PONE-D-23-05244Development of robust radiobiological optimization algorithms based on the mixed beam model for intensity-modulated carbon-ion therapyPLOS ONE

Dear Dr. Masashi Yagi

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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Xin A Wang, Ph.D.

Academic Editor

PLOS ONE

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"This work was partially supported by the JSPS KAKENHI 17K16437, 21K07700, and 22K07695. The authors acknowledge and thank the staff at OHITC for their help with the measurements related to the commissioning, the staff at Osaka Heavy Ion Administration Company for help in operating the accelerator in the commissioning, Mr. Kenji Matsuda (Hitachi, Ltd. Smart Life Business Management Division) for supporting data analysis, and QA team in the Japan carbon-ion radiation oncology study group (J-CROS) and the QA committee in OHITC for a fruitful discussion on this work."

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Additional Editor Comments (if provided):

This manuscript evaluates some key features of a TPS in supporting IMCT. These include both the accuracy of physical and biologic dose calculation, plus the abilities of robust optimization. There are some valuable results such as the measurement of survival factions for in comparison to calculation. However, the manuscript is very difficult to read in current form. Overall, the manuscript is not written in a clear, consistent and coherency way. There are a lot of guessing on what the author is expressing. I strongly suggest the authors rewrite the manuscript with professional English editing.

Some specific comments include:

• It is unclear on the purpose of the manuscript. Most of work described in the manuscript is about validation of the TPS. Not much on the development except the description of SC and WC algorithms in the method and material section.

• Physical dose calculation validated by in house software. What makes the in house software the standard?

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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: Yes

Reviewer #2: Yes

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

Reviewer #1: N/A

Reviewer #2: N/A

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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

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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

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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 authors applied the mixed beam model in the physical and radiobiological dose optimization for intensity modulated carbon therapy (IMCT). Besides TPS, they have developed an independent dose calculation engine based on Python. Most importantly, they conducted cell irradiation to validated the accuracy of the TPS and independent dose engine. They found that the robust radiobiological optimization enhanced the sensitivity of the examined error by up to 19% compared to the conventional IMCT. Using the worst case scenario algorithm can even enhance the robustness more than the spot control algorithm. This is a very comprehensive study including TPS, independent dose verification engine, and cell irradiation experiments, phantom study, and optimization in patient case. I would recommend its acceptance for publication after minor revision. Nevertheless, I have to admit that this paper is really long and not easy to be understood especially for those who do not have experience in carbon therapy. Some comments are listed below:

(1) Page 8, line 37, it should be “surviving fraction”, not “survival fraction”. Please also change the label in figure 4.

(2) Page 8, line 47, what is “-a 0.6%”?

(3) page 16, line 279, in each plate. What type of cell culture plate did you use? Single-well petri dish?

(4) page 31, the last paragraph regarding the discussion of LET painting. I don’t think it is necessary to mention this because in carbon ion therapy, LET is no longer an appropriate quantity in plan optimization and evaluation. You have conducted the robustness analysis of radiobiological dose, which is the appropriate quantity. Because multiple secondary charged particles are generated in carbon therapy, the appropriate physical quantity is lineal energy and/or specific energy in microdosimetry, rather than LET.

(5) page 39, figure 4, there are results from experiment, experiment with SFUD and independent calculation, why isn’t there the surviving fraction predicted in your TPS by WC or SC algorithms?

Reviewer #2: This manuscript discusses an investigation of robust optimization strategies for intensity modulated carbon ion therapy (IMCT). The study included both physical uncertainties and biological doses using two optimization methods, spot control and worst case for testing phantom and patient cases. It also included both calculated biological effect and survival rate validation of a human salivary gland cell line. Both plan robustness and biological effect are important topics in clinical particle therapy currently and thorough investigations are needed. I think this manuscript should be of great interest for particle therapy researchers and practitioners. The authors did a good job in explaining the methodologies and providing detailed supporting data. However, I have several comments as summarized in below with an aim towards improving the clarity of the manuscript.

I would suggest the authors to consider revising the title of this study, as well as abstract and other discussions if related. First, it seems the robust biological optimization algorithms had been developed in previous studies or from existing TPS, e.g., spot control (SC) and worst case (WC) optimization algorithms, and RBE optimization based on local effect or MK models. I think “development” might not be appropriate in the title. Some options could be “evaluation” or “assessment”, etc. Secondly, the term “mixed beam” is not descriptive. It could mean a mix of photon and particle beams, or a mix of different beam lines, or different RBE models, without a definition. It should be stated clearly what “mixed” means in the title and its first appearance in the main text.

The measurement of survival factions for the selected cell line presented interesting results for readers. However, it was not discussed with more detail. It would be more helpful if the authors could comment on some important aspects, such as the correlation between calculated and measured results, any insights from the experiments, the progress concerning previous validation, the current approach, and maybe future works.

Some specific comments include:

• Line 54. It could be more appropriate to state “the impact of range and position uncertainties”, because robust optimization does not reduce uncertainties directly.

• Line 134. It may be not necessary to add “independently from non-IMCT” as it is inherent in IMCT that each field is independently modulated. Same for Line 148.

• Line 152. How are alpha_ij and beta_ij determined? Details or a previous publication could be useful.

• Line 220. Is there a typo in equation (16)? Terms in the bracket seem identical.

• Line 233. Is the “dose calculation engine” based on analytical model or Monte Carlo? Is there any validation work for it, maybe in another work?

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Reviewer #1: No

Reviewer #2: No

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PONE-D-23-05244R1Development of robust radiobiological optimization algorithms based on the mixed beam model for intensity-modulated carbon-ion therapyPLOS ONE

Dear Dr. Yagi,

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 Aug 07 2023 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,

Xin A Wang, Ph.D.

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:

This manuscript evaluates some key features of a TPS in supporting IMCT. These include both the accuracy of physical and biologic dose calculation, plus the abilities of robust optimization. The study provides some valuable results in the advancement of IMCT and is clearly worth the publication. Both reviewers feel the revision addresses their previous comments and concerns. I agree the revision has significant improvement from previous submission. However, there are still some concerns as listed below:

1. The revision is more readable. The abstract and introduction sections can be improved to make the manuscript appear in a clear, consistent and coherency way.

2. Strong recommendation on changing the title. The manuscript focused on the validation of the dose calculation of robust optimization algorithms. We expressed concern on using the world “development” which mismatch the purpose of the study.

3. Physical dose calculation validated by in house software. What makes the in house software the standard?

[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: All comments have been addressed

Reviewer #2: 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: Partly

Reviewer #2: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: N/A

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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: No

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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

**********

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: I don't have more questions. The authors have addressed all my concerns. I recommend its acceptance for publication.

Reviewer #2: (No Response)

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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

**********

[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.

Validation of robust radiobiological optimization algorithms based on the mixed beam model for intensity-modulated carbon-ion therapy

PONE-D-23-05244R2

Dear Dr. Yagi,

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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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,

Xin A Wang, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

This manuscript evaluates some key features of a TPS in supporting IMCT. These include both the accuracy of physical and biologic dose calculation, plus the abilities of robust optimization. The study provides some valuable results in the advancement of IMCT and is clearly worth the publication.

The readability of manuscript was greatly improved through 2 revisions. It can be better but I feel it is publishable at present form. The new title really reflect the purpose of the study.

Reviewers' comments: