Dear Dr. Tangthongkum,

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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?

Reviewer #1: Partly

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: No

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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.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

Reviewer #4: Yes

Reviewer #5: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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Reviewer #1: 1. While vitamin C has shown potential in reducing chemotherapy-induced toxicities in other cancers – Sentence changed to chemotherapy-induced toxicities in some of cancers.

2. Common adverse effects include gastrointestinal symptoms, such as nausea, anorexia, oral mucositis, diarrhea, and dysphagia, hematological toxicities (e.g., neutropenia, anemia, and thrombocytopenia), electrolyte imbalances (e.g., hyponatremia and hypokalemia). – Reference should be include.

3. Recent studies have largely focused on IVC, with doses ranging from 1 to 10 g per session, - How many sessions (its per day or something else? Its needs to be clarify in the manuscript.

4. Sixty-eight patients diagnosed with NPC and scheduled for CCRT were enrolled. – Which stage of NPC patients chosen for this study?

5. Regarding laboratory parameters, reductions in platelet count and serum sodium level were significantly less in the vitamin C group compared with the placebo group. – As of your results in the tables, there’s no difference in vitamin C and placebo groups.

6. However, platelet count reductions were significantly less in the vitamin C group than in the placebo group following chemotherapy – Mention the values in the manuscript.

7. Abbreviations should be include in the manuscript.

8. Quality of figures must be improved.

9. Based on your results there’s not much improvement of an adverse effects from chemotherapy. What is your conclusion about your study?

10. Why are you choosing 2g IVC for your study? As per literature it was 1-10g, please explain these in the manuscript.

Reviewer #2: Introduction

1. Author need to enhance the introduction part

2. Author missed the rational study objection

3. Author provide the FDA toxicological data in the intro part

4. Methodological part need to improve

5. Author need to rewrite result part with statistical comparison

6. Discussion is Very short, author need rewrite mechanistic discussion with result comparison

7. Conclusion not covey the correct way

8. Figure 2 very poor presentation and all the statistical error look like similar, author recheck the statistical error value

Reviewer #3: This study demonstrated that before the CCRT administration, IVC was effective in mitigating the reduction of platelet counts in patients with nasopharyngeal carcinoma (NPC). As the authors mentioned, this study has limitations, including a small patient sample size and short-term follow-up; however, it is very interesting in that it suggests IVC may have clinically meaningful benefits. I suggest that the authors should improve the following comments;

-The abstract contains too much methodological detail. It should be revised to briefly describe the study design and focus on the key findings.

-The manuscript lacks a detailed description of how hematological values were adjusted for individual patients in the graphical representations. Please clarify whether baseline normalization, delta changes, or other statistical adjustments were applied to account for inter-patient variability.

-The introduction should provide more focused literature references regarding vitamin C’s effect on platelet counts in specific cancer types.

-The conclusion should be revised to emphasize the potential clinical benefit of IVC in mitigating platelet count reduction, which would better highlight the significance of this study.

Reviewer #4: This manuscript presents a well-designed randomized, double-blind, placebo-controlled clinical trial addressing an important supportive care question in nasopharyngeal carcinoma. The study is methodologically rigorous, with clear eligibility criteria, appropriate randomization and blinding procedures, and transparent reporting in line with CONSORT guidelines. The authors provide a balanced interpretation of both positive and null findings, particularly highlighting the clinically relevant observation of platelet preservation. Overall, the work adds meaningful evidence to the limited literature on intravenous vitamin C in this setting and is clearly written and well-structured. Hence this manuscript may be recommended.

Reviewer #5: This paper describes what appears to be a well conducted study randomised trial comparing Vitamin-C with Placebo. Nevertheless, there are a few issues as listed below.

1. The primary endpoints are regarded as GI adverse events. So that when justifying the trial size of 22 per group (sensibly increased to 30), although power and test size are specified the anticipated difference between the groups is not. This difference should be specified.

2. Table 1 Patient demographics: As this is a randomised trial then, by definition, any differences observed between characteristics in this table are ‘random’. So, testing statistical differences is wrong and the p-values in the table should be deleted.

3. Table 1: Probably better to describe minimum and maximum age rather than the SD. Also, for the pretreatment values WBC, Haemoglobin, etc.

4 Table 2: For Nausea, the total of Grade 1 and Grade 2 adverse events with Vitamin C sums to greater than 30. So there so there is some double counting which makes the statistical testing invalid. The totals here should then be replaced by (say) the highest grade of adverse event experienced by the patient. The numbers experiencing zero adverse events should also be included to ensure that each sub table sums to 30 in each treatment group.

5. Table 2: In any event, although all may be incorrect because of the double counting, p-values are best quoted to 2 significant figures. So, 0.123 to 0.12 but ‘079’ remains as ‘0.079’, 0.155’ to 0.16’ and so on.

6. Table 2: Also, it would have helped to present, for example, for Oral mucositis (adding the zero group and presuming no double counting) the proportion of each Grade of adverse event in the margins of the sub tables. Here 7/25 = 0.28, 16/23 = 0.70, 3/3 = 0.5 and 4/6 = 0.67.

On a positive note, the authors when presenting results concerning the laboratory parameters refer to a Bayesian logistic regression. This is an unusual addition from a statistical perspective, but if retained needs much more explanation of what the methodology does and how the results are to be interpreted.

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what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Rajesh SelvarajRajesh SelvarajRajesh SelvarajRajesh Selvaraj

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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Effect of intravenous vitamin C administration on chemotherapy-induced adverse events in patients with nasopharyngeal cancer

PONE-D-25-67982R1

Dear Authors,

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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Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #5: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #5: Yes

**********

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

Reviewer #5: 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.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 #5: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #5: Yes

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Reviewer #5: Many thanks to the authors. They have addressed all the points I raised in my earlier review.

MMany thanks to the authors. They have addressed all the points I raised in my earlier review.

Many thanks to the authors. They have addressed all the points I raised in my earlier review.

Many thanks to the authors. They have addressed all the points I raised in my earlier review.

Many thanks to the authors. They have addressed all the points I raised in my earlier review.

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what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..-->

Reviewer #5: No

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