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. 2021 Mar 4;16(3):e0248205. doi: 10.1371/journal.pone.0248205

Risk factors for gastric perforation after cytoreductive surgery in patients with peritoneal carcinomatosis: Splenectomy and increased body mass index

Martina Aida Angeles 1,‡,#, Carlos Martínez-Gómez 1,2,‡,#, Mathilde Del 1, Federico Migliorelli 3, Manon Daix 1, Anaïs Provendier 1, Muriel Picard 4, Jean Ruiz 4, Elodie Chantalat 1, Hélène Leray 1, Alejandra Martinez 1,2, Laurence Gladieff 5, Gwénaël Ferron 1,6,*
Editor: Wen-Chi Chou7
PMCID: PMC7932550  PMID: 33661999

Abstract

Background

Gastric perforation after cytoreductive surgery (CRS) is an infrequent complication. There is lack of evidence regarding the risk factors for this postoperative complication. The aim of this study was to assess the prevalence of postoperative gastric perforation in patients undergoing CRS for peritoneal carcinomatosis (PC) and to evaluate risk factors predisposing to this complication.

Methods

We designed a unicentric retrospective study to identify all patients who underwent an open upfront or interval CRS after a primary diagnosis of PC of different origins between March 2007 and December 2018 at a French Comprehensive Cancer Center. The main outcome was the occurrence of postoperative gastric perforation.

Results

Five hundred thirty-three patients underwent a CRS for PC during the study period and 13 (2.4%) presented a postoperative gastric perforation with a mortality rate of 23% (3/13). Neoadjuvant chemotherapy was administered in 283 (53.1%) patients and 99 (18.6%) received hyperthermic intraperitoneal chemotherapy (HIPEC). In the univariate analysis, body mass index (BMI), peritoneal cancer index, splenectomy, distal pancreatectomy, and histology were significantly associated with postoperative gastric perforation. After multivariate analysis, BMI (OR [95%CI] = 1.13 [1.05–1.22], p = 0.002) and splenectomy (OR [95%CI] = 26.65 [1.39–509.67], p = 0.029) remained significantly related to the primary outcome.

Conclusions

Gastric perforation after CRS is a rare event with a high rate of mortality. While splenectomy and increased BMI are risk factors associated with this complication, HIPEC does not seem to be related. Gastric perforation is probably an ischemic complication due to a multifactorial process. Preventive measures such as preservation of the gastroepiploic arcade and prophylactic suture of the greater gastric curvature require further assessment.

Introduction

Peritoneal carcinomatosis (PC) is the dissemination within the abdominal cavity of any form of cancer, whether or not it originated from the peritoneum itself, and is most commonly caused by abdominopelvic malignancies [1]. Depending on the origin of the malignancy, cytoreductive surgery (CRS) represents the standard of care in order to remove all macroscopic disease [2–5], including different surgical procedures such as extended peritonectomy, infragastric omentectomy, splenectomy, distal pancreatectomy, atypical partial gastrectomy, cholecystectomy, and Hudson procedure [6–8]. In some malignancies, hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with CRS, as a survival benefit has been described [3, 5, 9, 10]. Since the recent publication of a randomized trial in stage III ovarian cancer, which showed that the addition of HIPEC to CRS provided a higher recurrence-free and overall survival rate after three cycles of NACT, HIPEC has been introduced to clinical practice [9]. HIPEC is also the gold standard for pseudomyxoma peritonei (PMP) and diffuse malignant peritoneal mesothelioma (DMPM) [11, 12].

Cytoreductive procedures have been associated with non-negligible postoperative morbimortality rates, with around 20% of grade III/IV surgical complications [13] and a postoperative mortality rate of approximately 3% [14]. Morbimortality seems to increase with the association of CRS plus HIPEC [15, 16]. Different types of postoperative complications such as pleural effusion, pneumonia, intra-abdominal collection or abscess, bleeding, bowel anastomotic leakage, bowel perforation, and pancreatic fistula have been described. However, there are very few reports in the literature assessing the prevalence of gastric perforations after CRS. While some authors state that its occurrence is strongly associated with HIPEC, evidence regarding other associated risk factors is missing [17, 18].

The aim of our study was to assess the prevalence of postoperative gastric perforation in patients undergoing a CRS for PC of different origins and to evaluate the risk factors predisposing to this complication.

Materials and methods

Patient selection and study design

A computer-generated search in the institutional patient database was carried out in February 2020 to retrospectively identify all patients who underwent an open upfront or interval CRS after primary diagnosis of PC of different origins (ovarian cancer, endometrial cancer, colon cancer, PMP and DMPM) between March 2007 and December 2018 at the Institut Claudius Regaud Comprehensive Cancer Center—IUCT—Oncopole (Toulouse, France), which is an expert center for rare peritoneal diseases (RENAPE network). Patients undergoing a secondary CRS for recurrence of PC were excluded from our study. As well, patients with a previous incomplete surgery performed outside our institution and undergoing CRS at our center were excluded. All data that could possibly be used to identify individual patients was deleted and all records were anonymized during the retrieval procedure, before the final database was handed to the researchers. Institutional Review Board (Comité d’Ethique de Recherche Clinique) approval was obtained from our center.

Surgical technique

All surgical procedures were performed by three experienced oncological surgeons, using an open approach with a midline xyphopubic incision. The extent and spread of the disease throughout the 13 abdominopelvic regions were evaluated using the peritoneal cancer index (PCI) [19] and the cytoreductive surgical technique was performed following Surgarbaker’s principles of peritonectomy [6]. In case of remnant millimetric lesions in the mesentery or bowel serosa, visceral peritoneal destruction was performed using an electrosurgical ball-tip [20]. The main goal of the surgery was to obtain complete cytoreduction, evaluated using the Completeness of Cytoreduction score (CC-0: No residual tumor; CC-1: Residual disease less than 2.5 mm in diameter; CC-2: Residual nodules between 2.5 mm and 2.5 cm; and CC-3: Residual nodules greater than 2.5 cm or a confluence of unresectable disease) [19]. HIPEC was performed after CRS using the open coliseum technique with different drugs and protocols depending on the pathology. Infragastric omentectomy without preservation of the gastroepiploic arcade was performed using non-absorbable polymer locking clips (Hem-O-Lok®, Weck Closure Systems, Research Triangle Park, NC). In more recent years, in order to decrease the incidence of postoperative gastric perforation after CRS in patients undergoing an infragastric omentectomy combined with a splenectomy, two additional surgical techniques have been implemented in selected cases at the surgeon’s discretion. First, we try to preserve the gastroepiploic arcade when performing an infragastric omentectomy, if disease is absent at this localization (S1 Fig). Second, a prophylactic suture of the greater curvature of the stomach is performed, consisting in a seromuscular plication that may prevent gastric perforation, as it has been suggested by other authors (S2 Fig) [17]. Finally, proton-pump inhibitors were systematically administered in the postoperative period.

Study data

The main outcome was the occurrence of gastric perforation in the postoperative period. Patient demographic data (age, gender, body mass index [BMI], diabetes mellitus), neoadjuvant chemotherapy (NACT), PCI scores calculated during surgery, selected procedures performed during CRS that could have been related to postoperative gastric perforation (infragastric omentectomy with or without preservation of the gastroepiploic arcade, splenectomy, distal pancreatectomy, atypical partial gastrectomy, celiac lymph node resection, prophylactic suture of the greater gastric curvature), HIPEC and histological type were included in the database.

Extended and comprehensive data collection was performed in the patients presenting with postoperative gastric perforation in order to obtain a detailed description of each case.

Statistical analysis

Data were summarized by frequencies and percentages for categorical variables and by medians and ranges for continuous variables. Univariate analysis was performed using Fisher’s exact test and Wilcoxon’s rank-sum test for categorical and continuous variables, respectively. The characteristics that showed a significant association with the prevalence of gastric perforation during the previous analysis were included in a multivariate logistic regression model, from which odds ratios (OR) and their 95% confidence intervals (CI) were calculated. p-values below 0.05 were considered statistically significant. All statistical analyses were conducted using STATA 13.0 software.

Results

Five hundred thirty-three patients were included in our study. Among them, 13 (2.4%) patients experienced postoperative gastric perforation. The overall median age of the patients was 61.7 years (range 22.0–84.2) and the median BMI was 23.5 kg/m2 (range 14.3–53.4). There were 513 women in the cohort (96.3%) and 32 (6.0%) patients had medical history of diabetes mellitus.

All patients underwent a CRS, 429 (80.5%) for ovarian cancer, 25 (4.7%) for endometrial cancer, 12 (2.3%) for colon cancer, 40 (7.5%) for PMP, and 27 (5.1%) for DMPM. Two hundred eighty-three (53.1%) patients were treated with NACT before CRS. The median PCI in the cohort was 13 (range: 0–39) and 99 (18.6%) patients received HIPEC at the end of CRS. Table 1 summarizes the surgical procedures performed during CRS. All patients were considered CC-0 or CC-1 at the end of CRS.

Table 1. Surgical data of all patients included in the study (n = 533).

Surgical procedures, n (%)
Infragastric omentectomy 533 (100)
Splenectomy 192 (36.0)
Distal pancreatectomy 60 (11.3)
Celiac lymph node resection 86 (16.1)
Partial gastrectomy 10 (1.9)
Preservation of the gastroepiploic arcade 28 (5.3)
Prophylactic suture of the greater curvature of the stomach 13 (2.4)
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In univariate analysis, BMI, PCI, splenectomy, distal pancreatectomy, and histology were significantly associated with postoperative gastric perforation occurrence (Table 2). However, after multivariate analysis, only BMI and splenectomy remained significantly related to the primary outcome (Table 3).

Table 2. Factors associated with gastric perforation: Univariate analysis.

Patient characteristics Postoperative gastric perforation p-value
Yes (n = 13) No (n = 520)
Age (years), median (range) 65.4 (33.2–80.2) 61.6 (22.0–84.2) 0.110
Female gender, n (%) 12 (92.3) 501 (96.4) 0.395
Diabetes mellitus, n (%) 2 (15.4) 30 (5.8) 0.180
Body Mass Index (kg/m2), median (range) 27.1 (20.2–53.3) 23.5 (14.3–48.4) 0.014
 Missing 0 5
Neoadjuvant chemotherapy, n (%) 5 (38.5) 278 (53.5) 0.400
PCI, median (range) 24 (13–35) 13 (0–39) <0.001
 Missing 0 123
Surgical procedures, n (%)
 Infragastric omentectomy 13 (100) 520 (100) -
 Splenectomy 13 (100) 179 (34.4) <0.001
 Distal pancreatectomy 5 (38.5) 55 (10.6) 0.010
 Celiac lymph node resection 2 (15.4) 84 (16.2) 1.000
 Partial gastrectomy 0 (0) 10 (1.9) 1.000
 Preservation of the gastroepiploic arcade 0 (0) 28 (5.4) 1.000
 Prophylactic suture of the greater gastric curvature 1 (7.7) 12 (2.3) 0.277
HIPEC, n (%) 5 (38.5) 94 (18.1) 0.074
Histology 0.005
 Ovarian cancer 6 (46.2) 423 (81.4)
 Endometrial cancer 1 (7.7) 24 (4.6)
 Colon cancer 0 (0) 12 (2.3)
 PMP 5 (38.5) 35 (6.7)
 DMPM 1 (7.7) 26 (5.0)
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PCI: Peritoneal cancer index.

HIPEC: Hyperthermic intraperitoneal chemotherapy.

PMP: Pseudomyxoma peritonei.

DMPM: Diffuse malignant peritoneal mesothelioma.

Table 3. Factors associated with gastric perforation: Multivariate analysis.

Variable OR (CI 95%) p-value
Body mass index (kg/m2) 1.13 (1.05–1.22) 0.002
PCI 1.05 (0.98–1.12) 0.206
Splenectomy 26.65 (1.39–509.67) 0.029
Distal pancreatectomy 1.43 (0.42–4.95) 0.566
Ovarian histology 0.47 (0.15–1.50) 0.205
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OR: Odds ratio.

CI: Confidence interval.

PCI: Peritoneal cancer index.

Among the thirteen patients with a gastric postoperative perforation, the median age was 65.4 years (range 33.9–80.2) and the median BMI was 27.1 kg/m2 (range 20.2–53.3). Six patients were diagnosed with high grade serous ovarian carcinoma, 5 patients had PMP, 1 patient had DMPM, and 1 patient presented with endometrial clear cell carcinoma. NACT was administered in 5 patients before CRS and the median PCI was 24 (range 13–35). All patients underwent an infragastric omentectomy combined with a splenectomy, and the gastroepiploic arcade was not preserved in any of them. A prophylactic suture of the greater curvature of the stomach was performed in one patient. HIPEC was performed in 5 patients using a protocol based on oxaliplatin 360mg/m2 during 30 minutes using the coliseum technique. At the end of the surgery a nasogastric tube without suction was placed in all patients. The median operative time was 323 minutes (range 200–602). The median time to diagnosis of the perforation was 5 days (range 2–15). The clinical presentation of our patients was a combination of the following signs and symptoms: Acute and severe abdominal pain, abdominal tenderness, nausea, vomiting, gastric fluid in the abdominal drain, fever and/or clinical deterioration. In all cases the diagnosis was made using an abdominal computed tomography (CT) and confirmed during surgery. The median perforation size was 10 mm (range 2–30) and in all cases the perforation was located at the upper portion of the greater curvature of the stomach (S3 Fig).

All patients received prompt surgical management of the gastric perforation, which consisted in an atypical gastrectomy using an automatic stapler reinforced with a manual gastric suture. Three patients experienced a concomitant gastro-pleural fistula, among whom two required pleural decortication by thoracotomy and a long-term insertion of a dual lumen nasogastric tube. Three (23.1%) patients died at the Intensive Care Unit (ICU) at the 7th, 93rd and 111th postoperative day. The first patient experienced refractory septic shock due to a digestive peritonitis caused by the gastric perforation, which was followed by multivisceral failure. The second patient developed multiple complex fistulas during the postoperative course of gastric perforation surgery, leading to a chronic septic status with secondary multiorgan failure (respiratory and acute kidney injury with prolonged mechanical ventilation and continuous veno-venous hemodiafiltration). Finally, an ethical therapeutic limitation was decided upon in the multidisciplinary meeting and the patient died 93 days after CRS. The third patient also developed multiple digestive fistulas leading to a chronic septic status. Acute massive abdominal bleeding occurred 111 days after CRS and, after a multidisciplinary ethical decision, urgent surgery was not performed, therefore, end of life care was given. The remaining 10 patients were discharged from the ICU after a median hospitalization length of 34 days (range 14–68). The median overall hospitalization length of these 10 patients was 53 days (range 21–98). Table 4 shows a detailed description of patient’s characteristics, surgical and follow-up data.

Table 4. Description of the 13 patients with postoperative gastric perforation after cytoreductive surgery.

Patient number; age; gender. Diag-nosis WHO perfor-mance status; BMI; Diabetes mellitus NACT PCI Surgical procedures HIPEC Operative time (minutes); CC-score; naso-gastric tube Interval to diagnosis (days) Perfo-ration size (mm); conco-mitant gastro-pleural fistula Hospita-lization length* (days) Current status
1; 33; F PMP 0; 35.6; no No 13 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, cholecystectomy, mesenteric and bowel vaporization, and hysterectomy. Yes, oxaliplatin 294; CC-0 3 3; yes 67 NED 3047 days after surgery
2; 60; F HGSOC 0; 53.3; no Yes 26 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, rectosigmoid resection, mesenteric and bowel vaporization, pelvic and paraaortic lymphadenectomy, bilateral adnexectomy, and hysterectomy. No 412; CC-1 5 20; yes 98 DOD 688 days after CRS
3; 74; F PMP 1; 44.9; yes No 21 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, distal pancreatectomy, cholecystectomy, mesenteric and bowel vaporization, bilateral adnexectomy, and hysterectomy. No 323; CC-1 2 3; no 93 Dead from PCs 93 days after CRS
4; 75; F HGSOC 0; 24.2; no Yes 25 Extended peritonectomy, infragastric omentectomy, splenectomy, distal pancreatectomy, rectosigmoid resection, mesenteric and bowel vaporization, pelvic and paraaortic lymphadenectomy, bilateral adnexectomy, and hysterectomy. No 355; CC-0 4 20 and 20; no 73 DOD 197 days after CRS
5; 64; F DMPM 0; 21.9; no No 30 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, distal pancreatectomy, cholecystectomy, mesenteric and bowel vaporization, bilateral adnexectomy and hysterectomy. Yes, oxaliplatin 602; CC-0 15 20; no 111 Dead from PCs 111 days after CRS
6; 80; F HGSOC 0; 22.3; no No 18 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, distal pancreatectomy, rectosigmoid resection, bilateral adnexectomy, and hysterectomy. No 200; CC-0 7 2; no 95 DOD 544 days after CRS
7; 48; M PMP 0; 26.7; no Yes 35 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, distal pancreatectomy, ileo-cecal resection, mesenteric and bowel vaporization, celiac lymhadenectomy. Prophylactic suture of the gastric greater curvature. Yes, oxaliplatin 550; CC-0 2 10; no 37 DOD 406 days after CRS
8; 63; F HGSOC 0; 24.9; no No 20 Extended peritonectomy, infragastric omentectomy, splenectomy, cholecystectomy, rectosigmoid resection, mesenteric and bowel vaporization, pelvic, paraaortic and celiac lymphadenectomy, bilateral adnexectomy and hysterectomy. No 232; CC-0 2 30; no 48 DOD 1968 days after CRS
9; 73; F PMP 0; 23.8; no No 34 Extended peritonectomy, infragastric omentectomy, splenectomy, cholecystectomy, ileocolic resection, mesenteric and bowel vaporization, pelvic and paraaortic lymphadenectomy, bilateral adnexectomy and hysterectomy Yes, oxaliplatin 321; CC-0 4 20; no 21 NED 1520 days after surgery
10; 65; F HGSOC 0; 27.8; no Yes 16 Extended peritonectomy, infragastric omentectomy, splenectomy, pelvic and paraaortic lymphadenectomy, bilateral adnexectomy and hysterectomy. No 221; CC-0 5 5; no 53 DOD 954 days after CRS
11; 71; F HGSOC 0; 31.9; no Yes 24 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, distal pancreatectomy, cholecystectomy, transvers colic resection, mesenteric and bowel vaporization, pelvic and paraaortic lymphadenectomy, bilateral adnexectomy, and hysterectomy. No 287; CC-0 6 10; no 7 Dead from PCs 7 days after CRS
12; 72; F ECC 0; 32.3; yes No 18 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, pelvic and paraaortic lymphadenectomy, bilateral adnexectomy, and hysterectomy. No 324; CC-0 5 10; yes 25 AWD, recurrence 409 days after CRS
13; 62; F PMP 0; 20.2; no No 29 Extended peritonectomy, infragastric and supragastric omentectomy, splenectomy, cholecystectomy, mesenteric and bowel vaporization, pelvic and paraaortic lymphadenectomy, bilateral adnexectomy, and hysterectomy. Yes, oxaliplatin 372; CC-0 12 3; no 23 NED 723 days after surgery
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WHO: World Health Organization.

BMI: Body mass index.

NACT: Neoadjuvant chemotherapy.

PCI: Peritoneal carcinomatosis index.

HIPEC: Hyperthermic intraperitoneal chemotherapy.

CC-score: Completeness of cytoreduction score.

* including hospitalization at intensive care unit.

F: Female.

M: Male.

PMP: Pseudomyxoma peritonei.

HGSOC: High-grade serous ovarian carcinoma.

DMPM: Diffuse malignant peritoneal mesothelioma.

ECCC: Endometrial clear cell carcinoma.

PCs: Postoperative complications.

DOD: Dead of disease.

NED No evidence of disease.

AWD: Alive with disease.

CRS: Cytoreductive surgery.

Discussion

Gastric perforation after CRS is a very rare postoperative complication, with a prevalence of 2.4% in our experience. Our findings show a slightly higher prevalence compared to previously published incidences ranging from 0.3 to 1.9% [17, 18, 21–24]. Its occurrence is associated with a high mortality rate (23%), as three patients died in the ICU following the diagnosis of the complication. The mortality rate in our study is in line with previous reports describing the outcome of patients undergoing surgery for perforated peptic ulcers (deceased in around 20–30% of the cases) [25]. However, most studies focusing on gastric perforation after CRS described that this type of complication was not related to a fatal outcome [17, 18, 21–24], while only one study reported a single death due to sepsis caused by the perforation [26]. Nevertheless, most of these series described isolated cases of postoperative gastric perforations [21–24, 26], whereas only two of them included 4 and 6 events [17, 18]. Therefore, it is highly probable that this postoperative complication, and its related mortality, may be underdiagnosed or underreported.

We found that splenectomy was associated with postoperative gastric perforation, and was performed in all patients who experienced this complication. Similarly, the four cases of gastric perforation after CRS and HIPEC reported by Zappa et al. underwent a greater and lesser omentectomy and a splenectomy without gastric resection [17]. In Kyang et al. study, five out of the six patients with this complication underwent a splenectomy during CRS [18]. Our hypothesis is that gastric perforation could be explained by a reduced blood perfusion of the greater curvature of the stomach due to the ligation of short gastric and gastroepiploic vessels during the splenectomy [27]. In all of our cases, the perforation was found in the upper part of the gastric greater curvature, which corresponds to the abovementioned area of devascularization. Concordantly, previous studies systematically found the perforation to be located at or near the greater curvature, close to the area of the left gastroepiploic vessels [17, 18]. In case of ligation of the short gastric and gastroepiploic vessels, the only remaining vascularization of the stomach is the one provided by the left and right gastric arteries, running along the lesser curvature. Therefore, the upper third of the greater curvature becomes the less vascularized area of the stomach [27]. In this study, we could not analyze if infragastric omentectomy was a risk factor for gastric perforation as all patients underwent this procedure during CRS. Still, associated omentectomy and splenectomy may have an additive effect on the devascularization of the greater curvature of the stomach, as right and left gastroepiploic and short gastric vessels are usually sectioned when performing these procedures together. We did not find distal pancreatectomy to be associated with postoperative gastric perforation, which may be explained by the low number of patients in our series undergoing this procedure. Distal pancreatectomy may increase the devascularization of the greater curvature, thereby favoring the risk of gastric perforation.

According to our results, gastroepiploic arcade preservation and prophylactic suture of the greater gastric curvature over the ligated vessels have not been shown to prevent gastric perforation. However, these procedures have only recently been introduced in this type of surgeries in our center, therefore, only few patients benefited from these prophylactic measures (6% gastroepiploic arcade preservation and 2% prophylactic suture). The rationale for preserving the gastroepiploic arcade is to reduce the devascularization of the greater curvature, thereby decreasing the ischemia of the region and the subsequent risk of postoperative gastric perforation [17]. As previously mentioned, gastric perforations are commonly located in the upper portion of the greater curvature. Therefore, preserving the gastroepiploic arcade during an omentectomy would reduce the risk of perforation, particularly in patients undergoing this procedure combined with a splenectomy. On the other hand, the rationale for a prophylactic suture would be to reinforce the gastric wall and to invaginate the areas of the stomach at higher risk of perforation. In our series, one of the perforated patients underwent a prophylactic suture. However, she had a hiatal hernia and the prophylactic suture performed during the CRS was done in the middle part of the greater curvature instead of in the upper segment, probably being insufficient to prevent the perforation.

Our data have also shown that gastric perforation was associated with high BMI. In fact, for each additional BMI point, the risk of perforation was increased by approximately 13%. This association is biologically plausible as there is large evidence showing that obesity is correlated to deficient wound healing and to other postoperative complications, probably due to inherent anatomic features of adipose tissue, vascular insufficiencies, cellular and composition modifications, oxidative stress, alterations in immune mediators, and nutritional deficiencies [28]. To our knowledge, no previous studies have reported an association between BMI and gastric perforation in patients undergoing CRS [17, 18, 21–24, 26].

Regarding the role of HIPEC, most authors concluded that it was associated with gastric perforation after CRS [17, 18, 21–24, 26]. It has been suggested that HIPEC could have a direct thermal and toxic effect damaging the stomach wall, as well as a systemic effect which would include a temporarily retarded repair of gastric mucosa due to the systemic absorption of the drugs [17]. However, these studies only included patients undergoing CRS plus HIPEC [17, 18, 21–24, 26], without assessing the risk of gastric perforation in patients undergoing CRS alone, of which there are no previous reports. Thus, this postoperative complication may be also present in patients undergoing CRS alone, occurring independently of the addition of HIPEC. Although almost 20% of our cohort underwent HIPEC, we did not find any correlation between the occurrence of postoperative gastric perforation and HIPEC. Along the same lines, we did not find NACT to be associated with gastric perforations.

All patients that experienced gastric perforation in our study were surgically managed with partial gastrectomy in order to remove the ischemic tissue. Even though conservative management of perforated gastric ulcers has been demonstrated to be feasible [29], almost all cases of gastric perforation after CRS reported in the literature have been surgically treated [17, 21, 22, 24]. Moreover, patients with a perforated gastric ulcer still have the omentum which can cover the gastric defect in case of conservative management, whereas patients undergoing CRS have a devascularized greater gastric curvature due to the omentectomy. The high postoperative mortality rate of gastric perforation highlights the importance of promptly assessing any suspicion to avoid the delay in diagnosis. This complication can be clinically suspected if signs of peritonitis or gastric fluid content in intraperitoneal drain are present, or using imaging techniques, such as abdominal CT (S4 Fig). Once diagnosed, gastric perforation should be managed rapidly in order to decrease postoperative mortality rates.

The main strength of our study is the high number of patients included in the analysis. To our knowledge, we report the largest monocentric series of gastric perforation after CRS. Unlike the other reports, the majority of which only presented data on patients with gastric perforation, we included information about those individuals who did not have this complication, allowing us to statistically analyze the possible risk factors of postoperative gastric perforation, going further than the mere suggestion of possible associations. Moreover, the majority of previous series exclusively included patients who underwent CRS plus HIPEC, whereas we also included patients undergoing CRS alone. Conversely, our study may also have some weaknesses. Its retrospective design may hinder the interpretation of our results as it may introduce biases linked to this type of study. Perioperative nutritional status may be a determining factor for gastric perforation and, due to the retrospective nature of our study, this information could not be assessed. Moreover, we only evaluated the variables that we believed could be related to postoperative gastric perforation, so there might be other factors associated with the outcome which we may have overlooked and unconsciously excluded from the study. Additionally, other postoperative complications than gastric perforations were not assessed in this study.

Conclusions

In conclusion, gastric perforation after CRS is an infrequent postoperative complication. Splenectomy and high BMI are found to be associated risk factors. However, it is probably a multifactorial process in which many causes may still be unknown. The roles of preservation of the gastroepiploic arcade during infragastric omentectomy -in case of no involvement- and of the prophylactic suture of the greater gastric curvature should be evaluated in further studies.

Supporting information

S1 Fig. Preservation of the gastroepiploic arcade during an omentectomy.

(DOCX)

Click here for additional data file. (2.1MB, docx)
S2 Fig. Prophylactic suture of the greater curvature of the stomach.

(DOCX)

Click here for additional data file. (690.6KB, docx)
S3 Fig. Postoperative gastric perforation located in the upper portion of the greater curvature.

(DOCX)

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S4 Fig. Gastric opacified computed tomography.

Gastric wall perforation and extraluminal free air are marked with yellow arrows.

(DOCX)

Click here for additional data file. (106.4KB, docx)

Abbreviations

BMI

body mass index

CC-score

completeness cytoreduction score

CI

confidence interval

CRS

cytoreductive surgery

CT

computed tomography

DMPM

diffuse malignant peritoneal mesothelioma

HIPEC

hyperthermic intraperitoneal chemotherapy

ICU

Intensive Care Unit

NACT

neoadjuvant chemotherapy

OR

odds ratio

PC

peritoneal carcinomatosis

PCI

peritoneal cancer index

PMP

pseudomyxoma peritonei

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Andrew Zbar

11 Jan 2021

PONE-D-20-33398

Risk factors for gastric perforation after cytoreductive surgery in patients with peritoneal carcinomatosis: splenectomy and increased body mass index

PLOS ONE

Dear Dr. Ferron,

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.

The authors present from their CRS database of PC the rare complication of gastric perforation with a UVA that suggests a role for BMI, PCI, splenectomy-distal pancreatectomy and primary histology but with BMI and splenectomy remaining of significance on MVA.

I have several caveats:

1. I would expand a little on the outcome advantages of CRS and HIPEC therapy in the introduction. Their use of HIPEC in a specialist environment is comparatively low. Can they expand on their annual practice referral pattern and decision making concerning management (in broad terms).

2. Can the authors expand a little on their diagnoses of gastric perforations and any delays in diagnosis as this can be a little notorious with a higher mortality when diagnosis is delayed. I thought the tables were excellent and easy to read. I am after a little bit more clinical information in the paper please about their early diagnosis suspicions, basic patient presentations, comments about the ability to make the early diagnosis. Can they comment on the findings at operation ion the perforated cases.

3. They go through the standard analyses of cause in their discussion. For such a paper I think the discussion can be reduced in length by about one quarter. The discussion can be more succinct. I think they could expand on gastroepiploic artery preservation preservation during omentectomy a little more. If they wished to include an image here and had one that would be of more interest.

4. Some of the imagery (although nice) is not necessary and does not add to the quality of the paper.

I enjoyed this well written and well constructed paper. I would favour some minor revisions with a reduction and focus of the discussion, a slight expansion on gastroepiploic arcade preservation and a little bit more clinical information . I would also consider the cogent suggestions of the two reviewers as a minor revision. I would be pleased to see the manuscript revision.

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We look forward to receiving your revised manuscript.

Kind regards,

Andrew Zbar

Academic Editor

PLOS ONE

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Reviewer #2: Yes

**********

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Reviewer #1: This is an interesting study looking at possible risk factors for gastric perforation following CRS, mainly in paitents with gynecologic malignancy and peritoneal carcinomatosis. The study is well written and highly detailed and I ongragulate the authors for this work. However, there are still some points in need of clarification prior to publication, in m opinion -

1. The main issue with the manuscript in my opnion is that proton pump inhibitors are not mentioned in the study at all - are they part of the routine treatment following surgical interventions ? were they given to all patients? In addition, I think it is impossible to discuss gastric perforations without mentioning the ongoing debate about the post-operative treatment with PPI.

2. The authors detail the possible reasons why splenectomy is a risk factor although in the univariate analysis distal pancreatectomy was also found to be a significant risk factor. I think that with more patients, pancreatectomy would also be a significant risk factor. Did the authors document pancreatic leaks in thier cohort as well? were there cases in which a pancreatic fistula was the causative factor?

3. I am interested to know whether the authors changed anything in thier practice due to the findings? In addition, i am interested to know if the authors think that in patients with an expected splenectomy, would a selective or completed embolization of the spleen help to avoid such catastrophic complication (to allow collaterel vessels to strengthen the blood supply to the area).

Overeall, this is a well desgined study that I enjoed reading and I would like to thank the authors.

Reviewer #2: The authors present data on the risk of gastric perforation following cytoreductive surgery (CRS). In their cohort of 533 patients, they recorded 13 instances of post operative gastric perforations, amounting to 2.4% of the cohort. The authors correctly point out that there is a paucity of data concerning this rare complication, and indeed they report an incidence higher than previously reported, notably the Sugarbaker paper (ref 17) and the Kyang paper (ref 18).

The main causes found in multivariate analysis were splenectomy and BMI, Although obviously gastric perforation is multifactorial, as for example the combination of splenectomy and infragastric omentectomy would contribute together to gastric devascularization and the threat of ischemia.

I have several comments on the data. First, the patient cohort is heavily skewed towards gynecologic malignancies, (454 of 533, 82%) yet 6 of the 13 patients with gastric perforation have disease of colonic and/or mesothelioma, 46% and not of gyn origin, which I find curious. Although the cytoreductive aspect of surgery should be identical in the differing histologies, one can’t help but notice this aspect of the data and, this should be considered in the discussion.

In addition, although the use of systemic treatment was not found to be statistically significant in perforations, again what jumps out of the data, is that 9/13 or 69% , patients with perforations underwent some form of systemic therapy, either neoadjuvant or HIPEC. It is possible that the small number of perforations from the overall cohort precluded the statistical significance of systemic treatment, nonetheless, it is difficult to categorically exclude systemic therapy from being a major cause of perforation, as this could directly cause poor tissue healing. It is increasingly common for gynecologic malignancies to be treated with a combination of chemotherapy and bevacizumab, which is well known to be a risk factor for poor wound healing and GI perforations, so I would like to know if Avastin was looked at specifically as a possible factor in a multifactorial cascade. This, along with the use of oxaliplatin in the HIPEC cases, could have played some part in tissue disruption, and the small numbers were not powered enough to find statistical significance.

In the discussion, the paragraph on nasogastric suction as a possible cause of perforation is simply rehashing what was found in previous papers, such as the Sugarbaker and Kyang paper, and is sheer conjecture and seems to be dubious. NG drainage has been an integral part of abdominal surgery for many years and has not been directly implicated in gastric perforations, anecdotal case reports notwithstanding, and thus can be omitted.

The photographs in Figure 2 and 3 are superfluous and unnecessary, this paper is directed to a readership of operating surgical oncologists, and they do not need to be shown what a gastric perforation looks like in situ or on CT, kindly omit. Figure 2 looks like almost the same photo shown in the Kyang paper, and there it is to my mind also superfluous. Kindly omit these figures.

Some minor English language editing is needed. Please have a native English speaker edit.

**********

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Reviewer #1: Yes: Nir Horesh

Reviewer #2: No

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PLoS One. 2021 Mar 4;16(3):e0248205. doi: 10.1371/journal.pone.0248205.r002

Author response to Decision Letter 0

16 Feb 2021

Response to Reviewers Letter

Dr. Andrew Zbar

Academic Editor

PLOS ONE

Dear Editor,

Please find enclosed the second version of our manuscript "Risk factors for gastric perforation after cytoreductive surgery in patients with peritoneal carcinomatosis: Splenectomy and increased body mass index", after including the suggested amendments.

You will find below these lines the corrections and observations regarding the revision process. Following your instructions, we are also attaching both a revised manuscript file (clean version) and a tracked changes manuscript file (marked version) illustrating the modifications. Hopefully, they will meet your evaluation criteria.

On behalf of all authors, I want to thank you for considering our paper for publishing. Likewise, we want to show our gratitude to the reviewers for their comments, as they have surely improved our work.

We remain at your complete disposal for any further comment or clarification that you find necessary to address to us.

Yours faithfully,

Dr. Gwénaël Ferron

Corresponding author

Comments from the Reviewers:

Reviewer #1:

This is an interesting study looking at possible risk factors for gastric perforation following CRS, mainly in paitents with gynecologic malignancy and peritoneal carcinomatosis. The study is well written and highly detailed and I ongragulate the authors for this work. However, there are still some points in need of clarification prior to publication, in m opinion -

Thank you very much for your revision as it has certainly improved our work.

1. The main issue with the manuscript in my opnion is that proton pump inhibitors are not mentioned in the study at all - are they part of the routine treatment following surgical interventions ? were they given to all patients? In addition, I think it is impossible to discuss gastric perforations without mentioning the ongoing debate about the post-operative treatment with PPI.

We completely agree with the reviewer. It is essential to mention the role of proton-pump inhibitors when evaluating postoperative gastric perforations. The proton-pump inhibitors are part of our routine treatment protocol following cytoreductive surgery. We have added this information to the Methods section (page 7 lines 146-147, underlined the new words):

"Finally, proton-pump inhibitors were systematically administered in the postoperative period."

2. The authors detail the possible reasons why splenectomy is a risk factor although in the univariate analysis distal pancreatectomy was also found to be a significant risk factor. I think that with more patients, pancreatectomy would also be a significant risk factor. Did the authors document pancreatic leaks in thier cohort as well? were there cases in which a pancreatic fistula was the causative factor?

We completely agree with the reviewer in that distal pancreatectomy may have been found to be a significant risk factor for gastric perforation in a larger cohort of patients. However, postoperative gastric perforation is a rare complication and larger cohorts of patients are difficult to obtain.

We have added the following sentences to the Discussion (page 13 lines 269-272, underlined the new words):

"We did not find distal pancreatectomy to be associated with postoperative gastric perforation, which may be explained by the low number of patients in our series undergoing this procedure. Distal pancreatectomy may increase the devascularization of the greater curvature, thereby favoring the risk of gastric perforation."

Among the 13 patients in our cohort who experienced a gastric perforation, none of them had a pancreatic fistula during the postoperative course. Therefore, it is not possible to evaluate its association with gastric perforation in our study.

Moreover, as mentioned in the limitations, we only evaluated the risk factors of one type of complication - gastric perforation - and other complications such as pancreatic fistula were not assessed. It would be interesting to evaluate the risk factors of postoperative pancreatic fistula in future studies.

3. I am interested to know whether the authors changed anything in thier practice due to the findings? In addition, i am interested to know if the authors think that in patients with an expected splenectomy, would a selective or completed embolization of the spleen help to avoid such catastrophic complication (to allow collaterel vessels to strengthen the blood supply to the area).

Yes, we have changed our clinical practice after these findings. Currently, we systematically perform a prophylactic suture of the greater gastric curvature after omentectomy plus splenectomy during cytoreductive surgeries. Even though this measure was not found to prevent postoperative gastric perforation, we believe it is indeed possible and this result was rather due to the low proportion of patients who underwent this prophylactic suture in our series. Moreover, whenever possible, we try to preserve the gastroepiploic arcade during infragastric omentectomy to decrease gastric devascularization.

As stated by the reviewer, it would be interesting to evaluate if preoperative spleen embolization could decrease the risk of gastric perforation by creating collateral vascularization. However, spleen involvement is usually discovered during cytoreductive surgery and we believe it might be difficult to schedule a splenectomy before surgery. Moreover, we have some concerns regarding embolization before the splenectomy as we believe that collateral vascularization may render more difficult the procedure.

Overeall, this is a well desgined study that I enjoed reading and I would like to thank the authors.

We really appreciate all your positive comments which motivate us to keep working and improving our work.

Reviewer #2:

The authors present data on the risk of gastric perforation following cytoreductive surgery (CRS). In their cohort of 533 patients, they recorded 13 instances of post operative gastric perforations, amounting to 2.4% of the cohort. The authors correctly point out that there is a paucity of data concerning this rare complication, and indeed they report an incidence higher than previously reported, notably the Sugarbaker paper (ref 17) and the Kyang paper (ref 18).

The main causes found in multivariate analysis were splenectomy and BMI, Although obviously gastric perforation is multifactorial, as for example the combination of splenectomy and infragastric omentectomy would contribute together to gastric devascularization and the threat of ischemia.

Thank you for your interesting remarks and your comprehensive review of our manuscript.

I have several comments on the data. First, the patient cohort is heavily skewed towards gynecologic malignancies, (454 of 533, 82%) yet 6 of the 13 patients with gastric perforation have disease of colonic and/or mesothelioma, 46% and not of gyn origin, which I find curious. Although the cytoreductive aspect of surgery should be identical in the differing histologies, one can’t help but notice this aspect of the data and, this should be considered in the discussion.

We completely agree with the reviewer regarding this issue. In fact, this association has been evaluated in this study and we found that histology was related to gastric perforation in the univariate analysis. However, in the multivariate analysis, non-ovarian histology did not remain significantly associated with gastric perforation.

As the Editor has requested to shorten the length of the Discussion and to focus on the subject of vascularization, we have not added any comments on the histology to the Discussion.

However, if the Editor or the Reviewer finds it necessary, we can add a few sentences on this issue.

In addition, although the use of systemic treatment was not found to be statistically significant in perforations, again what jumps out of the data, is that 9/13 or 69% , patients with perforations underwent some form of systemic therapy, either neoadjuvant or HIPEC. It is possible that the small number of perforations from the overall cohort precluded the statistical significance of systemic treatment, nonetheless, it is difficult to categorically exclude systemic therapy from being a major cause of perforation, as this could directly cause poor tissue healing. It is increasingly common for gynecologic malignancies to be treated with a combination of chemotherapy and bevacizumab, which is well known to be a risk factor for poor wound healing and GI perforations, so I would like to know if Avastin was looked at specifically as a possible factor in a multifactorial cascade. This, along with the use of oxaliplatin in the HIPEC cases, could have played some part in tissue disruption, and the small numbers were not powered enough to find statistical significance.

We completely agree with the reviewer's comment. We have therefore analyzed if the use of any type of chemotherapy (neoadjuvant chemotherapy [NACT] or HIPEC) was associated with the occurrence of postoperative gastric perforation.

We have included in the univariate analysis the variable systemic therapy (either NACT or HIPEC):

Gastric perforation Yes

n=13 No

n=520 p value

Systemic therapy, n (%) 9 (69.2) 322 (61.9) 0.775

As stated by the reviewer, 69% of women with gastric perforation previously had either NACT or HIPEC. However, among the women without gastric perforation, 62% also had NACT or HIPEC. This difference was not found to be significant.

Among the 13 patients with gastric perforation: 1 had both NACT and HIPEC, 4 had HIPEC, 4 had NACT and 4 did not receive these treatments.

Among the 520 patients without gastric perforation: 50 had both NACT and HIPEC, 44 had HIPEC, 228 had NACT and 198 did not receive these treatments.

We have not added this information to the manuscript as we had already reported the n (%) of patients undergoing neoadjuvant chemotherapy and HIPEC separately. However, if the Reviewer or the Editor finds it necessary, we will gladly add it.

Regarding the use of bevacizumab, it is not biologically plausible for its use to be associated with postoperative gastric perforation, as bevacizumab was not administered before cytoreductive surgery in any patient. Moreover, it is usually administered with adjuvant chemotherapy after the first two cycles. Therefore, none of the patients with a postoperative gastric perforation received bevacizumab before the complication.

In the discussion, the paragraph on nasogastric suction as a possible cause of perforation is simply rehashing what was found in previous papers, such as the Sugarbaker and Kyang paper, and is sheer conjecture and seems to be dubious. NG drainage has been an integral part of abdominal surgery for many years and has not been directly implicated in gastric perforations, anecdotal case reports notwithstanding, and thus can be omitted.

Following the reviewer's suggestion, we have deleted the paragraph on nasogastric suction from the Discussion section (page 15 line 311, deleted words crossed out):

"There are other hypothesis that have been suggested to explain why gastric perforations may occur after these surgeries. After CRS, a nasogastric tube is usually placed, which is relatively rigid and may create a pressure ischemia on the stomach mucosa. As well, the prolonged suction may contribute to the risk of perforation[17,18,30]. Although all the 13 patients with a postoperative gastric perforation had a nasogastric tube without suction placed intraoperatively, we did not have the information of all of the 533 patients included in the study and, therefore, it could not be analyzed as a risk factor."

The photographs in Figure 2 and 3 are superfluous and unnecessary, this paper is directed to a readership of operating surgical oncologists, and they do not need to be shown what a gastric perforation looks like in situ or on CT, kindly omit. Figure 2 looks like almost the same photo shown in the Kyang paper, and there it is to my mind also superfluous. Kindly omit these figures.

We agree with the reviewer that Figures 2 and 3 are unnecessary for oncological surgeons to whom this research is directed. Following the reviewer's request, we have removed Figures 2 and 3, and moved them as Supplementary Figures 2 and 3 (Supporting information).

Some minor English language editing is needed. Please have a native English speaker edit.

Following the reviewer’s recommendation, the English grammar and spelling of our manuscript have been revised by a native English proofreader. All the corrections are shown with the track changes option throughout the manuscript.

Editor:

The authors present from their CRS database of PC the rare complication of gastric perforation with a UVA that suggests a role for BMI, PCI, splenectomy-distal pancreatectomy and primary histology but with BMI and splenectomy remaining of significance on MVA.

I have several caveats:

1. I would expand a little on the outcome advantages of CRS and HIPEC therapy in the introduction. Their use of HIPEC in a specialist environment is comparatively low. Can they expand on their annual practice referral pattern and decision making concerning management (in broad terms).

Due to the large cohort of patients of our study (mainly ovarian cancer patients), we agree with the Editor that it may seem that we have a low rate of HIPEC during CRS.

However, before the publication of the Van Driel et al. study in 2018, HIPEC was not used in our daily clinical practice for ovarian carcinomatosis. Before that study, HIPEC was only employed within clinical trials in ovarian cancer patients.

Since the publication of the OVHIPEC trial, HIPEC is routinely offered to stage III patients undergoing interval cytoreductive surgery after three cycles of neoadjuvant chemotherapy.

As requested by the Editor, we have highlighted the advantages of CRS plus HIPEC, particularly in ovarian cancer, but point out that it was not introduced in clinical practice until the OVHIPEC trial (page 5 lines 88-93, new words underlined and deleted words crossed out):

"Since the recent publication of a randomized trial in stage III ovarian cancer, which showed that the addition of HIPEC to CRS provided a higher recurrence-free and overall survival rate after three cycles of NACT, HIPEC has been introduced to clinical practice[9]. While in ovarian cancer, CRS plus HIPEC is considered an option[9], it represents. HIPEC is also the gold standard for pseudomyxoma peritonei (PMP) and diffuse malignant peritoneal mesothelioma (DMPM)[11,12]."

2. Can the authors expand a little on their diagnoses of gastric perforations and any delays in diagnosis as this can be a little notorious with a higher mortality when diagnosis is delayed. I thought the tables were excellent and easy to read. I am after a little bit more clinical information in the paper please about their early diagnosis suspicions, basic patient presentations, comments about the ability to make the early diagnosis. Can they comment on the findings at operation ion the perforated cases.

As requested by the Editor, we have added some clinical information regarding symptoms presented at diagnosis. In all cases the diagnosis was made using abdominal computed tomography and confirmed during surgery.

We have added this information to the Results section (page 10 lines 205-209, new words underlined and deleted words crossed out):

"The clinical presentation of our patients was a combination of the following signs and symptoms: Acute and severe abdominal pain, abdominal tenderness, nausea, vomiting, gastric fluid in the abdominal drain, fever and/or clinical deterioration. In all cases the diagnosis was made using an abdominal computed tomography (CT) and confirmed during surgery."

The size and location of the perforation found during the surgery appears in the manuscript and is also shown in Table 4 (page 10 lines 209-211):

"The median perforation size was 10 mm (range 2-30) and in all cases the perforation was located at the upper portion of the greater curvature of the stomach (S3 Fig)."

3. They go through the standard analyses of cause in their discussion. For such a paper I think the discussion can be reduced in length by about one quarter. The discussion can be more succinct. I think they could expand on gastroepiploic artery preservation preservation during omentectomy a little more. If they wished to include an image here and had one that would be of more interest.

As suggested by the Editor, we have reduced the length of the Discussion section. All changes can be seen all over the manuscript with the track changes option.

Additionally, we have added the following sentences to the Discussion section in order to lengthen the discussion on gastroepiploic arcade preservation (page 13 lines 280-284, new words underlined):

"As previously mentioned, gastric perforations are commonly located in the upper portion of the greater curvature. Therefore, preserving the gastroepiploic arcade during an omentectomy would reduce the risk of perforation, particularly in patients undergoing this procedure combined with a splenectomy."

Finally, we have added a picture of gastroepiploic arcade preservation during omentectomy (Supplementary Figure 1).

4. Some of the imagery (although nice) is not necessary and does not add to the quality of the paper.

As also requested by the second reviewer, we have removed Figures 2 and 3, and moved them as Supplementary Figures 2 and 3.

I enjoyed this well written and well constructed paper. I would favour some minor revisions with a reduction and focus of the discussion, a slight expansion on gastroepiploic arcade preservation and a little bit more clinical information . I would also consider the cogent suggestions of the two reviewers as a minor revision. I would be pleased to see the manuscript revision.

We really appreciate your encouraging comments and that you are considering our manuscript for publication. As requested, we have lengthened the Discussion on gastroepiploic arcade preservation and added further clinical information:

- "As previously mentioned, gastric perforations are commonly located in the upper portion of the greater curvature. Therefore, preserving the gastroepiploic arcade during an omentectomy would reduce the risk of perforation, particularly in patients undergoing an associated splenectomy." (page 13 lines 280-284, new words underlined)

- "The clinical presentation of our patients was a combination of the following signs and symptoms: Acute and severe abdominal pain, abdominal tenderness, nausea, vomiting, gastric fluid in the abdominal drain, fever and/or clinical deterioration. In all cases the diagnosis was made using an abdominal computed tomography (CT) and confirmed during surgery." (page 10 lines 205-209, new words underlined)

Additionally, we have reduced the overall length of the Discussion and we have made the modifications suggested by the reviewers. All these modifications can be seen all over the manuscript with the track changes option.

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We have added the following statement to the Methods section (page 6 lines 118-120, new words underlined):

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We have provided the additional information requested by the Journal in the Methods section (page 6 lines 110-116, new words underlined):

A computer-generated search in the institutional patient database was carried out in February 2020 to retrospectively identify all patients who underwent an open upfront or interval CRS after primary diagnosis of PC of different origins (ovarian cancer, endometrial cancer, colon cancer, PMP and DMPM) between March 2007 and December 2018 at the Institut Claudius Regaud Comprehensive Cancer Center - IUCT - Oncopole (Toulouse, France), which is an expert center for rare peritoneal diseases (RENAPE network).

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As requested by the Journal, Figures 1 and 2 have been added as Supplementary Figures 1 and 2 (Supporting information).

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We have tried to include the tables within the manuscript, but due to Word formatting issues, the tables (mainly Table 4) are not shown as we would like. For this reason, we added a remark indicating where these tables should be placed (e.g., Insert Table 1 here).

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"Martina Aida Angeles acknowledges the grant support from ”la Caixa” Foundation, Barcelona (Spain), ID 100010434. The fellowship code is LCF/BQ/EU18/11650038."

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Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (38.8KB, docx)

Decision Letter 1

Wen-Chi Chou

23 Feb 2021

Risk factors for gastric perforation after cytoreductive surgery in patients with peritoneal carcinomatosis: Splenectomy and increased body mass index

PONE-D-20-33398R1

Dear Dr. Ferron,

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.

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #2: After going over the revised manuscript, I think the authors have addressed the concerns of the reviewers and editor. And I can say that the manuscript is much better now in its current form and advise to accept.

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Reviewer #1: Yes: Nir Horesh

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Acceptance letter

Wen-Chi Chou

24 Feb 2021

PONE-D-20-33398R1

Risk factors for gastric perforation after cytoreductive surgery in patients with peritoneal carcinomatosis: Splenectomy and increased body mass index 

Dear Dr. Ferron:

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.

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on behalf of

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Associated Data

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

    Supplementary Materials

    S1 Fig. Preservation of the gastroepiploic arcade during an omentectomy.

    (DOCX)

    Click here for additional data file. (2.1MB, docx)
    S2 Fig. Prophylactic suture of the greater curvature of the stomach.

    (DOCX)

    Click here for additional data file. (690.6KB, docx)
    S3 Fig. Postoperative gastric perforation located in the upper portion of the greater curvature.

    (DOCX)

    Click here for additional data file. (2.2MB, docx)
    S4 Fig. Gastric opacified computed tomography.

    Gastric wall perforation and extraluminal free air are marked with yellow arrows.

    (DOCX)

    Click here for additional data file. (106.4KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (38.8KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting information files.

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