PONE-D-24-47321Biweekly CAPOX versus Triweekly CAPOX in the adjuvant therapy of post-surgery CRC: a randomized controlled trialPLOS 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: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

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: Thank you for an interesting article that clearly outlines what was done and how to interpret the findings. I have a few comments to further clarify the article:

Abstract: "This study aims" - please add an s.

line 139: 0.44 effect size - isn't this a calculation based on a difference in proportions between the two groups? What proportions were used? was the proportion of all grade or grade 3+ the quantity of interest? Please provide a calculation that matches the incidence endpoint. Be clear if it is a rate estimated at any time during treatment, or if it is calculated from a time to event variable, which is possible if the AEs can take time to be experienced and there is differing times of follow up.

Non-inferiority is mentioned in the discussion - if the study was designed to test non-inferiority, please clearly indicate this in the sample size section of the paper.

What happened if a patient in the 3-month group experienced thrombocytopenia at 4 months - was that counted as an event? Be clear if the adverse events were collected within 6 months of starting treatment or just during study treatment.

Figure 2F - state p>0.99

The description of the results is valid.

Could 95% confidence intervals be added to the rates in Figures 2 and 3?

Reviewer #2: The authors present their single center randomized phase II study for high risk stage II and stage III colon cancer patients who received either biweekly or triweekly capeox. The rationale for the study is clear. The arms of the study are fairly well balanced and the results are presented appropriately. Limitations of the study are presented. Although T and N characteristics are presented it would be helpful to describe the numbers of Stage III A, B, C patients and high risk stage II patients and to describe which factors resulted in designating a stage II patient high risk. Although there were some differences in toxicities between the 2 regimens the differences are not striking and it is doubtful these results are practice changing.

Reviewer #3: The study titled "Biweekly CAPOX versus Triweekly CAPOX in the adjuvant therapy of post-surgery CRC: a randomized controlled trial" is a well-designed and clinically relevant investigation that addresses an important question in the management of colorectal cancer (CRC). The authors have conducted a randomized controlled trial to compare the safety and efficacy of a modified biweekly CAPOX regimen with the conventional triweekly CAPOX regimen in high-risk stage II and stage III post-surgery CRC patients. The study is particularly commendable for its focus on reducing treatment-related adverse events, such as thrombocytopenia and neutropenia, while maintaining therapeutic efficacy. The findings suggest that the biweekly CAPOX regimen is associated with fewer hematological adverse events and comparable 3-year disease-free survival (DFS) rates, which could have significant implications for improving patient tolerance and adherence to adjuvant chemotherapy. The study is well-written, methodologically sound, and provides valuable insights into optimizing adjuvant chemotherapy for CRC patients.

Comments for Revision:

1. While the study mentions that the sample size was calculated based on the primary outcome of thrombocytopenia, it would be beneficial to provide more details on the assumptions used for this calculation (e.g., expected incidence rates, effect size, power, and significance level). This will help readers understand the robustness of the study design and whether the sample size was adequate to detect clinically meaningful differences.

2. The study reports a median follow-up period of 42 months, which is commendable. However, it would be useful to discuss whether this follow-up duration is sufficient to capture long-term outcomes, particularly for DFS and overall survival (OS). Consider providing a rationale for the chosen follow-up period and whether longer follow-up is planned.

3. The study briefly mentions subgroup analyses based on treatment duration (3-month vs. 6-month). It would be valuable to provide more detailed results of these subgroup analyses, particularly in terms of adverse events and DFS. This could help identify specific patient populations that may benefit more from the biweekly regimen.

4. The study uses Kaplan-Meier estimation for DFS analysis and Cox proportional hazard models for hazard ratios (HRs). It would be helpful to clarify whether any adjustments were made for multiple comparisons, especially given the secondary endpoints. Additionally, consider discussing the potential impact of confounding variables on the results and whether any multivariate analyses were performed.

5. While the study reports a lower incidence of thrombocytopenia and neutropenia in the biweekly group, it would be beneficial to provide more detailed information on the severity and management of these adverse events. For example, how many patients required dose reductions, treatment delays, or supportive care interventions?

6. The discussion section could be expanded to include a more detailed discussion of the clinical implications of the findings. For instance, how might the reduced incidence of hematological adverse events impact patient quality of life, treatment adherence, and overall healthcare costs? Additionally, consider discussing how these findings might influence clinical guidelines or practice.

7. The study acknowledges that it is a pilot study with a limited number of patients. It would be helpful to elaborate on other potential limitations, such as the single-center design, potential selection bias, and the generalizability of the findings to other populations or settings.

8. The conclusion could be strengthened by suggesting directions for future research. For example, are there plans for a larger, multicenter trial to confirm these findings? Could future studies explore the use of biomarkers or molecular profiling to further personalize adjuvant chemotherapy regimens?

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes:  Mohammad Ebrahimnezhad

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Attachments

Attachment

Submitted filename: comments 14.docx

Biweekly CAPOX versus Triweekly CAPOX in the adjuvant therapy of post-surgery CRC: a randomized controlled trial

PONE-D-24-47321R1

Dear Dr. Zhang,

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.

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Kind regards,

Keun-Yeong Jeong

Academic Editor

PLOS ONE

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 #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 #2: Yes

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

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 #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 #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 #2: The authors have extensively addressed all the reviewers' comments and have made appropriate changes within the manuscipt

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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 #2: No

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