Severe pulmonary complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are common and contribute to decreased overall survival.

BACKGROUND AND OBJECTIVES: Extensive abdominal surgery is associated with the risk of postoperative pulmonary complications. This study aims to explore the incidence and risk factors for developing postoperative pulmonary complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and to analyze how these complications affect overall survival.
METHODS: Data were collected on 417 patients undergoing surgery between 2007 and2017 at Uppsala University Hospital, Sweden. Postoperative pulmonary complications were graded according to the Clavien-Dindo classification system where Grade ≥ 3 was considered a severe complication. A logistic regression analysis was used to analyze risk factors for postoperative pulmonary complications and a Cox proportional hazards model to assess impact on survival.
RESULTS: Seventy-two patients (17%) developed severe postoperative pulmonary complications. Risk factors were full thickness diaphragmatic injury and/or diaphragmatic resection [OR 5.393, 95% CI 2.924-9.948, p = < 0.001]. Severe postoperative pulmonary complications, in combination with non-pulmonary complications, contributed to decreased overall survival [HR 2.285, 95% CI 1.232-4.241, p = 0.009].
CONCLUSIONS: Severe postoperative pulmonary complications were common and contributed to decreased overall survival. Full thickness diaphragmatic injury and/or diaphragmatic resection were the main risk factors. This finding emphasizes the need for further research on the mechanisms behind pulmonary complications and their association with mortality.

Introduction

Peritoneal metastasis (PM) represents the third most frequent metastatic site after hepatic and pulmonary deposits in colorectal cancer [1]. Historically, the diagnosis has been associated with a poor prognosis [2] but the 1990s saw the introduction of a curative treatment for selected patients with PM: cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) [3]. The aim of this procedure is to resect all visible tumor tissue and perioperatively flush the abdominal cavity with heated chemotherapy, targeting microscopic residual tumor tissue [3]. CRS and HIPEC has led to an increased survival rate in patients with PM [4] but postoperative morbidity and mortality rates still range between 10% and 30% and 1% and 5% respectively [5-8].

Postoperative pulmonary complications (PPCs), such as pneumonia and respiratory failure, are common in the period after abdominal surgery [9] and studies on PPCs after CRS and HIPEC quote an incidence between 6.8% and 69% [10-13]. Non-pulmonary complications such as hemorrhage and wound infection are also frequent after CRS and HIPEC: reports suggest that the overall severe morbidity rate is around 12% [8]. Some of the proposed risk factors for developing PPCs after abdominal surgery are poor general health status, smoking, lung disease, and the type and duration of surgery [9,14]. Suggested prophylactic measures include pre- and postoperative interventions such as smoking cessation, prophylactic physical therapy, and continuous positive airway pressure (CPAP) in the postoperative period [15-17]. A better understanding of the risk factors for developing PPCs after CRS and HIPEC could improve the perioperative treatment of patients with PM and potentially decrease the incidence of PPCs.

There is currently limited information regarding risk factors related to PPCs after CRS and HIPEC, and to what extent PPCs impact survival rates. The aim of this study was to determine the incidence and risk factors for developing severe PPCs after CRS and HIPEC. Another aim was to investigate whether PPCs impact overall survival.

Materials and methods

Patient selection and data collection

This was a cross-sectional study on all patients who underwent CRS and HIPEC at the Uppsala University Hospital between 2007 and 2017. Data were extracted from both medical records and the Swedish Intensive Care Unit Registry (PasIva) [18]. Demographic and clinical data were collected on gender, age, body mass index (BMI), lung disease (defined as chronic obstructive pulmonary disease, asthma, chronic bronchitis and/or sleep apnea), smoking (current or former smoker), the American Society of Anesthesiologists’ physical status classification (ASA), and primary tumor origin. Data were also collected on operative variables such as the peritoneal cancer index (PCI) [19], completeness of cytoreduction score (CC score) [20], duration of surgery, liver resection, splenectomy, diaphragmatic peritonectomy, full thickness diaphragmatic injury and/or diaphragmatic resection, type and grade of pulmonary complications, as well as type and grade of non-pulmonary complications. The study was approved by the Swedish Ethical Review Authority in Uppsala, Sweden (reference no. 2013/203). The data were analyzed anonymously and therefore, written/verbal consent was not required or obtained.

Patient selection for CRS and HIPEC is based on the absence of unresectable metastatic disease, PCI and patient ability to withstand extensive surgery [21]. To identify patients for inclusion, we used a local register from Uppsala University Hospital of patients who had undergone surgery because of PM. All 438 adult patients who underwent CRS and HIPEC between January 1, 2007 and December 31, 2017 were eligible for the study and the primary tumor origin was colon, rectum, appendix, small intestine, stomach, ovarium or peritoneum. The most frequently used chemotherapy regimens were Mitomycin C (for 90 minutes) for appendiceal tumors or Oxaliplatin (for 30 minutes) for tumors of colorectal origin.

Grading of complications

In this study the Clavien-Dindo classification of surgical complications [22] was used to grade both pulmonary and non-pulmonary complications. The classification system consists of seven severity grades including two subgrades for Grades 3 and 4. Grade 1 refers to a deviation from the normal postoperative course without the need for pharmacological (with some exceptions), surgical, radiological or endoscopic treatment. Grade 2 corresponds to complications that need pharmacological treatment, blood transfusion or total parenteral nutrition. Complications that require surgical, endoscopic or radiological interventions are classified as Grade 3 and the two subcategories within Grade 3 divide the interventions into (a) interventions not under general anesthesia or (b) interventions under general anesthesia. Examples of a Grade 3 complication are pleural effusion that requires drainage and reoperation because of anastomotic leaks. A Grade 4 category corresponds to life-threatening complications requiring ICU management where single organ dysfunction is graded 4a and multi-organ dysfunction is graded 4b. In this study respiratory complications that required prolonged mechanical ventilation (defined as longer than what was routine) and/or reintubation or non-invasive ventilation due to respiratory complications were graded 4. Surgical complications that required intensive care were sepsis and various heart conditions. Death is graded 5. In this study, we classified PPCs Grade ≥ 3 as being severe PPCs. For the purpose of this study, patients were divided into two groups based on the occurrence of PPCs: patients with PPCs Grade < 3 (including those with no PPCs) and patients with PPCs Grade ≥ 3 according to the Clavien-Dindo classification of surgical complications. All PPCs occurring during the hospital stay at Uppsala University Hospital were identified and graded. All non-pulmonary complications were grouped together and split into two groups: Grade < 3 or Grade ≥ 3.

Statistical analysis

Demographic, clinical and operative characteristics were presented descriptively in relation to the presence or absence of severe PPCs. Continuous data were presented with means and standard deviations. Categorical data were presented with frequencies and percentages. A univariate analysis of risk factors considered to be associated with severe PPCs was performed. Variables with a p-value ≤ 0.1 in the univariate analysis and variables previously well established as risk factors were included in the multivariate logistic regression model and the odds ratio (OR) for each variable was estimated. A Kaplan-Meier estimation including a log rank test and a Cox proportional hazards model was performed to analyze survival rates between patients with different grades of PPCs and/or non-pulmonary complications. Variable selection was performed by conducting a univariate analysis of variables considered to be associated with overall survival. A Cox proportional hazards model was then built from the variables with a p-value ≤ 0.1 in the univariate analysis and variables known to be correlated with overall survival. Overall survival was defined as the time from surgery to date of death. Patients who were alive at the end of the data collection (April 25, 2019) were censored. All data were processed and analyzed with IBM SPSS Statistics for Windows version 23 (IBM Corp, Armonk, NY, USA). The significance threshold was set at < 0.05.

Results

Baseline characteristics

A total of 438 patients underwent CRS and HIPEC between January 1, 2007 and December 31, 2017. After excluding patients with an unknown CC score (n = 4), CC-2 (n = 6) and CC-3 (n = 11), 417 patients were included in the analyses (Fig 1). Patient characteristics are presented in Table 1.

Fig 1

Flowchart of inclusions and exclusions of the study.

CRS Cytoreductive surgery HIPEC Hyperthermic intraperitoneal chemotherapy CC score Completeness of cytoreduction score.

Table 1

Characteristics of 417 patients undergoing CRS and HIPEC between 2007 and 2017.

	PPCs Grade <3 (n = 345)	PPCs Grade ≥3 (n = 72)
Gender (male)	143 (41%)	31 (43%)
Age, years
Mean, SD	57 ± 13.0	60 ± 11.5
BMI	25.8 ± 4.1	26.6 ± 5.4
ASA score
1	95 (27.5%)	14 (19.5%)
2	192 (56%)	42 (58%)
3	45 (13%)	13 (18%)
4	5 (1.5%)	2 (3%)
Missing	8 (2%/)	1 (1.5%)
Smokinga	87 (25%)	24 (33%)
Lung diseaseb	26 (7.5%)	7 (10%)
Primary tumor
Colon	133 (38.5%)	27 (37.5%)
Appendix	119 (34.5%)	21 (29%)
Rectum	13 (4%)	5 (7%)
Small intestine	9 (3%)	4 (5.5%)
Ovarium	12 (3.5%)	4 (5.5%)
Appendix (benign)	7 (2%)	0 (0%)
Gastric	2 (0.5%)	1 (1.5%)
Mesothelioma	14 (4%)	2 (3%)
Unknown primary	36 (10%)	8 (11%)
Diagnosis
PMP, no neoplastic cells	153 (44%)	25 (35%)
Colorectal, mesothelioma and others	192 (56%)	47 (65%)
PCI	15.2 ± 10.5	20.0 ± 10.0
Duration of surgery (min)	470 ± 149.4	530 ± 137.3
Liver resection	65 (19%)	23 (32%)
Splenectomy	110 (32%)	30 (42%)
Diaphragmatic peritonectomy	171 (50%)	55 (76%)
Full thickness diaphragmatic injury and/or diaphragmatic resection	35 (10%)	30 (42%)
CC score
0	275 (80%)	47 (65%)
1	70 (20%)	25 (35%)
Non-pulmonary complicationsc
No	327 (95%)	52 (72%)
Yes	18 (5%)	20 (28%)

CRS Cytoreductive surgery HIPEC Hyperthermic intraperitoneal chemotherapy PPCs Postoperative pulmonary complications SD Standard deviation BMI Body mass index ASA American Society of Anesthesiologists.

PCI Peritoneal Cancer Index CC score Completeness of cytoreduction score.

a Current or former smoker.

b Chronic obstructive pulmonary disease, asthma, chronic bronchitis and/or sleep apnea.

c Including abdominal abscess, hemorrhage, cardiac complications, gastrointestinal perforations, sepsis, wound dehiscence, anastomotic leaks and ileus.

Incidence of complications and risk factors for severe PPCs

The incidence of PPCs Grade ≥ 3 was 17% (72 out of 417 patients) and the types of PPCs were pleural effusion or pneumothorax requiring drainage (n = 60) and postoperative reintubation or prolonged need of mechanical ventilation/non-invasive ventilation because of pulmonary complications such as respiratory failure and pneumothorax (n = 25). The percentage of patients developing one or more non-pulmonary complications Grade ≥ 3 was 9% (38 out of 417 patients) and reoperation was required in 25 (66%) of these patients. The types of non-pulmonary complications Grade ≥ 3 were abdominal abscess (n = 15), hemorrhage (n = 11), cardiac complications (n = 6), gastrointestinal perforations (n = 6), sepsis (n = 5), wound dehiscence (n = 5), anastomotic leaks (n = 4) and ileus (n = 2). In all, 52/72 of PPCs Grade ≥ 3 were isolated pulmonary complications whereas 20 (28%) occurred together with non-pulmonary complications Grade ≥ 3 (Table 1). Full thickness diaphragmatic injury and/or diaphragmatic resection [OR 5.393, 95% CI 2.924–9.948, p = < 0.001] were the most influential variables in the multivariate model, while neither age, smoking, PCI, liver resection nor diaphragmatic peritonectomy contributed statistically significantly to the model (Table 2).

Table 2

Unadjusted and adjusted results of odds ratios and p-values for the variables included in the final model on risk factors for severe pulmonary complications after CRS and HIPEC.

	Unadjusted results	P-valuea	Adjusted results	P-valuea
	OR (95% CI)		OR (95% CI)
Age	1.000 (1.000–1.000)	0.104	1.000 (1.000–1.000)	0.095
BMI
< 18.5	1.926 (0.369–10.045)	0.437
18.5–25	Reference
> 25–30	1.219 (0.681–2.182)	0.506
> 30	1.712 (0.857–3.418)	0.128
ASA score
1	Reference
2	0.368 (0.065–2.085)	0.259
3	0.547 (0.103–2.915)	0.480
4	0.722 (0.125–4.165)	0.716
Smokingb	1.483 (0.858–2.562)	0.158	1.605 (0.866–2.975)	0.133
PCI	1.043 (1.018–1.068)	0.001	1.020 (0.986–1.054)	0.255
Liver resection	2.022 (1.150–3.554)	0.014	1.576 (0.831–2.991)	0.164
Splenectomy	1.526 (0.907–2.568)	0.111
Diaphragmatic peritonectomy	3.292 (1.837–5.900)	< 0.001	1.828 (0.872–3.832)	0.110
Full thickness diaphragmatic injury and/or diaphragmatic resection	6.327 (3.526–11.351)	< 0.001	5.393 (2.924–9.948)	< 0.001

CRS Cytoreductive surgery HIPEC Hyperthermic surgery OR Odds ratio CI Confidence interval BMI Body mass index ASA score American Association of Anesthesiologists score PCI Peritoneal cancer index.

a Logistic regression.

b Current or former smoker.

PPCs and overall survival

In the Cox proportional hazards model, PPCs Grade ≥3 were not independently associated with decreased overall survival (p = 0.3). However, having both PPCs Grade ≥3 and non-pulmonary complications Grade ≥3 was associated with decreased overall survival (Fig 2), [HR 2.285, 95% CI 1.232–4.241, p = 0.009] when adjusted for gender, age, BMI, ASA score, diagnosis, CC score and PCI (Table 3).

Fig 2

Kaplan-Meier curves on overall survival in relation to PPCs Grade ≥3, non-pulmonary complications Grade ≥3 or combined PPCs Grade ≥3 and non-pulmonary complications Grade ≥3.

PPCs Postoperative pulmonary complications Non-pulmonary complications Including abdominal abscess, hemorrhage, cardiac complications, gastrointestinal perforations, sepsis, wound dehiscence, anastomotic leaks and ileus.

Table 3

Unadjusted and adjusted results of hazard ratios and p-values for the variables included in the final model on overall survival after CRS and HIPEC.

	Unadjusted results	P-valuea	Adjusted results	P-valuea
	HR (95% CI)		HR (95% CI)
Gender (male/female)	0.732 (0.539–0.994)	0.045	0.625 (0.445–0.876)	0.006
Age	1.000 (0.999–1.000)	0.602	1.000 (1.000–1.000)	0.870
BMI
< 18.5	2.773 (1.007–7.631)	0.048	4.683 (1.640–13.369)	0.004
18.5–25	Reference		Reference
> 25–30	0.808 (0.572–1.143)	0.228	0.726 (0.503–1.048)	0.088
> 30	1.035 (0.671–1.596)	0.876	0.911 (0.576–1.442)	0.691
Comorbidity (yes/no)	0.914 (0.665–1.257)	0.580
ASA score	1.260 (1.000–1.587)	0.050	1.198(0.931–1.540)	0.160
Diagnosis (PMP, no neoplastic cells/colorectal, mesothelioma, others)	7.988 (5.122–12.456)	< 0.001	8.085 (5.106–12.801)	< 0.001
CC score (0/1)	0.775 (0.529–1.136)	0.192	0.581 (0.370–0.913)	0.019
PCI	1.021 (1.007–1.035)	0.003	1.035 (1.018–1.053)	< 0.001
Liver resection	1.060 (0.740–1.520)	0.750
Splenectomy	0.894 (0.646–1.238)	0.500
No complication	Reference		Reference
PPCs ≥3	1.285 (0.809–2.042)	0.288	1.311 (0.793–2.167)	0.291
Non-pulmonary complications ≥3	1.389 (0.679–2.840)	0.368	1.259 (0.613–2.586)	0.531
PPCs + non-pulmonary complications ≥3	3.328 (1.826–6.064)	< 0.001	2.285 (1.232–4.241)	0.009

CRS Cytoreductive surgery HIPEC Hyperthermic intraperitoneal chemotherapy HR Hazard ratio CI Confidence interval.

BMI Body mass index ASA score American Association of Anesthesiologists score PMP Pseudomyxoma peritonei.

CC score Completeness of cytoreduction score PCI Peritoneal cancer index PPC Postoperative pulmonary complication.

Cox regression.

Discussion

In this large cohort of patients, we found severe PPCs to be common after CRS and HIPEC and to contribute to decreased overall survival. The multivariate model of risk factors identified full thickness diaphragmatic injury and/or diaphragmatic resection as significantly associated with severe PPCs.

To date, our study is the largest one conducted on the incidence and risk factors for PPCs after CRS and HIPEC. Previous studies have presented a wide range of incidence numbers, 6.8%-69%, and have also used a variety of grading systems [10-13], which complicates comparison. Sinukumar et al. [10], Arakalian et al. [11], and Cascales Campos et al. [12] all used different versions of the Common Terminology Criteria for Adverse Events (CTCAE) [23] whereas Preti et al. [13] used a customized classification system for their study. We found a higher incidence of PPCs than the majority of these studies and we believe that this could be partially explained by the use of a different grading system. Unfortunately, we could find no previous studies on PPCs in patients with peritoneal metastases using the same classification system as we did, the Clavien-Dindo classification system, making it difficult to conduct a valid comparison between the results.

The main risk factors in our study were full thickness diaphragmatic injury and/or diaphragmatic resection, both of which are sometimes unavoidable when trying to reach a complete cytoreduction [24-26]. The role of diaphragmatic procedures such as peritonectomy along with full thickness diaphragmatic injury and/or diaphragmatic resection as risk factors for PPCs is controversial [12,13]. In our cohort, diaphragmatic peritonectomy was not a significant risk factor for PPCs, in contrast to previous studies such as the one from Cascales Campos et al. [12] who identified diaphragmatic peritonectomy as the main risk factor. However, they did not find prophylactic chest tubes indicated since the number of patients requiring chest tubes in their study was low. Likewise, Ye et al. [27] did not recommend prophylactic chest tubes after diaphragmatic peritonectomy, but they proposed that they should be considered after full thickness diaphragmatic resection. With the knowledge that severe PPCs, such as pleural effusion requiring chest tubes, might be related to increased mortality, our study suggests a re-evaluation of the use of prophylactic chest tubes. This is supported by Sandadi et al [28] who found that prophylactic chest tubes decreased the incidence of pleural effusion after diaphragmatic procedures as a part of CRS. The management of chest tubes is not without complications since they present the potential for injuries to the stomach and infections [29]. However, tubes inserted intraoperatively under full control are probably safer to use.

Surprisingly, neither smoking nor age, both established risk factors for the development of PPCs [14,30-32], were associated with severe PPCs in this cohort. This is interesting and might be a result of patient selection for CRS and HIPEC where heavy smokers with obstructive pulmonary disease might have been ineligible for surgery. Patients with PM are also younger on average than many other cancer patient groups and this might reduce the impact of age in this cohort. These results concur with previous studies of patients with PM [12,13].

This study adds a new perspective regarding the impact of PPCs on overall survival after CRS and HIPEC. Both increased in-hospital mortality [33] and long-term mortality [34] have been associated with PPCs, but this is the first study to examine the effects in patients with peritoneal metastases. In our cohort, neither PPCs Grade ≥ 3 nor non-pulmonary complications ≥ 3 alone affected survival rates but when combined, they were associated with decreased overall survival. It has not been established whether it is the PPC itself or the effect of multiple complications that contributes to the decreased overall survival and further studies are required to fully understand the mechanisms behind the increased mortality rates. It would also be useful to investigate whether PPCs are working as a proxy for some other processes in the body affecting mortality.

Some limitations of this study must be considered when interpreting the results. First, data on cause of death were not available in the medical records. Unfortunately, data on recurrence were only partly registered in the medical records since follow up was handled by the referring hospitals. Furthermore, we must also consider that only data on PPCs occurring during the hospital stay at Uppsala University Hospital were accessible. This means that complications occurring later in the postoperative period that might have had an impact on survival rates could have been missed. The incidence rate of severe PPCs presented in this study might also be affected by the short follow-up period. This study suggests that severe PPCs might play a major role for overall survival. However, this needs more thorough investigation.

One of the strengths of our study is that it uses a standardized grading system that is well established in surgical care and all grades of complications are included. This gives a broad picture on the incidence of severe PPCs after CRS and HIPEC and facilitates future comparisons. Another strength of the study is that we included all tumor types, which resulted in a large cohort and a valid representation of the CRS and HIPEC population.

We are unable to draw conclusions on whether it is the PPC itself or the effect of multiple complications that is responsible for the negative correlation with overall survival in this study but regardless of the underlying mechanisms, we suggest that the prevention of severe PPCs can benefit survival rates. It has previously been established that PPCs after abdominal surgery can, to some extent, be prevented [35] and while some complications such as pleural effusion might be rather difficult to avoid when performing diaphragmatic interventions [12,36], others can be more easily prevented. Preoperative physical therapy including inspiratory muscle training (IMT) is one example that has been shown to decrease the risk of pneumonia after major abdominal surgery [35]. There are no studies on physical therapy focused on pre-habilitation performed on patients undergoing CRS and HIPEC, but this might be a promising preoperative intervention to decrease the risk of PPCs and, by extension, it might also affect overall survival.

This study highlights the impact severe PPCs might have on survival rates, but the underlying mechanisms are still unclear. Evaluating the effect of pre-habilitation interventions on PPCs in patients with peritoneal metastases would be an interesting research subject which might shed light on whether the prevention of PPCs, and thus the potential for avoiding decreased overall survival after CRS and HIPEC, is possible.

Conclusion

Severe PPCs are common after CRS and HIPEC and in our study, full thickness diaphragmatic injury and/or diaphragmatic resection were the most influential risk factors. We also found that having both PPCs Grade ≥ 3 and non-pulmonary complications Grade ≥ 3 was associated with decreased overall survival. These results suggest the need for further research on PPCs and mortality to be able to fully understand the mechanisms.

Supplementary file regression analyses.

(DOCX)

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26 Jul 2021

PONE-D-21-23694

Severe pulmonary complications after cytoreductive surgery and HIPEC are common and contribute to decreased overall survival

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24 Sep 2021

1. No uncommon abbreviation or acronyms in the Title, please! What is HIPEC?

Thank you for pointing this out. We have now made revisions according to the guidelines of PLOS ONE and spelled out the acronym hyperthermic intraperitoneal chemotherapy. We appreciate that you made us aware of this error.

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Thank you for making us aware of this error. The information provided in the “Funding information” section now matches the information provided in the “Financial Disclosure”. For clarity, we received funding from the Swedish Cancer. Society (Cancerfonden) grant/award number 160411 and Wilhelm Graf was the one who received this research grant.

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Thank you for allowing us to clarify this. We have now added the requested information in the Data availability statement and it reads as follows: The data underlying the results presented in this study contain potentially sensitive and identifying participant information and cannot be shared publicly due to GDPR. The data are available upon request from registrator@uu.se (reference UU-DsO 2021/106).

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29 Nov 2021

PONE-D-21-23694R1Severe pulmonary complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are common and contribute to decreased overall survivalPLOS ONE

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Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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

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

Reviewer #1: Yes

Reviewer #2: No

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

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

Reviewer #1: In the discussion section, line 216 to line 2018, the authors state that "Unfortunately, we could find no previous studies on PPCs in patients with peritoneal metastases using the Clavien-Dindo classification system, thus making it difficult to compare result". I came across another study, using a rather different, but used Clavien-Dindo classification and included postoperative pulmonary complications among other postoperative complications of CRS and HIPEC.

Sinukumar S, Mehta S, Damodaran D, Rajan F, Zaveri S, Ray M, Katdare N, Sethna K, Patel MD, Kammer P, Peedicayil A, Bhatt A. Failure-to-Rescue Following Cytoreductive Surgery with or Without HIPEC is Determined by the Type of Complication-a Retrospective Study by INDEPSO. Indian J Surg Oncol. 2019 Feb;10(Suppl 1):71-79. doi: 10.1007/s13193-019-00877-x. Epub 2019 Jan 14. PMID: 30886497; PMCID: PMC6397122.

I do not think that the findings of that study would add much to the current work in consideration, but I think that, for the sake of perfection, the mentioned sentence should be omitted or the other work get discussed.

Reviewer #2: (No Response)

**********

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

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

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Reviewer #1: Yes: Salah-Eldin Abdelmoneim

Reviewer #2: No

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7 Dec 2021

1. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

The reference list has been reviewed as requested. No article in the reference list has been retracted.

2. 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: No

We would like to clarify our statement regarding data availability once more. It is due to the General Data Protection Regulation (GDPR) and the potentially sensitive and identifying nature of our data that we cannot share our data publicly. The data are however available upon request from registrator@uu.se (reference UU-DsO 2021/106).

3. Reviewer #1: In the discussion section, line 216 to line 2018, the authors state that "Unfortunately, we could find no previous studies on PPCs in patients with peritoneal metastases using the Clavien-Dindo classification system, thus making it difficult to compare result". I came across another study, using a rather different, but used Clavien-Dindo classification and included postoperative pulmonary complications among other postoperative complications of CRS and HIPEC.

Sinukumar S, Mehta S, Damodaran D, Rajan F, Zaveri S, Ray M, Katdare N, Sethna K, Patel MD, Kammer P, Peedicayil A, Bhatt A. Failure-to-Rescue Following Cytoreductive Surgery with or Without HIPEC is Determined by the Type of Complication-a Retrospective Study by INDEPSO. Indian J Surg Oncol. 2019 Feb;10(Suppl 1):71-79. doi: 10.1007/s13193-019-00877-x. Epub 2019 Jan 14. PMID: 30886497; PMCID: PMC6397122.

I do not think that the findings of that study would add much to the current work in consideration, but I think that, for the sake of perfection, the mentioned sentence should be omitted or the other work get discussed.

Reviewer #2: (No Response)

Thank you for your thorough review and for enlightening us on this study. After reading the article, we have modified the section and the suggested article is mentioned in the revised version. However, in the study by Sinukumar et al., they used the CTCAE classification and not the Clavien-Dindo classification but for the sake of completeness, this article is now discussed and included in the reference list.

4. (Added Dec 7th) Thank you for including your ethics statement on the online submission form: "The study was approved by the Swedish Ethical Review Authority in Uppsala, Sweden (reference no. 2013/203). The data were analyzed anonymously and therefore written/oral consent was not required or obtained.". To help ensure that the wording of your manuscript is suitable for publication, would you please also add this statement at the beginning of the Methods section of your manuscript file.

Thank you for allowing us to make this revision to our manuscript. We have now added this statement at the beginning of the Methods section both in the main manuscript file and in the manuscript with track changes file.

We look forward to hearing from you in due time regarding our submission and to respond to any further questions and comments you may have.

Sincerely,

Olivia Sand

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

13 Dec 2021

Severe pulmonary complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are common and contribute to decreased overall survival

PONE-D-21-23694R2

Dear Dr. Sand,

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

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

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Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

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

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

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

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

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

Reviewer #1: Yes: Salah-Eldin Abdelmoneim

Reviewer #2: No

17 Dec 2021

PONE-D-21-23694R2

Severe pulmonary complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are common and contribute to decreased overall survival

Dear Dr. Sand:

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

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

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

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

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Robert Jeenchen Chen

Academic Editor

PLOS ONE