PONE-D-20-31679

Feasibility and safety of targeted focal microwave ablation of the index tumor in patients with low to intermediate risk prostate cancer: results of the FOSTINE trial

PLOS ONE

Dear Dr. Delongchamps:

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Neal Shore, MD FACS

Academic Editor

PLOS ONE

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N Barry Delongchamps is Consultant for Koelis"

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. 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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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3. 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

Reviewer #3: Yes

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4. 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

Reviewer #3: No

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5. 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: The manuscript entitled ‘Feasibility and safety of targeted focal microwave ablation of the index tumor in patients with low to intermediate risk prostate cancer: results of the FOSTINE trial’ with the aim to assess the feasibility, safety and precision of organ-based tracking (OBT)-fusion targeted focal microwave ablation (FMA), in patients with low to intermediate risk prostate cancer.

Comments

Abstract & Results

Line 36, Line 127, Line 132, Line 177, word IQR to be stated in the text.

Patients and Methods

Sample size calculation

Line 113-117, 1 or 2 tailed test to be stated. Any reason why alpha 0.10 was chosen?

Statistical analysis

Line 118, statistical analysis section and the statistical test(s) to be stated.

Line 119, the sentence ‘Proportions were reported as means (sd) or medians [IQR], when appropriate.’ requires revision.

Results

Baseline characteristics of the patients to be provided.

Line 156, the sentence Median [Q1-Q3] largest dimension of necrosis was of 17.5 [16-22] mm’ requires revision.

Line 160-164, ensure the data are presented in Table 2.

Table 3, the statistical test to be denoted in the table footnote. Decimal point for p value to be standardized. Effect size, 95% CI could be explored/presented. Table alignment could be improved.

Line 191-192, the number of patients at various time period to be clearly denoted/stated in the table footnote.

Data were collected at various time point but statistical analyses were performed between baseline and 6-month. Nonetheless, due to 'small' sample size, the statistical analysis to be treated with cautious.

Figure 1, the time period, n to be stated. The number of patients assessed/evaluated for each measure to be illustrated in the figure or to be stated in the method/results section.

List of references could be improved e.g. spacing of page number.

Reviewer #2: 1. For the three patients with multifocal disease, what is the maximal core length on non-targeted biopsies and what is the number of systematic biopsies involved out of 10-12 cores ? Did these patients have inferior PSA response at 6 months?

2. What is the rationale of using 1 or 2 treatments? Is it for coverage of a larger tumor or larger margin?

3. The authors described the treated area is based on pre-clinical predictive ablation chart. How did the post-treatment largest dimension of necrosis area on T1-contrast sequence compare with the predictive ablation chart in each of the 10 patients? Please show the largest dimension of the necrosis and also the expected dimension.

4. What is the reason that 2 patients had only 25-40% of the necrosis of the index tumor? Was it due to treatment power (inadequate treatment) or accuracy of targeting (necrosis size adequate BUT not overlapping well with tumor area)?

5. For the patient with radical prostatectomy performed showing pT3a Gleason 3+3, what was the size of the residual tumor and also the size of the treated area?

6. Was the radical prostatectomy difficult after microwave treatment?

7. Microwave treatment in liver would lead to shrinkage of treated area. Would the extent of necrosis be under-estimating the actual treated area ?

8. What is the reason that 4 out of 8 patients with 100% necrosis of index tumor be having residual tumor? Would it be underestimation of tumor by MRI +/- lack of margin coverage?

9. In Figure 2, there are 4 tumors that are in peripheral zone. Are they more than 5mm from rectum during treatment? Would close proximity to rectum be the cause of potential undertreatment and local recurrence? Can you add the Patient number to the tumor locations in Figure 2?

10. Can you show the pre and post treatment MRI films of the 4 tumors in peripheral zone?

11. There are 3 cases with pre-op systematic biopsies showing no Gleason 3+4 cancer but post-op 6 month biopsy showing Gleason 3+4. So, the pre-op MRI missed 3 out of 10 clinically significant cancer, which was much higher than the reported figure (around 90% sensitivity). Would this be due to quality of MRI or just a matter of inadequate systematic sampling (10-12 cores) via transrectal biopsy?

12. Line 251: Can you add margin suggestion in consensus statement on focal therapy?

13. What intra-prostatic margin would you suggest for microwave ablation for prostate tumors?

14. Minor amendments:

a. Please change IPSS-QDV to QOL in English.

b. Line 239: recal -> recall

c. Please update reference 2.

Reviewer #3: This manuscript reported that the “first” experiment of OBT-targeted FMA for the treatment of patient with low to intermediate risk prostate cancer. The main concern was safety of this technique in the patients, which is very significative for the focal therapy in the low to intermediate risk prostate cancer patients.

However, there are some points for improvement in this manuscript.

There are many grammatical and linguistic errors throughout the manuscript. The authors should let the entire manuscript be reviewed by a professional English-speaking writer.

Title

Please explain the word “FOSTINE”.

Abstract

Line 33, the word “at day 7” should be changed into “one week after ablation” or “7 days after ablation”, which is more precise.

Line 33, Please adjust the sentence “Secondary endpoints were adverse events, urinary and sexual functional outcomes, assessed with IPSS, IIEF5 and MSHQ-EjD-SF, and oncological outcomes, assessed with PSA at 2 and 6 months, and re-biopsy at 6 month” to make more clear in the presentation.

Introduction

Line 56, Please explain the word “Index tumor”, and give the theory and significances about ablation on the index lesion of prostate cancer.

Line 58 Through you gave the reference about the “organ-based tracking (OBT) MRI-ultrasound fusion”, may be it is more appropriate to provide a brief explanation and explanation about the OBT MRI-ultrasound fusion.

Patients and Method

Line 79 Why the age in the inclusion criteria is between 45 and 76 years?

Line 78-85 Whether the coagulation function, infection status and cardio-pulmonary function in the inclusion and exclusion criteria.

Line 92-93 The expression that “(2) The urinary and sexual outcomes, assessed with IPSS, IIEF5 and MSHQ-EjD-SF, self-questionnaires, respectively” will be more precise.

Line 97-103 Please describe the preoperative preparation, such as bowel preparation and so on.

Please add images of fusion and puncture or ablation process.

Line 108-109 How to calculate the proportion? By volume or by length?

Line 113-117 How to calculate the sample? What formula or software is used?

Line 119 Please detailed description that the data for application of means (sd) or medians [IQR].

Results

Line 127 “The median age was 64 [61-72] years”.

The number should be described consistently, such as “seven and 3” or “7” and so on.

Line 135 and Line 168 Please change the table caption into a complete sentence.

Line 136 Please draw the diagram properly. This table is very terrible, which is confusion.

Line 145-147 How to judge the ablation necrosis cover the tumor mass during the ablation?

Line 149 Please try to explain the cause of spontaneous micturition in the discussion. Does any patient had hematuresis symptoms?

Line 143-151 How to protect the urethra during ablation? Whether the indwelling catheter was needed during the ablation process? Whether to take antibiotics after ablation?

Line 169 Please draw the table properly.

Discussion

Line 219 The first sentence will be more appropriate if changed into “The results of this study was satisfactory”.

Line 219-220 What does mean for the sentence that “First, no patient experienced adverse events nor was altered sexual or urinary function reported during the 6-month follow-up, confirming the safety of this technique.”

Line 234-235 What does mean for the “but oriented from the right to the left.”

Line 246 In term of oncological outcome, dose any changes was detected from image other than PAS changes.

Line 287-289 Why do the index tumor lesions vary in size from the figure? Should they be scaled according to actual size?

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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PONE-D-20-31679R1

Feasibility and safety of targeted focal microwave ablation of the index tumor in patients with low to intermediate risk prostate cancer: results of the FOSTINE trial

PLOS ONE

Dear Dr. Delongchamps,

Thank you for submitting your manuscript to PLOS ONE. The reviewers  are very pleased to accept your revised manuscript if you would be willing to address only a few additional reviewer comments. If you can address these, then I will rapidly review and then we can proceed with publication. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by March 30,2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Neal Shore, MD FACS

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: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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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

Reviewer #3: Yes

**********

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

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: 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: Minor comment(s)

Line 127 - two-tailed test to be placed in the statement.

Table 4 - at least 2 decimal points for p value to be presented. The reason for different 'n' in the follow up to be described in the results.

For the demographic characteristics, apart from age, were there any other information could be displayed to describe the patients i.e ethnicity etc.

In the abstract, it was mentioned that IPSS, IIEF-5 and MSHQ-EjD-SF were not statistically different at baseline, 7 days, 2 and 6 months but there was no statistical test performed to look into the difference between the time points except baseline and 6 months. This requires revision.

Reviewer #2: Thank you for addressing all the comments. The figures clearly showed the tumor locations and the table showed the ablation dimensions well.

Reviewer #3: Dear Author:

Thank you for revising your paper. The paper was better than last time in the understanding the meaning of the text and the format. However, there are some small nibs for improvement in this manuscript.

1. Where is reference 1 in the text?

2. The table in the paper should be in third line in format, which including the table top line, column line, and bottom line, but without the vertical line. Obviously, the table 1 and table 2 did not conform to this format. Besides, there were two headers in table 1, which is confusion.

3. Which sequences are included in multi-parameter MRI? Please give a detailed explanation in this paper.

4. The author did not answer the question that how to calculate the proportion of necrosis to the index tumor in the mpMRI 7 days after ablation? By volume or by length? Please describe this in the method.

5. Did these ten patients in this pilot clinical trial take antibiotics after ablation? Please add the information to the text.

6. It is pleasure for the results that there was no urethral injury in all the patients. Could you provide the distance between the lesion and the urethra? I think this can offer certain guidance to the clinical application in the future.

7. In regard to the question that whether to take antibiotics after ablation?

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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: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Feasibility and safety of targeted focal microwave ablation of the index tumor in patients with low to intermediate risk prostate cancer: results of the FOSTINE trial

PONE-D-20-31679R2

Dear Dr. Delongchamps,

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,

Neal Shore, MD FACS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for your diligence in responding to all of the reviewer comments

Reviewers' comments: