PONE-D-25-21057Dosimetric comparison of VMAT lung cancer plans on Halcyon Accelerators using Monte Carlo, Acuros XB, and AAA algorithmsPLOS ONE

Dear Dr. Du,

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Academic Editor

PLOS ONE

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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: Partly

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

Reviewer #1: Yes

Reviewer #2: 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

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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: Title: Dosimetric comparison of VMAT lung cancer plans on Halcyon Accelerators using Monte Carlo, Acuros XB, and AAA algorithms

General comments:

This manuscript aims to compare dose distributions calculated by using the RayStation based on Monte Carlo (MC), Anisotropic Analytical Algorithm (AAA), and Acuros XB (AXB) to ensure dose calculation accuracy across different platforms. They also wanted to report dosimetric impact of choosing calculation algorithm on patient dose expectation. The TPS should be fast as possible while it ensures acceptable accuracy compatible to the MC, which has been regarded as a golden standard but requires large amount of time to calculate patient dose distribution. It is essential to validate the accuracy of TPS by comparing the MC simulation. Since many algorithms have been used in the medical institutions, in addition, guarantee of accurate dose calculation across different algorithms is necessary. However, there have been studies on comparing the MC, AAA, and AXB for several years even the beam or tumor site is different (Zaman, et al., 2019, Sarin et al, 2022, Tsuruta, et al., 2014, Han et al., 2011, Seniwal et al., 2020). Authors should suggest their unique findings different from previous studies, but I’m not sure with the current manuscript. I hope they provide them in the next revision of the manuscript or it may be better to submit the manuscript as a technical note.

Specific comments:

- Avoid using abbreviations in the Title.

- Use of RayStation must accompany with using Eclipse to apply the plans to Halcyon machine. Then, is there any advantages of using both the TPSs rather than solely using the Eclipse if the recalculation with the Eclipse must be carried out?

- The abbreviation “haMC”, “haAAA”, and “haAXB” were explained in the Results. As they appears from Materials and Methods, they should be explained its first appearance.

- Even though the RayStation provides MC based calculation, I’m not sure it is compatible with the full-MC simulation as it seems to have adjusted algorithm to make the calculation faster. There may be assumptions to increase calculation speed.

- According to my knowledge, the full-MC has been considered as a gold standard. I wonder that the RayStation can be considered same as the full-MC simulations using the codes such as EGS, Geant4, TOPAS, etc. I think it would be better to include Full-MC simulation result.

- It would be better to provide the required calculation time for obtaining dose distribution with the RayStation since it was considered as the MC calculation and authors explained statistical uncertainty and size of the calculation grid.

- The authors defined the ROIs in the water phantom with different radii, 3 and 5 cm. Is the reason for this to consider both high and low dose region?

- The authors should also provide statistical constraints in the MC calculation in the water phantom study as did they in patient case study.

- The authors categorized their cohort according to tumor stage. Is there any reason for this? This manuscript is not related to treatment outcomes or other biological effects.

- Authors stated they used three algorithms: haMC, haAXB, and haAAA. However, I guess these are labels of data, not the name of the algorithm. I think they should be changed to MC, AXB, and AAA.

- According to the authors, did the AXB also produce dose deviations in boundary regions since the gamma pass rate of AXB&AAA was higher than that of MC&AXB? The gamma pass rate was remarkably increased and this needs to be clarified.

- It would be better to provide gamma analysis for the patient case study similar to the water phantom study.

- What about providing graphs for stating distribution of the parameters such as CI, HI, GI, NTID?

- Please use the same color for the same organ in Figure 12.

Reviewer #2: Dosimetric comparison of VMAT lung cancer plans on Halcyon Accelerators using Monte Carlo, Acuros XB, and AAA algorithms

Manuscript Description

The submitted manuscript presents a valuable comparison of dose calculation algorithms—RayStation’s Monte Carlo (MC) and Eclipse’s Acuros XB (AXB) and AAA—in the context of Halcyon VMAT plans for lung cancer treatment. By recalculating treatment plans originally computed with Raystation’s Monte Carlo algorithm using both AcurosXB and AAA, the authors directly compare these algorithms. Their work demonstrates good agreement between MC and AXB across multiple dosimetric metrics in clinical patient cases while AAA shows slight but clinically acceptable deviations. The study’s strengths include the use of a real patient cohort in addition to a simple water phantom and rigorous statistical analysis. Overall, this manuscript makes a noteworthy contribution by demonstrating the reliability of algorithmic transitions for lung VMAT planning on the Halcyon platform.

However, the manuscript requires some major revisions before it can be considered for publication. I offer the following suggestions for revision:

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General Comments

1. The introduction should provide a more compelling rationale for the research work. Especially, making it clear that this study is filling in the gap of the work Saini et al. (2021) would be important to show the originality of the study. Also, much of the discussion section about algorithm comparisons needs to be in the introduction, giving previous results as background knowledge.

2. The reasoning behind recalculating without dose renormalization for the prescription dose to cover 95% of the PTV does not seem persuasive enough. The method that “users at other institutions” use seem definitely more acceptable. Further argument backed up with references that support the claim that the CTV still receives the prescribed dose would be helpful for justifying the method used in the study.

Specific Comments

• Halcyon prefixes: Choose either “haMC/haAXB/haAAA” or “MC/AXB/AAA,” and define the “ha” prefix if retained.

• CI vs PCI: Replace “CI” with “PCI” to accurately denote the Paddick Conformity Index to avoid confusion

• Decimal formatting: In tables, ensure consistent decimal formatting (e.g., one decimal place).

• Relative difference calculation: Express relative differences as (Comparing value−Reference)/Reference×100%.

• Consistent Reference Choose an algorithm to serve as the reference (e.g., haMC) and apply it uniformly across all comparisons.

• (p. 1, l. 4): Cite a source to support “VMAT has emerged as a key option…”

• (p. 2, l. 34): Add a reference when comparing AAA to Pencil Beam Convolution.

• (p. 4, l. 127): Include manufacturer name and location for the CT simulator.

• Figure 2: Revisit PTV expansion for Patients 22, 55, and 61—small CTVs appear to have disproportionately large PTVs.

• (p. 5, l. 203): The mentioned NTID isn’t shown in the OAR result

• Table 3 typo: Correct “ClClinical” to “Clinical"

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Reviewer #1: No

Reviewer #2: No

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PONE-D-25-21057R1Dosimetric Comparison of Monte Carlo, Acuros XB, and Anisotropic Analytical Algorithm for Lung Cancer Plans on Halcyon AcceleratorsPLOS ONE

Dear Dr. Du,

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 Oct 09 2025 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,

Minsoo Chun, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

2. 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:

The manuscript is generally well-prepared with sufficient data and analysis. However, to further improve the clarity and completeness of the work, the following points should be addressed:

1. Ensure consistent terminology throughout the manuscript (MC, AXB, AAA).

2. More clearly highlight the novelty and contribution of this study compared with prior works.

3. Provide stronger clinical interpretation of the numerical differences, explaining their implications in treatment decision-making.

4. Maintain balanced discussion of TPS advantages, acknowledging that integration benefits may vary by institutional setting.

5. Strengthen references, particularly for definitions of indices (HI, GI, NTID) and for statements regarding algorithm characteristics (e.g., the similarity between AXB and AAA).

5. Provide a clearer discussion of specific results where RayStation MC showed closer agreement with AAA than AXB (e.g., NTID or OAR doses), including possible physical or algorithmic reasons for these findings.

7. Revise the conclusion to emphasize not only the summary of results but also the practical clinical applicability of your findings.

Addressing these points will help enhance the clarity, balance, and overall impact of the manuscript.

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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

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: Yes

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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

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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: Title: Dosimetric Comparison of Monte Carlo, Acuros XB, and Anisotropic Analytical Algorithm for Lung Cancer Plans on Halcyon Accelerators

General comments:

The authors have well revised their manuscript and I appreciate their efforts in addressing most of the comments in the first revision. All the inquiries were clarified clearly. The motivation, novelty and strengths of their works were enhanced and clear. However, one point still needs clarification. I still think that the RayStation calculates based on the MC method but it doesn’t represent the MC typically refers to in this research field. It would be more precise to describe the calculation as “RayStation MC” or an equivalent term rather than simply “MC”.

Other comments are listed below as the specific comments.

Specific comments:

- Please specify which accelerator model parameters were adjusted during the TPS commissioning.

- Authors previously responded to the comment on the rationale for using different ROI sizes in water phantom test but their clarification is not sufficient. They should provide the reasons why 3-cm-radious ROI is more appropriate to assess the high dose uniform region rather than 2 or 4 cm. Similarly, they should also clarify why 5-cm-radious ROI is suitable for representing the dose gradient or lower-dose regions than the ROIs with any other sizes. For example, in my assumption, authors could use the ROIs with the most similar sizes for both high or low dose region.

- It would be better to cite more relevant references for definitions or equations of HI and GI.

- Please add reference for convincing that the AXB and AAA share similar dose calculation approximations, because they are implemented in the same TPS.

- According to understanding, the RayStation MC shows better agreement with the AXB than with the AAA. However, some results (e. g. NTID, OAR doses) showed better agreement between the RayStation and AAA than between the RayStation and AXB. The authors should clarify this.

- Authors clarified that one of their strengths over previous researches were that the validation is specified for Halcyon accelerator. I assume there are not substantial differences in beams of the same energy, such as 6 MV FFF. The differences between the accelerator types, C-type or O-type, are not expected to affect the TPS dose calculation accuracy. Could the authors clarify whether significant differences exist?

- Authors suggested one of the advantages of RayStation over Eclipse is integrated workflow. But the Eclipse seems to be more integrated in the case of medical facilities equipped exclusively with Varian accelerators.

Reviewer #2: The authors' response to the reviewers' comments seems to have been well reflected in this revised paper.

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Reviewer #1: No

Reviewer #2: No

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[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.

Dosimetric Comparison of Monte Carlo, Acuros XB, and Anisotropic Analytical Algorithm for Lung Cancer Plans on Halcyon Accelerators

PONE-D-25-21057R2

Dear Dr. Du,

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,

Minsoo Chun, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I am pleased to accept this manuscript. Ensure that the reviewer’s minor remarks are addressed in the final submission.

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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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

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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 really appreciate your revision with consideration of my suggestions. Now, the manuscript seems to be ready to go on. I don't have any further inquiries or comments on this manuscript.

Reviewer #2: Since the authors have addressed Reviewer 1’s comment by distinguishing between 'Monte Carlo (MC)' and 'RayStation Monte Carlo (RMC),' I suggest also replacing 'haMC' with 'haRMC' to maintain consistency and avoid confusion.

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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

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