Intraoperative Radiotherapy with Balloon-Based Electronic Brachytherapy System—A Systematic Review and First Bulgarian Experience in Breast Cancer Patients

Round 1

Reviewer 1 Report

1) Introduction: also interstitial brachytherapy is characterized by increased therapeutic window , limited time for repopulation of remaining tumor cells and the possibility for re-irradiation in cases of cancer recurrence. I suggest to write "IORT is characterized by ..... as well as......"

The Introduction have to be more clear

2) Introduction, line 80: the sentence is not correct. Indeed there are studies that used one fraction with interstitial brachytherapy. Accelerated partial breast irradiation in the elderly: 5-Year results of the single fraction elderly breast irradiation (SiFEBI) phase I/II trial. Hannoun-Lévi JM, Lam Cham Kee D, Gal J, Schiappa R, Hannoun A, Fouche Y, Gautier M, Boulahssass R, Chand ME.Hannoun-Lévi JM, et al. Brachytherapy. 2020 Jan-Feb;19(1):90-96.

Introduction, line 162: delete intraoperative ra-162 diotherapy and write only IORT. The sentence is not clear. The authors have to declare the first and the secondary endpoint.

Matherial and methods: I suggest to read the following paper "The role of brachytherapy (interventional radiotherapy) for primary and/or recurrent vulvar cancer: a Gemelli Vul.Can multidisciplinary team systematic review" and adjust the paper following this structure

Discussion: there are no published results of any phase III studies using Axxent® eBx but the authors should compare their results with Others APBI techniques

The authors should describe the limitation of IORT and not only the limitations of the study

Author Response

Dear reviewer, 

Thank you very much for your comments. We hope we have met all your requirements. 

1) Introduction: also interstitial brachytherapy is characterized by increased therapeutic window , limited time for repopulation of remaining tumor cells and the possibility for re-irradiation in cases of cancer recurrence. I suggest to write "IORT is characterized by ..... as well as......"

The Introduction have to be more clear

Thank you very much for your comment. We have changed and improved the introduction.

2) Introduction, line 80: the sentence is not correct. Indeed there are studies that used one fraction with interstitial brachytherapy. Accelerated partial breast irradiation in the elderly: 5-Year results of the single fraction elderly breast irradiation (SiFEBI) phase I/II trial. Hannoun-Lévi JM, Lam Cham Kee D, Gal J, Schiappa R, Hannoun A, Fouche Y, Gautier M, Boulahssass R, Chand ME.Hannoun-Lévi JM, et al. Brachytherapy. 2020 Jan-Feb;19(1):90-96.

Thank you very much for your comment. Since other reviewers also disagreed with this sentence we deleted it.

Introduction, line 162: delete intraoperative ra-162 diotherapy and write only IORT. The sentence is not clear. The authors have to declare the first and the secondary endpoint.

Thank you very much for your comment. We corrected that.

Matherial and methods: I suggest to read the following paper "The role of brachytherapy (interventional radiotherapy) for primary and/or recurrent vulvar cancer: a Gemelli Vul.Can multidisciplinary team systematic review" and adjust the paper following this structure

Thank you very much. We read the paper and we tried to improve accordingly. We added the table with the search strategy in the methods and material section. We can not give the exact number of excluded trials with the reason for exclusion for each, because we have not collected this information during the initial search. 

Discussion: there are no published results of any phase III studies using Axxent® eBx but the authors should compare their results with Others APBI techniques

Thank you very much for your comment. The idea of the manuscript is not to compare the results of eBx with other APBI techniques, but to collect at one place all available data for this particular technique. With 7 eBx devices and more than 3 single fraction techniques for IORT the comparison will make the manuscript too long.

The authors should describe the limitation of IORT and not only the limitations of the study.

Thank you very much for your comment. The limitations are described in the introduction section as the main limitation by now is the higher recurrence rate reported in some studies and the differences in dose prescriptions, treatment volumes, and dosimetry.

Reviewer 2 Report

Abstract –

What were the criteria for inclusion in the systematic review?

Why did the authors choose to only focus on Xofgt Axxent system – when it is well known that there is no randomised evidence to support its use.

The abstract should emphasise that there was data to compare the outcomes with a control treatment (e.g. external beam radiotherapy), and therefore the conclusion is not accurate.

The current evidences demonstrate the Xoft Axxent® eBx 51 system as a safe and feasible technique for delivery of IORT in EBC patients.

This sentence should be deleted from the abstract because it is not supported by the data.

Still, better patient 52 selection and a reimbursement strategy have to be proposed in order to extend the application of 53 this technique also in the Bulgaria.

The largest series (Sileverstein, n=1000) as presented in February 2020, found a 5.9% local recurrence rate at 5 years  which goes up to 10.5% in grade 3 cancers The authors  need to include these  data from this study.

Instead, the conclusion should read: currently there is no randomised evidence to support the use of Xoft Axxent system.

Main paper

There are several errors in this paper –

Introduction

In the introduction itself there were several factual errors, no reference to key studies, etc (As shown in the attached file)

I found so many errors in the one type of IORT (Intrabeam) I believe similar errors will be present in other types of IORT systems as well.

Methods

It is not right to restrict to papers on IORT to be published before 2019- Several major studies were reported in 2020 – eg. Silverstein et al, Vaidya et al, NSABP, RAPID, etc.. they need to be included in the introduction / discussion.

The only new data in this paper is the 20 cases treated in Bulgaria, which is not at a stage or completeness of data suitable for publication. 

The picture 1 shows 3 different cases at different FU times – so it is not useful – it should be the same case at diff follow up times to have any meaning

There are several typographic errors and references are very poorly formatte.

Many new references about IORT are not included

 Line 418 – should have page numbers

Line 422 should be Herskind C, Wenz F (not just WF), and other authors et al, etc.

Line 423 should have page numbers  

Line 437  should have page numbers

Line 440 – should be “Vaidya JS, Wenz F, Bulsara M et al”, not “Vaidya JW, Frederik”. The Journal name (The Lancet)  is not included in the reference either

Comments for author File: Comments.pdf

Author Response

Dear Reviewer, 

Thank you very much for your comments. We hope we succeed to answer your questions and correct the manuscript accordingly. 

Abstract –

What were the criteria for inclusion in the systematic review? 

Thank you very much for your comment, we have included list of the the exclusion criteria in the methods and materials section.

Why did the authors choose to only focus on Xoft Axxent system – when it is well known that there is no randomised evidence to support its use.

  Thank you very much for your comment. We have included only Xoft Axxent, because this is the technology that we are currently working with and our interest is focussed on its applicability in our country and the existing evidence of its effectiveness.

The abstract should emphasise that there was data to compare the outcomes with a control treatment (e.g. external beam radiotherapy), and therefore the conclusion is not accurate.

Thank you very much for your comment.  We don't compare outcomes with other techniques such as external beam radiotherapy. We don't have a control arm in the current study. 

The current evidence demonstrates the Xoft Axxent® eBx 51 system as a safe and feasible technique for delivery of IORT in EBC patients.

This sentence should be deleted from the abstract because it is not supported by the data.

  Thank you very much for your comment. Unfortunately, we disagree with this comment. The safety and feasibility of a technique is a question, answered by phase I studies. This technique has been tested in such studies and proved as safe and feasible. Its long term effectiveness is questionable.   

Still, better patient 52 selection and a reimbursement strategy have to be proposed in order to extend the application of 53 this technique also in the Bulgaria.

   Thank you very much for your comment. Unfortunately, we disagree with this comment. The need for better patient's selection is obvious from our results. From 20 patients, treated in Bulgaria 5 (25%) were referred  to external beam radiotherapy after the treatment with IORT. Currently, the IORT with Axxent is not performed in Bulgaria due to the big part of "out of pocket" payment by the patient. 

The largest series (Sileverstein, n=1000) as presented in February 2020, found a 5.9% local recurrence rate at 5 years  which goes up to 10.5% in grade 3 cancers The authors  need to include these  data from this study.

 Thank you very much for your comment. It seems that this conference paper has been published in February 2021 and has not been found during our search. https://cancerres.aacrjournals.org/content/81/4_Supplement/PS15-11 

We are happy to add this publication as an update of the previous one, that we have in our study.

Instead, the conclusion should read: currently there is no randomised evidence to support the use of Xoft Axxent system.

 Thank you for your comment. We added your suggestion to the conclusion.

Main paper

There are several errors in this paper –

Introduction

In the introduction itself there were several factual errors, no reference to key studies, etc (As shown in the attached file)

I found so many errors in the one type of IORT (Intrabeam) I believe similar errors will be present in other types of IORT systems as well.

Methods

It is not right to restrict to papers on IORT to be published before 2019- Several major studies were reported in 2020 – eg. Silverstein et al, Vaidya et al, NSABP, RAPID, etc.. they need to be included in the introduction / discussion.

 Thank you very much for your comment. We have included Silverstain report from 2021, Vaidya report of TARGIT from 2020 and NSABP. RAPID trial is comparing expernal with external beam and therefore is not of the scope of the current manuscript. 

The only new data in this paper is the 20 cases treated in Bulgaria, which is not at a stage or completeness of data suitable for publication. 

 Unfortunately, we cannot do anything about this. We do not expect to have more patients anytime soon.

The picture 1 shows 3 different cases at different FU times – so it is not useful – it should be the same case at diff follow up times to have any meaning

 Thank you very much for your comment. Unfortunately we cannot provide a picture of the same patient through the whole follow up.

There are several typographic errors and references are very poorly formatte.

We have corrected the topographic errors.

Many new references about IORT are not included

 Line 418 – should have page numbers - There is no such information in the publisher website: https://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S0378-48352004000700013 

Line 422 should be Herskind C, Wenz F (not just WF), and other authors et al, etc.

Done

Line 423 should have page numbers   

Done

Line 437  should have page numbers

No page number available: https://www.birpublications.org/doi/10.1259/bjr.20150002?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed 

Line 440 – should be “Vaidya JS, Wenz F, Bulsara M et al”, not “Vaidya JW, Frederik”. The Journal name (The Lancet)  is not included in the reference either

Corrected

Reviewer 3 Report

The study design is clear and well-written.

You should write more clear the inclusion and exlusion criteria that you used to include the previous studies in your systemic review. I consider a diagram which includes the number of studies you found and how many , finally you used, is helpfull for the reader. 

Author Response

Dear Reviewer, 

Thank you very much for your comment and suggestions. We added a table with search strategy in the methods and materials section.  We can not give the exact number of excluded trials with the reason for exclusion for each, because we have not collected this information during the initial suearch. We hope this table will add the missing value.

Best regards, 

Reviewer 4 Report

In this manuscript, researchers have introduced an intraoperative radiotherapy with balloon-based electronic brachytherapy system and the clinical trial on the human patient. The potential clinical impact is significant. The technical writing has been organized and prepared well, with sufficient literature support. The review's table and the depiction are also convincing. "Acceptance" is suggested.

Author Response

Dear Reviewer, 

Thank you very much for your comment!

Best regards,