive and experienced-based than properly supported by scientific evidences, it seems to comply with the objectives of our ERP. Indeed, the results of the logistic regression analysis taking into account predictors of a prolonged hospitalization showed a non-statistically significant trend in favor of RAL reducing the likelihood of a LPO superior to 3 days.

Modified sentence: As a consequence, the two groups (RAL and CL) are too different to allow a reliable comparison. This prevents us from firmly concluding on the influence of this strategy of choosing the surgical route on the LPO. Despite this major impediment, our study gives us a hint on the value of RAL to manage complex patients and procedures. Indeed, the results of the logistic regression analysis taking into account predictors of a prolonged hospitalization showed a non-statistically significant trend in favor of RAL being associated to a reduced likelihood of a LPO superior to 3 days.

7. The interpretation of operative time is questionable if not corrected for all the possible confounders related to the difference between the two population.

This is absolutely true, however, our results show that isolated procedures were performed with similar operative time with RAL and CL despite the population of the RAL group presenting more elements of surgical complexity (BMI, age…). Similarly, for combined procedures, the operative time is inferior with RAL than with CL despite these elements. Nevertheless, we cannot rule out other confounders that are not reported in this article. For that reason, we tried to attenuate the interpretation of our results:

Orginal sentence: The operative time for isolated procedures was, however, similar for the two approaches, suggesting that the increased LPO is attributable to other features of RAL, such as the number and width of incisions. For combined procedures, there was a non-significant statistical trend in favor of RAL reducing LPO. Operative time was also decreased for combined procedures performed by RAL.

Modified sentence: The interpretation of the operative time is subject to the same limitations since we cannot take into account all the possible confounders related to the differences between the two populations. The operative time was decreased for combined procedures performed by RAL. For isolated procedures it was, however, similar for the two approaches, suggesting that the increased LPO in this subgroup could be attributable to other features of RAL, (such as the number and width of incisions). or to other confounders (age, BMI).

8. Line 259. Why should the observational design be a weakness?

Reviewer #2 is obviously right. The observational design of this study complies well with our main objective which was to describe and compare the characteristics of procedures for gynecologic cancers that were performed with either CL or RAL in our unit in the context of an ERP. We simply deleted this sentence:

Deleted sentence: The observational nature of the present study is its main weakness.

9. Study limits should be improved and better reported.

We agree with reviewer #2, the limits were insufficiently discussed. We already addressed some of the concerns regarding the comparability of the patients by answering to the comment #5. On the advice of the Editor, we also added a paragraph on fertility preservation. We acknowledge that we need to improve our limitation paragraph with the comments of Reviewer #2:

Original paragraph: Surgical approaches have clearly been chosen by surgeons with the a priori belief of a better profitability of RAL for more complex procedures. As a consequence, the low number of observations for combined procedures performed by CL prevented us from determining whether there is a significant difference in LPO between the two approaches in this subgroup of interest. Furthermore, we have not reported data on estimated blood loss, post-operative pain or oncological outcomes, as our report focused on the main objectives of the ERP (morbidity and length of stay).

Modified paragraph: Our primary objective was to describe and compare the characteristics of procedures for gynecologic cancers that were performed with either CL or RAL in our unit. Although we determined that surgeons from our unit preferentially choose to use RAL to perform complex procedures, two major impediments prevented us from concluding whether this strategy is effective to reduce the LPO. Firstly, surgical approaches have clearly been chosen by surgeons with the a priori belief of a better profitability of RAL for more complex procedures and patients. As a consequence, we obtained two groups with very different features which make it difficult to compare outcomes. We have attempted to overcome this bias by conducting a subgroup analysis and a logistic regression analysis. These analyses must be interpreted with the utmost precaution and cannot provide sufficient evidence to recommend one surgical approach or the other regardless of complexity. Secondly, our study population presents a high degree of heterogeneity since it includes patients suffering from different gynecological cancers. We chose to conduct our subgroup analysis by regrouping patients who underwent similar procedures rather than regrouping patients with the same cancer localization. Although this method is suitable for analyzing the surgical complexity, it does not account the specific difficulties associated with the surgical treatment of each cancer. Furthermore, our study focused mainly on the LPO which is the easiest way to assess the efficiency of an ERP. However, it does not render the whole complexity of the treatment of gynecological cancers. Indeed, we have not reported data on the oncological outcomes such as the relapse-free survival. The long-term quality of life is also missing from our reported data. In particular, we did not report any data on the fertility preservation which is strongly linked to the well-being of young patients suffering from gynecological cancers [27-31]. Thus, we cannot formally conclude on the profitability of each surgical approach, and can only describe the elements that we use to decide which MIS technique will be used. Finally, the reproducibility of our findings is limited to MIS expert centers where surgeons have advanced skills both for RAL and CL.

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Reviewer #1: No

Reviewer #2: No

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

1 Apr 2020

Choosing the most appropriate minimally invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center

PONE-D-20-01006R1

Dear Dr. Netter,

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

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Academic Editor

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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

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: In this article the authors tried to compare the characteristics of procedures for gynecologic cancers conducted with laparoscopy or robotic-assisted laparoscopy. However, authors responded fully to the reviewers' requests.

Thanks

Reviewer #2: I was pleased to revise the manuscript entitled “Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center” (Manuscript Number: PONE-D-20-01006).

The study was approved by the local Institutional Review Board and written informed consent was obtained from all patients enrolled in this study.

In general, this manuscript was aimed to compare the characteristics of procedures for gynecologic cancers conducted with conventional laparoscopy (CL) or robotic-assisted laparoscopy (RAL) in the context of an enhanced recovery program (ERP). In my honest opinion, the topic is interesting enough to attract the readers’ attention. Moreover, the authors addressed all the suggested revisions, and I appreciated the manuscript improvement.

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Reviewer #1: No

Reviewer #2: No

10 Apr 2020

PONE-D-20-01006R1

Choosing the most appropriate minimally invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center

Dear Dr. Netter:

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