Combined Interval Cytoreductive Surgery and Carboplatin-Based Hyperthermic Intraperitoneal Chemotherapy in Advanced Primary High-Grade Serous Ovarian Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript presents a retrospective analysis of 40 highly selected uniform cohort of patients having serous high grade ovarian cancer, stage IIIC/V, treated with NACT and interval debulking surgery combined with carboplatin based chemotherapy.

The introduction and scientific question being explored are based mainly on OVHIPEC study. However, I would strongly suggest to add into the introduction or discussion an important fact associated with OVHIPEC study. And that is that significantly more patients in surgery arm (40 %) had a platinum resistant disease compared to the surgery plus HIPEC arm (26%). As platinum resistant disease has by its nature and lack of systemic treatment worse prognosis one needs to be careful to draw conclusions. 

The methods and results are clearly presented. 

I would suggest to comment the average days for recovery in terms of parenteral nutrition, time to initiate diet and number of days having nasogastric tube. Is ERAS implemented in this centre? If yes please comment the necessity of such long times. Is this associated with adding of HIPEC?

It would also substantially improve the manuscript if comparison of postoperative period would be able with patients having had only surgery with no HIPEC. Is it possible within the same centre to retrospectively analise patients having had the same surgical procedures and no intraoperative chemotherapy? In terms of short and long term complications as well as recovery?

Furthermore, is it possible for authors to find similar retrospective cohort of patients having had only surgery without HIPEC and compare the outcomes between the groups? Or at least to compare survival rates with general data from the national/institutional cancer registry? To at least in one way discuss the survival benefit of HIPEC in comparison to no HIPEC.

It is of utmost importance not only to be able to conclude that adding HIPEC may be associated with acceptable morbidity. If we add a treatment modality to standard of care treatment the morbidity needs to be comparable (not worse) and the survival benefit must be clinically important and clear. Authors should somehow discuss this.

The language is clear and understandable.

Author Response

Dear reviewer, 

We thank you for your time and your comments. Please find below our response to each of your suggestions. 

• The manuscript presents a retrospective analysis of 40 highly selected uniform cohort of patients having serous high grade ovarian cancer, stage IIIC/V, treated with NACT and interval debulking surgery combined with carboplatin based chemotherapy.The introduction and scientific question being explored are based mainly on OVHIPEC study. However, I would strongly suggest to add into the introduction or discussion an important fact associated with OVHIPEC study. And that is that significantly more patients in surgery arm (40 %) had a platinum resistant disease compared to the surgery plus HIPEC arm (26%). As platinum resistant disease has by its nature and lack of systemic treatment worse prognosis one needs to be careful to draw conclusions.
  • We have not been able to find this information in the published article. We can gladly add this precision in the background section, but is it possible to provide us with the source of the information. 

• The methods and results are clearly presented. I would suggest to comment the average days for recovery in terms of parenteral nutrition, time to initiate diet and number of days having nasogastric tube. Is ERAS implemented in this centre? If yes please comment the necessity of such long times. Is this associated with adding of HIPEC? Fait, explications ajouté dans méthodes et discussion
  • We have clarified our local protocol for resuming diet post-operatively in the methods (section 2.2)  and discussion sections

• It would also substantially improve the manuscript if comparison of postoperative period would be able with patients having had only surgery with no HIPEC. Is it possible within the same centre to retrospectively analise patients having had the same surgical procedures and no intraoperative chemotherapy? In terms of short and long term complications as well as recovery?
  • Unfortunately, we do not have the possibility to compare our group of patients with similar patients undergoing cytoreductive surgery alone at our center. Most of our patients who did not receive HIPEC had a CC-2 and are therefore fundamentally different. These cases are quite rare as well since we make sure to operate on patients which we are confident to achieve a CC-0. 

• Furthermore, is it possible for authors to find similar retrospective cohort of patients having had only surgery without HIPEC and compare the outcomes between the groups? Or at least to compare survival rates with general data from the national/institutional cancer registry? To at least in one way discuss the survival benefit of HIPEC in comparison to no HIPEC
  • Unfortunately, we do not have a provincial or national database available. Also, the unique collaboration with surgical oncologists makes the comparison difficult with solely the gynecologic oncological practice.
  •  As presented in the background section, all the articles regarding carboplatin-based HIPEC are included. The benefits of HIPEC are well demonstrated for cisplatin-based HIPEC as shown by the OVHIPEC trial for example and the NCCN guidelines. 

• It is of utmost importance not only to be able to conclude that adding HIPEC may be associated with acceptable morbidity. If we add a treatment modality to standard of care treatment the morbidity needs to be comparable (not worse) and the survival benefit must be clinically important and clear. Authors should somehow discuss this.
  • We have improved the section regarding future research. 
  • We agree that we are not able to conclude that carboplatin-based HIPEC is better than cisplatin-based HIPEC based on our results. We argue that it is an interesting alternative, especially in particular cases of contraindications or adverse toxicities to cisplatin, which warrant further studies. We definitely need more information and data prior to recommend a change in practice. 

• The language is clear and understandable.

Reviewer 2 Report

Comments and Suggestions for Authors

My dears,

This is an interesting paper tackling an important clinical issue. Please find my comments in the attached pdf file.

Best of luck with your work!

Comments for author File: Comments.pdf

Author Response

Dear reviewer, 

We thank you for your time and your comments. Please find below our response to each of your suggestions. 

• Abstract
  • CRS for cytoreductive surgery is a common and accepted acronym in the literature and we have decided to keep it. 
• Introduction
  • Clarification of HIPEC mechanism added as suggested
• Methods
  • Ethics approval number added
  • 2.1: clarification of the terminology of completeness of cytoreduction
  • 2.5: clarfication of inclusion into multivariate regression model
• Results
  • 3.1: Ca 125 units at our center are kU/L which is equivalent to units/ml. We have made the change to the more common units used (units/ml)
  • Table 2:
    • We did not add the Aletti complexity score because none of our patients had primary debulking surgery. All the patients in our cohort had interval debulking surgery.
    • CC2 was removed since there were no patient in the category
  • Table 4:
    • We have added the confidence interval for PFS and OS.
    • We have removed the 2 patients with CC-1 from the "recurrence" calculations. We present the 2 cases as progression in the table
  • Table 5: 
    • We added a comment in the discussion regarding the fact that there were only 2 patients with CC-2, which is probably the reason that CC is not statistically significative for OS and DFS in the multivariate analysis
    • We have contacted our statistician to include the duration of exposure to carboplatin (60 vs 90 minutes) in the univariate and multivariate analysis (if p<0.2). We do not expect to find a significative difference because of the small cohort. It will also be important to keep in mind that patients in the 90-min group have a shorter follow-up and might seem to have a less favorable prognosis. This will be discussed once we have the results.

Reviewer 3 Report

Comments and Suggestions for Authors

The title of the work submitted for review is: Combined interval cytoreductive surgery and carboplatin-based hyperthermic intraperitoneal chemotherapy in advanced primary high-grade serous ovarian cancer.

The aim of the work (as presented by the authors) sent for review is: “The objective of this study was to report on the safety and feasibility of combined 168 interval complete CRS with carboplatin-based HIPEC on patients with advanced primary 169 high-grade serous ovarian cancer.

The manuscript is clear and relevant to the field. The submission of the manuscript titled "Combined interval cytoreductive surgery and carboplatin-based hyperthermic intraperitoneal chemotherapy in advanced primary high-grade serous ovarian cancer" is most appropriate for Current Oncology (Special Issue: Surgery Advances in Gynecologic Tumors). The layout is good and it reads well.

Citations are appropriately selected. Of the 26 citations, 11 are from the last 5 years, including one from 2023.

All tables and one figure are clear and their descriptions understandable.

The conclusions are consistent with the data presented and refer to the main question asked.

Further studies with larger patient samples will be necessary. The study would have a better effect if multiple centers were included in the study.

The work is written correctly and reads well. It raises an important topic.

Comments for author File: Comments.pdf

Author Response

Dear reviewer, 

We thank you for your time and your comments. Please find below our response to your suggestion. 

• Further studies with larger patient samples will be necessary. The study would have a better effect if multiple centers were included in the study.
  • We agree that larger and multi-centric studies are required prior to including carboplatin-based HIPEC in formal practice. We hope that this article raises interest on the matter and leads to further consideration of this agent, especially in patients with contraindications or prior toxicities to cisplatin.   

 

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Author,

I carefully read your article entitled “Combined interval cytoreductive surgery and carboplatin-based hyperthermic intraperitoneal chemotherapy in advanced primary high-grade serous ovarian cancer”. Ovarian cancer with PSM was considered terminal disease but at the end of the last millennium novel surgical techniques arised, such as peritonectomy, multivisceral resections and HIPEC. Many studies in literature confirm the role of the combination of intraperitoneal chemotherapy and hyperthermia on the microscopic peritoneal tumor deposits at the end of cytoreductive surgery and many other studies assess the role of HIPEC in increasing sensitivity to chemotherapeutic agents.

 

In literature there are studies about Carboplatin HIPEC for recurrent platinum-sensitive OC and studies about HIPEC after PDS; and as You reported at lines 62-65 there are also few studies about Carboplatin HIPEC after IDS.

 

 

I have some advice for the Author:

·       You evaluated 40 patients between 2014 and 2020 but as specified at line 97-99 the HIPEC regimen changed during the study period, some patients received a dose of 800 to 900 mg for 60 minutes and some patients received a dose of 1000 mg for 90 minutes. This can affect the result as You said in the “strength and weaknesses” paragraph, but which one can be considered the better regimen to perform, the second one? Why? Please specify

·       Moreover You have to fix the percentages about how many patients received 60 minutes or 90 minutes because at line 130 You say “60 minutes (25% of patients) or over 90 minutes (75% of patients)” but in Table 2 You say the opposite: 30 patients for 60 min and 10 patients for 90 min. Please correct

·       At line 61 You affirm that Carboplatin HIPEC has a favorable side effect profile compared to cisplatin in systemic use: can You explain better or give some examples? I suggest to mention this article: “Hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin induces distinct transcriptomic changes in ovarian tumor and normal tissues”. Lea A Moukarzel, Lorenzo Ferrando, Higinio Dopeso et Al.

·       It’s confirmed in literature that completeness of cytoreduction or amount of residual disease is the strongest predictor of OS; in Your study at lines 152-157 You showed no significant impact of completeness of cytoreduction on OS: how can You explain this?

 

 

For sure the data presented are interesting, well analyzed and appropriate, tables are detailed and useful for the reader. Unfortunately, the study is retrospective and single center, the sample size is small and the follow up is short.

 

In future the oncological outcomes of Carboplatin based HIPEC must be deepened, for example comparing DFS and OS in two groups of patients: IDS + HIPEC versus no HIPEC, as was done in the OVHIPEC-1 trial.

At line 174-180 and 188-197 You wisely compare the outcomes of Your study with the outcomes of Cisplatin-based HIPEC studies (as OVHIPEC). But it should be even more interesting to compare oncological outcomes and procedure-related complications between Cisplatin-based HIPEC versus Carboplatin-based HIPEC in a RCT where patients are randomly assigned to one of the two procedures.

Comments on the Quality of English Language

Minor editing of English language required

Author Response

Dear reviewer, 

We thank you for your time and your comments. Please find below our response to each of your suggestions. 

• You evaluated 40 patients between 2014 and 2020 but as specified at line 97-99 the HIPEC regimen changed during the study period, some patients received a dose of 800 to 900 mg for 60 minutes and some patients received a dose of 1000 mg for 90 minutes. This can affect the result as You said in the “strength and weaknesses” paragraph, but which one can be considered the better regimen to perform, the second one? Why? 
  • We have requested to add the duration of HIPEC exposure in the univariate and multivariate analysis to our statistician. It will be important to keep in mind that the 90-min group has a shorter follow up and might seem to have a less favorable prognosis. 
  • We have improved the discussion on the choice of regimen and change to the regimen. 

• Moreover You have to fix the percentages about how many patients received 60 minutes or 90 minutes because at line 130 You say “60 minutes (25% of patients) or over 90 minutes (75% of patients)” but in Table 2 You say the opposite: 30 patients for 60 min and 10 patients for 90 min. Please correct
  • Thank you for pointing it out, the correction have been made in the table. 

• At line 61 You affirm that Carboplatin HIPEC has a favorable side effect profile compared to cisplatin in systemic use: can You explain better or give some examples? I suggest to mention this article: “Hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin induces distinct transcriptomic changes in ovarian tumor and normal tissues”. Lea A Moukarzel, Lorenzo Ferrando, Higinio Dopeso et Al. 
  • We have added the reference in the background to offer a better explanation of the mechanism of carboplatin in the context of HIPEC. 

• It’s confirmed in literature that completeness of cytoreduction or amount of residual disease is the strongest predictor of OS; in Your study at lines 152-157 You showed no significant impact of completeness of cytoreduction on OS: how can You explain this?
  • We have added a comment on the matter in the discussion. We believe that the low number of patients with CC-1 (only 2) explains the lack of significance. We can see a trend in the multivariate analysis.

• In future the oncological outcomes of Carboplatin based HIPEC must be deepened, for example comparing DFS and OS in two groups of patients: IDS + HIPEC versus no HIPEC, as was done in the OVHIPEC-1 trial. 
  • We agree and we have improved the future research section

• At line 174-180 and 188-197 You wisely compare the outcomes of Your study with the outcomes of Cisplatin-based HIPEC studies (as OVHIPEC). But it should be even more interesting to compare oncological outcomes and procedure-related complications between Cisplatin-based HIPEC versus Carboplatin-based HIPEC in a RCT where patients are randomly assigned to one of the two procedures.
  • We agree and we hope that our work encourages future studies as such. We have improved the future research section to make it more explicit. 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I am attaching OVHIPEC manuscript with marked text (in green) about platinum-resistant disease. It is of utmost importance. If 40 % of patients in surgery only arm had platinum-resistant disease and 26 % of patients in surgery plus HIPEC had platinum resistant disease we compare different diseases. Authors should comment this. As HIPEC may be present as a possible option in NCCN guidelines it is far from everyday standard of care in majority of gynecologic oncology centres. Results of present study need to be put in this perspective as well. 

Comments for author File: Comments.pdf

Author Response

Dear reviewer,

Thank you for providing the reference. We have added a section commenting on these findings in the discussion section. 

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

Please check the comments in the attached manuscript. As said, HIPEC is NOT accepted at majority gynecologic oncology centres for several reasons. And authors should aknowledge and accept this and include this fact in all aspects of the manuscript. Starting with the abstracts. As pointed out, there are no clear results that HIPEC prolong survival as the major prospective trial has important drawbacks. I believe this manuscript can add to the knowledge about comparison between cisplatin and carbolatin used in HIPEC. But that is it. The manuscript needs to be put in broader perspective throughout all subchapters.

Comments for author File: Comments.pdf

Author Response

Dear reviewer,

We thank you for your comments. We have added some nuances to the background and discussion sections to represent that HIPEC is not universally accepted or performed. We have removed the previous comment that you highlighted.

Our aim is to share our local experience and be thought-provoking regarding the consideration of carboplatin as a potential agent for HIPEC. Our goal is not to address the controversies surrounding the acceptance of HIPEC at large, but, as you mentioned, to offer a comparison with the literature on cisplatin-based HIPEC. We do not wish to debate whether HIPEC should be used or not, but whether on the preferred regimen when it is performed. We hope that these new considerations could lead to future studies to lower the risks and maximize the benefits of HIPEC.

Thank you for your time,