PONE-D-23-36160Progressive Relaxation Training in Patients with Breast Cancer Receiving Aromatase Inhibitor Therapy-Randomized Controlled TrialPLOS ONE

Dear Dr. BAHÇACI,

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.

==============================

==============================

Please submit your revised manuscript by Feb 02 2024 11:59PM. 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Peter Vuylsteke, MD

Academic Editor

PLOS ONE

Journal requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 

Additional Editor Comments:

This is an interesting article and hypothesis, and the results are food for thought. Congratulations for the work done.

Still the comments made by the reviewers are valid and need to be adressed and responded to in a satisfactory way, before going further in the process.

[Note: HTML markup is below. Please do not edit.]

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: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

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

**********

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

**********

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: A two-arm randomized controlled clinical trial was conducted which aimed to assess the efficacy of Progressive Relaxation Exercises on the side effects of aromatase inhibitors in patients with breast cancer. The intervention group reported significantly less pain severity and pain interference than the controls. No differences in quality of life and emotional status were found.

Minor revisions:

1- P-values never equal zero; express small p-values as < 0.001.

2- Line 122: Provide full details of the sample size calculation. The power calculation should include: (1) the estimated outcomes in each group; (2) the α (type I) error level; (3) the statistical power (or the β (type II) error level); (4) the target sample size (5) statistical testing method and (6) for continuous outcomes, the standard deviation of the measurements.

3- Line 140: Indicate if block randomization was used. If so, specify the block size.

4- Line 212: For improved clarity, replace “analyzed” with “summarized.”

5- Table 3: When data is not normally distributed, it is customary to summarize the results using median, first and third quartiles.

Reviewer #2: This -to my knowledge-is the first study testing 'Progressive Relaxation Exercises' in patients receiving an oral aromatase inhibitor in early breast cancer. The study is positive for some endpoints (Pain); the authors do caution their conclusions saying that longer follow-up is needed and that PRE has no effect on other studied endpoint.

Small comments

- Please use the offical term 'AIMSS' troughout the manuscript as this is the name given to this well known problem (aromatase inhibitor musculoskeletal syndrome)

- Please describe the pathophysiology of AI-MSS (refering to fluid retention in the joints as studies by MR imaging and ultrasound); Morales et al. J Clin Oncol 2008

- The authors report on mean and SD; What clinicians do want to know is whether women (in one group) with more pain at baseline were more likely to respond to PRE/no-PRE than those with less pain at baseline.

- Some minor edits to be corrected in the text

Reviewer #3: The authors, Bahcaci et al. present data from their RCT on “Progressive Relaxation Training in Patients with Breast Cancer Receiving Aromatase Inhibitor Therapy-Randomized Controlled Trial,” which addresses an important area of morbidity for a large proportion of breast cancer patients treated with AIs, however the small sample size and the lack of analytical rigor limit clinical interpretation of this data.

The specific comments are list below. Applicable comments for the abstract are expanded upon below:

Introduction

Paragraph 1 is not needed, especially since mechanism of action is not well-described, it adds minimal value to the context. It is OK to open with Paragraph #2.

For Paragraph 2 in addition to indication listed, it is important to expand on the magnitude of the problem that AI-related adverse events lead to discontinuation of therapy.

Paragraph #3 - be specific which adverse effects are mitigated by exercise interventions and what type of exercise interventions. The current description seems very broad and again non-specific.

Paragraph 4 mixes data on muscle relaxation and exercise interventions. It is important to define the components on muscle relaxation exercises and the effect sizes seen in other populations to establish scientific plausibility that PRE would work in AI-induced arthralgias.

Methods

The details of the sample size calculation are inadequate – the authors should define what effect size they expected to see with a power of 80% and alpha of 0.05. A sample size of 20 per arm is a very small number for meaningful effect size.

Was the PRE implemented to the study participants as a group – in which case peer support will be a big confounder? I.e. did scores in pain and QALY improved due to the community/support aspect of the group and not necessarily the intervention in and of itself?

Should the analysis be intent to treat – patients excluded if they missed 10% of sessions? How did you establish fidelity of the at home sessions?

Not sure if statistical approach evaluating means is the appropriate approach, Eg. for table 3, authors assess mean in comparing scores on outcome instruments, but median and non-parametric analysis as they listed would have been most appropriate.

Results

Baseline characteristics should have also included stage of breast cancer as well as number of years on AI.

Table 3 – baseline scores for Table 3 for BPI-PS are higher for control group than for study group, and especially since the significance level is based on 1-point differences in report scores, I think this should be discussed as a limitation in interpreting effect size. Perhaps the model should have adjusted for baseline level of pain assessment. Results should also be interpreted in terms of what is a clinically significant difference between the groups – effect size between groups is not significant for any of the instruments. The instruments were described as assessing scores of 3-4 as mild, so is this study result clinically significant if the mean score @ 6 weeks for post groups fall within the mild range? In some cases, below the mild scale (<3).

Discussion:

The limitation section should be further expanded not a cursory statement that the sample size was small. Fidelity to home sessions should also be discussed. Authors should also discuss potential mediators of the effect noted. This should be an ITT analysis, is there a reason why the authors didn’t consider this?

Minor comments:

In the abstract, line 44 has an incomplete p value listed – 0.000.

**********

6. 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: Yes: Neven Patrick

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.

PONE-D-23-36160R1Progressive Relaxation Training in Patients with Breast Cancer Receiving Aromatase Inhibitor Therapy-Randomized Controlled TrialPLOS ONE

Dear Dr. BAHÇACI,

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.

Please submit your revised manuscript by Apr 08 2024 11:59PM. 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Peter Vuylsteke, MD

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.

Additional Editor Comments:

Dear author

Thank you for the revisions made.

Kindly attend to the minor revision suggestion of Reviewer 1, then we can go on and accept the article.

[Note: HTML markup is below. Please do not edit.]

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)

********** 

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

********** 

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

Reviewer #1: 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

********** 

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

********** 

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 revisions:

Table 2: In addition to frequencies, add the corresponding percentages.

********** 

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

**********

[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.

Progressive Relaxation Training in Patients with Breast Cancer Receiving Aromatase Inhibitor Therapy-Randomized Controlled Trial

PONE-D-23-36160R2

Dear Dr. BAHÇACI,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at http://www.editorialmanager.com/pone/ and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Peter Vuylsteke, MD

Academic Editor

PLOS ONE