Antiangiogenic Drug-Induced Proteinuria as a Prognostic Factor in Metastatic Colorectal Cancer

Round 1

Reviewer 1 Report

thank you for giving me the opportunity to review this paper which looks at the impact of proteinuria on oncological outcomes. The main remark concerns the methodology. it would have been more robust to perform a case-control study, at best a propensity score. regarding the study population, less than 1% of the patients were included in the study; how can we explain these results?

122/150 patients had a resection of the primary tumour; what were the indications? did the authors analyse the post-operative morbidity which influences the carcinological prognosis. among the patients with proteinuria, do the authors have the notion of resection of metastatic sites which again can influence the carcinological results.

the authors should also emphasise in the limitations the heterogeneity of the patients included whether synchronous or metachronous metastases, location and number of metastatic sites.

Author Response

 

Thank you for your thorough review of our work. We have done our best to respond below to the issues raised, point-by-point.

 

“The main remark concerns the methodology. It would have been more robust to perform a case-control study, at best a propensity score.”

We have indeed appreciated your suggestion to improve our methodology and consider as well the propensity score. This is a very pertinent advice, meant to strengthen the validity of our statistical conclusions. Our initial approach was deliberately chosen in order to be similar to the one used by other authors studying the impact of proteinuria on bevacizumab treated patients. We were interested to be able to compare some of these results with ours, but now we feel that by calculating the propensity score our statistical conclusions are strongly reinforced.

“Regarding the study population, less than 1% of the patients were included in the study”

This is a very pertinent observation. Thank you for raising this issue as it offers us the possibility to better explain our approach. The 3497 patients mentioned were indeed seen in our hospital by an oncologist during the 5 years period included in our analysis. However, as we are a regional referral tertiary cancer care center, more than half of these consultations (n= 2138 patients) were followed by treatments performed elsewhere. Another 44% (n = 598) did not receive bevacizumab as first line of treatment, while the remaining 611 patients were either lost to follow-up (particularly during the COVID-19 pandemic) or not included in the analysis because of missing data.

“122/150 patients had a resection of the primary tumour; what were the indications?”

Primary tumor resection was performed at diagnosis in 33.7 % (n = 41) patients who were non-metastatic, another 47.5% (n = 58) were emergency partial colectomies performed for bowel obstruction and for 18.8% (n = 23) of patients we have no data on the indication for primary tumor resection.

“Did the authors analyse the post-operative morbidity which influences the carcinological prognosis. among the patients with proteinuria, do the authors have the notion of resection of metastatic sites which again can influence the carcinological results.”

Postoperative morbidity was not formally analyzed. However, we did check patient records for severe and/or potentially lethal postoperative complications, and there were none registered. Hence, there was arguably no impact on oncological outcome. Upfront metastasectomy, whether synchronous with colectomy or metachronous, was considered part of curative intent surgery and not analyzed separately. We did not gather data on resections of secondary lesions performed later during the course of the disease. Retrospectively, we fully agree with you that this information would have been valuable for the accurate evaluation of disease prognosis.

“The authors should also emphasise in the limitations the heterogeneity of the patients included whether synchronous or metachronous metastases, location and number of metastatic sites.”

 

Your observation is correct and adequate, and we have modified the Discussion chapter accordingly, to include the suggested remarks on the lack of info about the characteristics of the metastatic disease as study limitations (Line 383-386).

 

 

 

Author Response File: Author Response.doc

Reviewer 2 Report

The paper is dealing with a topic that was already studied by other researchers - insufficiently or with inconclusive results. By including higher number of patients you succeeded in obtaining statistically significant results. In my opinion, this paper may show the way to the long awaited prognostic factor for bevacizumab treatment.

There are just two comments to improve the clarity of the article.

Abstract

Line 24: The sentence "Patients with anemia..." seems out of place. I suggest either moving this sentence to line 28 or removing it from the abstract altogether. Furthermore, the sentence is unclear. You mean that the OS in these patients was 20 months shorter than in patients without anemia, but this is not obvious.

Introduction

Lines 101 to 103: I suggest you define the doses because local standards may differ.

Author Response

Thank you for your kind remarks regarding our study that is indeed offering further arguments in favor of proteinuria as prognostic factor in bevacizumab treated patients. The study group could have been larger but we have tried to be as thorough as possible in respecting the inclusion/exclusion criteria. We sincerely hope our research will represent a step towards a better identification of patient subgroups deriving the greatest benefit from antiangiogenic treatments.

 

„Line 24: The sentence "Patients with anemia..." seems out of place. I suggest either moving this sentence to line 28 or removing it from the abstract altogether. Furthermore, the sentence is unclear. You mean that the OS in these patients was 20 months shorter than in patients without anemia, but this is not obvious.”

 

Indeed, this statement was not at all clear and it was misplaced in line 24. Anemia is however a factor of importance for the Overall Survival, hence we think is important to be mentioned in the abstract as well. We have thus took into consideration your excellent suggestion to introduce it in line 28, together with the mention of diabetes.

„Lines 101 to 103: I suggest you define the doses because local standards may differ.”

We have introduced a distinctive chapter that includes the various dosages used in the different chemotherapy protocols (Line 101-109).

 

Author Response File: Author Response.doc

Round 2

Reviewer 1 Report

the authors have responded point by point to the requests for revision. they have added a new analysis with a propensity score and limitations in their discussion

Author Response

Thank you again for your valuable suggestions. We have indeed appreciated your suggestion to improve our study.