Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for the opportunity to review this manuscript, which represents a courageous effort to explicitly analyse and present morbidity data relating to radical surgery for ovarian cancer from a single centre. Operative morbidity is often reported only in the context of interventional trials and literature focussing on real-world consequences of radical surgery is welcome. I would consider that the content is sufficient for publication, however the presentation of the research question, the demonstration of the need to fill a gap in knowledge through an exploration of the existing literature and the consideration of the weaknessess of this data need to to be addressed within the manuscript.

The introduction does not adequately set the research question in the context of current data, and does not clearly define the knowledge gap that the paper seeks to fill. The language is superficial at times, for example: on line 63 the authors state that there have been concerns about the safety of of extensive surgery without providing evidence or detail. There is no attempt to explain why morbidity data is lacking in the literature or to demonstrate that an effective review of available data has already taken place in order to ensure that the current presentation is novel and worthy of publication.

The research question is not explicitly stated. the title suggests that the primary outcome variable is time to chemotherapy, but this is not references in the final paragraph were an number of possible outcome variables are referenced without structure of a hierarchy of importance.

It is important for the casual (non-expert - important considering the general nature of this journal) reader to appreciate that pre-operative evaluation of the likelihood of a good surgical outcome and maximal-effort cytoreductive surgery is the standard of care in ovarian cancer, that this comes with a potential morbidity cost over other treatment strategies (NACT and IDS) and that whist controversy over PDS vs IDS exists, that the pursuit of complete macroscopic resection at primary surgery is a valid treatment option when the patient is adequately counselled.

Within the methods section the inclusion and exclusion criteria are not adequately expressed and this leads to uncertainty regarding the reason for inclusion of just 172/409 surgically managed patients. The description of work-up and primary treatment decision making does not make clear how patietns are selected for cytoreductive surgery and lacks detail. Examples of missing detail relate to the number and reason for MRI scanning or laparoscopy.

Considering the results, there are significant characteristic differences between groups (extensive vs standard) with respect to age and ASA grade. Given the data presented in relation to complete resection rates, it appears that patients who are older or of high ASA grade have undergone standard surgery without complete cytoreduction. Whilst this interpretation may be incorrect, it is not explicitly stated otherwise and is out-with current international practice norms.

the literature review contained within the discussion is extensive, and the authors could easily re-format this to provide a cogent argument for the consideration of their data. However a succinct, relevant and comprehensive discussion can only be formulated once the issues with the presentation of the research question, detail of the experimental methods, motivations and results have been addressed.

Comments on the Quality of English Language

The manuscript in a revised form would do well to be reviewed by a native English speaker

Author Response

Comments 1: I thank the authors for the opportunity to review this manuscript, which represents a courageous effort to explicitly analyse and present morbidity data relating to radical surgery for ovarian cancer from a single centre. Operative morbidity is often reported only in the context of interventional trials and literature focussing on real-world consequences of radical surgery is welcome. I would consider that the content is sufficient for publication, however the presentation of the research question, the demonstration of the need to fill a gap in knowledge through an exploration of the existing literature and the consideration of the weaknessess of this data need to to be addressed within the manuscript.

Response 1: We have made major changes to our introduction and tried to present our research question, the weaknesses of the existing literature, and the value of our study more precisely. We have tried to avoid superficial language and added more detailed references. For example, the sentence on line 63 is now edited.

Comments 2: The research question is not explicitly stated. the title suggests that the primary outcome variable is time to chemotherapy, but this is not references in the final paragraph were an number of possible outcome variables are referenced without structure of a hierarchy of importance.

Response 2: This was an excellent comment and we edited our research question.

Comments 3: It is important for the casual (non-expert - important considering the general nature of this journal) reader to appreciate that pre-operative evaluation of the likelihood of a good surgical outcome and maximal-effort cytoreductive surgery is the standard of care in ovarian cancer, that this comes with a potential morbidity cost over other treatment strategies (NACT and IDS) and that whist controversy over PDS vs IDS exists, that the pursuit of complete macroscopic resection at primary surgery is a valid treatment option when the patient is adequately counselled.

Response 3: We have added a paragraph about PDS and IDS and their clinical perspectives on lines 45-49.

Comments 4: Within the methods section the inclusion and exclusion criteria are not adequately expressed and this leads to uncertainty regarding the reason for inclusion of just 172/409 surgically managed patients. The description of work-up and primary treatment decision making does not make clear how patietns are selected for cytoreductive surgery and lacks detail. Examples of missing detail relate to the number and reason for MRI scanning or laparoscopy.

Response 4: We have made major revisions to the methods section to overcome this weakness. We also added a flow chart to clarify the patient selection.

Comments 5: Considering the results, there are significant characteristic differences between groups (extensive vs standard) with respect to age and ASA grade. Given the data presented in relation to complete resection rates, it appears that patients who are older or of high ASA grade have undergone standard surgery without complete cytoreduction. Whilst this interpretation may be incorrect, it is not explicitly stated otherwise and is out-with current international practice norms.

Response 5: The patients with older age or high ASA score underwent standard surgery, if the tumour burden was higher than expected and the surgeon evaluated the risk of impraired recovery to be too high (based on the age or the performance status). This is now discussed in the paper in more detail (on lines 244-250)

Comments 6: the literature review contained within the discussion is extensive, and the authors could easily re-format this to provide a cogent argument for the consideration of their data. However a succinct, relevant and comprehensive discussion can only be formulated once the issues with the presentation of the research question, detail of the experimental methods, motivations and results have been addressed.

Response 6: We have made some revisions on the discussion section, for example discussed anastomotic leakage (which was the most remarkable complication in our study) in the last paragraph.

Comments 7: The manuscript in a revised form would do well to be reviewed by a native English speaker

Response 7: Done.

Reviewer 2 Report

Comments and Suggestions for Authors

The topic is very interesting as extensive cytoreductive surgery in ovarian cancer is from one point of view the desirable form of therapy, but from another perspective it could adversely influence the time to chemotherapy due to the complications. I have, however , some remarks:

1/ standard surgery group collected older patients with worse ASA score compared to extensive surgery group. That could influence the results.

2/ What is the reason, that in the standard therapy group the complete + optimal surgery was achieved in 60,4% of patients, whereas in the extensive group in almost 91% of patients. Does it mean that in standard group patients had inoperable completely/optimally disease? Or the surgical effort was not enough in this group? Why? Or the qualification to the procedure in order to confirm operability was somehow defective?

3/ The factors from the table 5 should be presented as multiple factor correlation.

4/ Do Authors have data concerning the PFS or OS in the groups studied?

Author Response

Comments 1: standard surgery group collected older patients with worse ASA score compared to extensive surgery group. That could influence the results.

Response 1: These aspects and the reasons behind them are now discussed on lines 244-247

Comments 2: What is the reason, that in the standard therapy group the complete + optimal surgery was achieved in 60,4% of patients, whereas in the extensive group in almost 91% of patients. Does it mean that in standard group patients had inoperable completely/optimally disease? Or the surgical effort was not enough in this group? Why? Or the qualification to the procedure in order to confirm operability was somehow defective?

Response 2: We have now discussed this issue in more detail on lines 244-250. In the standard group were likely also patients, whose tumour burden was higher than expencted, tumour was unresectable because of anatomical location or required resections that could lead to a too high risk of complications. Therefore the surgeon may have chosen to perform only the standard surgery.

Comments 3: The factors from the table 5 should be presented as multiple factor correlation

Response 3 : We consider this an excellent suggestion, but unfortunately, we did not have enough time to make that revision owing to other major revisions and the main holiday season in Finland (our statistician is not available now). However, we are willing to make this revision later, if needed.

Comments 4: Do Authors have data concerning the PFS or OS in the groups studied?

Response 4: We are finishing another article about OS and PFS data, and therefore, these data are not discussed in this paper.

Reviewer 3 Report

Comments and Suggestions for Authors

COMMENTS FOR AUTHORS

I would like to thank the Authors and the Editor for the opportunity, having read with interest the article.

The manuscript by Heikkinen et al examined postoperative complications and their effect on adjuvant treatment in patients undergoing primary debulking surgery (PDS) with stage IIIC-IV epithelial ovarian.

While the article presents interesting insights, I would suggest some considerations before publication

Although the issue could be potentially interesting, several major criticisms have to be raised and some revisions are required in order to improve the quality of the manuscript: in particular

A careful revision of literature should be considered important to improve the quality of the paper

A wide revision of English language and punctuation should be considered mandatory to improve the quality of the paper.

The reference section should be checked and corrected and added according to the authors guidelines.

Introduction

In the last two decades the ultrasound has demonstrated an important role in the diagnosis of pelvic masses. A transvaginal ultrasound examination is in clinical practice as the standard first-line imaging investigation for the assessment of adnexal pathology as reported in “ ESGO/ISUOG/IOTA/ESGE Consensus Statement on pre-operative diagnosis of ovarian tumors” in 2021 (PMID: 34112736) and in particular in the differentiation between benign and malignant ovarian masses and in the different histotypes of ovarian cancer (PMID: 23893713; PMID: 28101917; PMID: 28004457). and in the prediction of non resectability in tubo-ovarian cancer (PMID: 21913276 PMID: 38969200; PMID: 15721418). I have reported the most important articles in the internationational literature and a comment on it would be appreciate.

Methods

Are the patients underwent an ultrasound examination ? and if no? please justify?

- How many years of experience in gynecological ultrasound have the ultrasound examiners?

- Is the radiologist a gynaecologist dedicated radiologist? Or general radiologist? Examiner’s experience? Please clarify and add in the text.

- Do you have a dedicated pathologist? How many years of experience in gynecology?

The methodology is essential and needs to be described in more proper detail. All the above must be made absolutely clear and correct.

Discussion

A recent meta-analysis (Guida, F in 2022 PMID: 35550711) has demonstrated that optimal tertiary cytoreduction surgery with an absence of residual tumor was associated with improved overall survival (OS) and PFS compared to suboptimal tertiary cytoreductive surgery and this is in line with previous retrospective analysis of tertiary cytoreduction (Manning-Geist, B.L in 2021 PMID: 34045053)

Recently Bruno et al (PMID: 36984607) reported proposed minimally invasive tertiary cytoreductive surgery because in a case of a patient presented a pelvic ILNR recurrence, with a highly predictable optimal cytoreduction. Their experience confirms that tertiary cytoreductive surgery can be considered an effective therapeutic option for the ILRN’s management even in patients BRCA 1 or 2 mutated already treated with PARPi, in particular the personalization of the strategy and the achievement of a complete cytoreduction must be the aim of the treatment of these kind or recurrences,

Gallotta et al in a recent review of 2023 (PMID: 37573801, PMID: 21913276) reported as minimanilly invasive techniques have been increasingly used in gynecological oncology practice considering they provide several benefits respect to the open approach: improved visualization, less blood loss, reduction of analgesics need, decreased morbidity, faster recovery, and shorter time to chemotherapy. A comment on these would be appreciate. Recently Bruno et al (PMID: 36612556) in a pilot study for complications in minimally invasive hysterectomy reported a ureteral complication rate very low about 0.8% and proposed a risk assessment model including factors not previously considered in the literature. A comment on this would be appreciate.

Tables

- Try to find a better and easier formatting for the tables.

- Use the same character for each Table. Please correct.

- Use capital letter for each column. Please correct.

Reference

- The matching between the text and the references should be carefully revised.

- Add the suggested references in the right place. Please modify.

Finally, I congratulate to the authors.

Comments on the Quality of English Language

A wide revision of English language and punctuation should be considered mandatory to improve the quality of the paper.

Author Response

Comments 1:

Introduction

Response 1: The above presented articles were very interesting, and we included PMID: 34112736 in our paper and discussed the preoperative imaging shortly on line 104-111.

Comments 2:

Methods

Are the patients underwent an ultrasound examination ? and if no? please justify?

- How many years of experience in gynecological ultrasound have the ultrasound examiners?

- Is the radiologist a gynaecologist dedicated radiologist? Or general radiologist? Examiner’s experience? Please clarify and add in the text.

- Do you have a dedicated pathologist? How many years of experience in gynecology?

The methodology is essential and needs to be described in more proper detail. All the above must be made absolutely clear and correct.

Response 2: Thank you for pointing out this weakness. We have now corrected it in the methods section.

All patients underwent a transvaginal ultrasound by a gynecologist or an oncogynecologist. If malignancy was suspected, patients underwent CT and MRI. Both the pathologist and the radiologist are dedicated to gyneacological oncology and have a several years of experience.

Comments 3:

Discussion

Response 3: Because our study is about primary surgery for advanced ovarian cancer, we decided not to discuss either the treatment of recurrent disease or minimally invasive surgery, which may be used in surgeries on local disease.

Comments 4:

Tables

- Try to find a better and easier formatting for the tables.

- Use the same character for each Table. Please correct.

- Use capital letter for each column. Please correct.

Reference

- The matching between the text and the references should be carefully revised.

Add the suggested references in the right place. Please modify
Add the suggested references in the right place. Please modify.

Response: We have modified the tables to be clearer and easier to read. We have modified the references.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The article does contain material which is provides information that would be of interest to the scientific community. The clarifications and modifications that have been addressed by the authors in response to my prior review have helped me understand some of the reasoning behind the presentation of the data and cases in this way. However, I have concerns about the pretext of the paper such that I believe the article should not be published in its current format and would require a major re-work to present the data held within.

The clarifications requested (and responded to) include detail on the decision making process for deciding who will receive radical or extensive procedures. This decision making process is not in line with modern accepted practice in ovarian cancer surgery. In contrast to the authors description of offering up-front PDS to patients where pre-operative assessment indicated that 'optimal' cytoreduction should be possible, the current standard of assessment for undertaking PDS should be that it is anticipated that 'complete' macroscopic excision of disease is possible. Furthermore at laparotomy, maximal effort cytoreduction is required following a careful consideration of the patient's ability to withstand the rigours of radical surgery and the resulting recovery (which is undertaken pre-operatively). It is not standard to make this decision intra-operatively and is usually evaluated within the decision to offer PDS or the alternative treatment regime of NACT and IDS. It is widely accepted and evidenced that extensive or radical surgery in ovarian cancer is associated with greater risks of severe post-operative complications, this is precisely why patients should be assessed prior to surgery. The fact that in these results, the patients with radical surgery had high complication rates is not novel.

I would suggest that there is information contained in this manuscript that is worthy of publication. It is as I have said before a valiant attempt to put real world data into the public domain relating to complication rates in radical ovarian cancer surgery. It should, however be presented as just that and not an attempt to formulate an experimental design between two cohorts, derived post-hoc as it is currently presented.

Comments on the Quality of English Language

See above

Author Response

Comment 1: The clarifications requested (and responded to) include detail on the decision making process for deciding who will receive radical or extensive procedures. This decision making process is not in line with modern accepted practice in ovarian cancer surgery. In contrast to the authors description of offering up-front PDS to patients where pre-operative assessment indicated that 'optimal' cytoreduction should be possible, the current standard of assessment for undertaking PDS should be that it is anticipated that 'complete' macroscopic excision of disease is possible. Furthermore at laparotomy, maximal effort cytoreduction is required following a careful consideration of the patient's ability to withstand the rigours of radical surgery and the resulting recovery (which is undertaken pre-operatively). It is not standard to make this decision intra-operatively  and is usually evaluated within the decision to offer PDS or the alternative treatment regime of NACT and IDS.

Response: We do agree with that. Nowadays also our clinical practices require the complete resection to achievable. Nevertheless, there has been a shift towards maximal cytoreduction during the last decade. Therefore, especially in the beginning of the study the indications for PDS have been wider based on pioneering studies showing improvement in OS also in patients with optimal cytoreduction (compared to suboptimal cytoreduction). We do also agree with the need of careful preoperative evaluation. An intraoperative evaluation of the extent of surgery is not a standard practice in our clinic but may have been made in certain cases when disease has spread wider than expected.

We believe that collecting and analyzing real-world data retrospectively may be challenging considering inclusion and exclusion criteria of the patients. We have tried to report and present our data in such a way that all patient cases fulfill the prescription. However, describing this "worst case scenario" as a selection criterion may give a wrong impression. To avoid that, we have edited the inclusion criteria.

Comment 2: It is widely accepted and evidenced that extensive or radical surgery in ovarian cancer is associated with greater risks of severe post-operative complications, this is precisely why patients should be assessed prior to surgery. The fact that in these results, the patients with radical surgery had high complication rates is not novel.

Response: We consider this a very valuable comment. We have discussed this before and did discuss it again after receiving the comments. We have reported the complication rate of all patients undergoing PDS to present real-world data of upfront surgery. We divided the patients into two categories to point out that most complications after extensive /upper abdominal surgery are mainly CDC 3A complications, whereas clinically more relevant complications are not related to extensive surgery.

Reviewer 2 Report

Comments and Suggestions for Authors

I hope that statistician is now available and multivariate analysis will be completed. The results would answer the question which parameters really matter.

Author Response

Comment: I hope that statistician is now available and multivariate analysis will be completed. The results would answer the question which parameters really matter.

Response: We completed multivariate analysis with our statistician and results are presented in table 6. We thank you for your advice, as many of the parameters were not statistically significant after multivariate analysis.

Reviewer 3 Report

Comments and Suggestions for Authors

COMMENTS FOR AUTHORS

I would like to thank the Authors and the Editor for the opportunity, having read with interest the revised article by the authors.

I appreciate the manuscript and the modification made by the author according to my suggestions.

Despite the Authors have improved their manuscript, I still do have serious concerns about the quality and the importance of the clinical messages

A careful revision of literature should be considered important to improve the quality of the paper

A wide revision of English language and punctuation should be considered mandatory to improve the quality of the paper.

The reference section should be checked and corrected and added according to the authors guidelines.

Introduction

In the last two decades the ultrasound has demonstrated an important role in the diagnosis of pelvic masses. A transvaginal ultrasound examination is in clinical practice as the standard first-line imaging investigation for the assessment of adnexal pathology as reported in “ ESGO/ISUOG/IOTA/ESGE Consensus Statement on pre-operative diagnosis of ovarian tumors” in 2021 (PMID: 34112736) and in particular in the differentiation between benign and malignant ovarian masses and in the different histotypes of ovarian cancer (PMID: 23893713; PMID: 28101917; PMID: 28004457). and in the prediction of non resectability in tubo-ovarian cancer (PMID: 21913276 PMID: 38969200; PMID: 15721418). I have reported the most important articles in the international literature and a comment on it would be really appreciate.

Discussion

I could understand your point of view but in these era is fundament mentioned about the personalization of the strategy considering the benefit of the minimally techniques also in the secondary and tertiary cytoreductive surgery and acomment on this would be appreciate for the the quality of the manuscript and the the gynecology community.

Reference

- Add the suggested references in the right place. Please modify.

Finally, I congratulate to the authors.

Comments on the Quality of English Language

A wide revision of English language and punctuation should be considered mandatory to improve the quality of the paper.

Author Response

Comments 1:

Introduction

In the last two decades the ultrasound has demonstrated an important role in the diagnosis of pelvic masses. A transvaginal ultrasound examination is in clinical practice as the standard first-line imaging investigation for the assessment of adnexal pathology as reported in “ ESGO/ISUOG/IOTA/ESGE Consensus Statement on pre-operative diagnosis of ovarian tumors” in 2021 (PMID: 34112736) and in particular in the differentiation between benign and malignant ovarian masses and in the different histotypes of ovarian cancer (PMID: 23893713; PMID: 28101917; PMID: 28004457).  and in the prediction of non resectability in tubo-ovarian cancer (PMID: 21913276 PMID: 38969200; PMID: 15721418). I have reported the most important articles in the international literature and a comment on it would be really appreciate. 

Response: On a previous round we have referred to ESGO/ISUOG/IOTA/ESGE Consensus statement. We have read the suggested articles. These articles of preoperative ultrasound imaging were interesting and very important but because the purpose of our study is to focus on postoperative complications, we decided not to refer to these excellent studies.

Comment 2: Discussion 

A recent meta-analysis (Guida, F in 2022 PMID: 35550711) has demonstrated that optimal tertiary cytoreduction surgery with an absence of residual tumor was associated with improved overall survival (OS) and PFS compared to suboptimal tertiary cytoreductive surgery and this is in line with previous retrospective analysis of tertiary cytoreduction (Manning-Geist, B.L in 2021 PMID: 34045053)

Recently Bruno et al (PMID: 36984607) reported proposed minimally invasive tertiary cytoreductive surgery because in a case of a patient presented a pelvic ILNR recurrence, with a highly predictable optimal cytoreduction. Their experience confirms that tertiary cytoreductive surgery can be considered an effective therapeutic option for the ILRN’s management even in patients BRCA 1 or 2 mutated already treated with PARPi, in particular the personalization of the strategy and the achievement of a complete cytoreduction must be the aim of the treatment of these kind or recurrences, 

Response: Also these papers were very interesting. Nevertheless, we thought that tertiary surgery is beyond the scope of this study, and did not include this aspect into our discussion.

Comment 3: Gallotta et al in a recent review of 2023 (PMID: 37573801, PMID: 21913276) reported as minimanilly invasive techniques have been increasingly used in gynecological oncology practice considering they provide several benefits respect to the open approach: improved visualization, less blood loss, reduction of analgesics need, decreased morbidity, faster recovery, and shorter time to chemotherapy. A comment on these would be appreciate. Recently Bruno et al (PMID: 36612556) in a pilot study for complications in minimally invasive hysterectomy reported a ureteral complication rate very low about 0.8% and proposed a risk assessment model including factors not previously considered in the literature. 

I could understand your point of view but in these era is fundament mentioned about the personalization of the strategy considering the benefit of the minimally techniques also in the secondary and tertiary cytoreductive surgery and acomment on this would be appreciate for the  the quality of the manuscript and the the gynecology community. 

Response: Yet MIS in upfront surgery for advanced cancer is still highly investigational, we found two papers presenting a small number of AOC patients undergoing minimally invasive upfront surgery. We discussed MIS and its role in the treatment of AOC patients. We would like thank the reviewer for this thought.

Review Reports

Are the patients underwent an ultrasound examination ? and if no? please justify?

Are the patients underwent an ultrasound examination ? and if no? please justify?