Dear Dr. Itano,

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We look forward to receiving your revised manuscript.

Kind regards,

Keun-Yeong Jeong

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?

Reviewer #1: Partly

Reviewer #2: Yes

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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

Reviewer #1: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1:  Main issues�

1.Inadequate Patient Allocation Justification�No explanation for the non-randomized assignment to HAIC-FOLFOX-B (n=20) vs. HAIC-FOLFIRI-B (n=22). Clarify selection criteria (e.g., physician discretion, tumor characteristics) to address potential selection bias.

2.Contradictory Efficacy Conclusions�Abstract claims HAIC-FOLFOX-B is effective (RR 25%), yet results show inferior median OS (12.9 months) vs. HAIC-FOLFIRI-B (17.4 months). Reconcile this discrepancy and clarify clinical significance given non-significant p-values (OS: p=0.116; PFS: p=0.053).

3.Incomplete Safety Reporting�Table 3 shows significantly higher anorexia in HAIC-FOLFIRI-B (18.2% vs. 0%, p=0.045) and artery occlusion (13.6% vs. 0%), yet these are not discussed. Expand safety analysis to address toxicity trade-offs between regimens.

4.Unclear Definition of "Refractory" Status�Lack of standardized criteria for prior chemotherapy failure (e.g., RECIST progression, cycles completed). Specify how "refractoriness" was determined to ensure patient homogeneity.

Reviewer #2:  This manuscript addresses an important clinical question about treatment options for patients with unresectable colorectal liver metastases refractory to standard systemic chemotherapy. The authors present a retrospective cohort study comparing two hepatic arterial infusion (HAIC) regimens combined with systemic bevacizumab. The topic is clinically relevant and the data are potentially useful for clinicians managing a difficult-to-treat patient population.

While the study is interesting, some major and minor issues should be addressed to improve its clarity, rigor, and presentation.

1. The manuscript mentions that all patients had previously failed systemic oxaliplatin-based and irinotecan-based therapies, but Table 1 shows heterogeneity in prior treatments (ranging from 2 to 7 prior lines). Please clarify how “refractory” was defined.

2. The p-values reported for OS and PFS between the two HAIC regimens are >0.05, yet the discussion sometimes implies superiority of one regimen over another.

3. Some toxicities (e.g., 16.7% grade 3–4 anemia, hepatic artery occlusion) are not trivial. Please clarify.

4. Figures are not visible in the PDF.

5. Table 4 is extensive but difficult to follow.

6. The abstract does not specify that the study was retrospective or single-center.

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

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Reviewer #1: No

Reviewer #2: No

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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.

Hepatic arterial infusion is effective in patients with unresectable colorectal liver metastases refractory to standard systemic chemotherapy: A retrospective cohort study

PONE-D-25-22185R1

Dear Dr. Itano,

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,

Keun-Yeong Jeong

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

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

Reviewer #2: Yes

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

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: Yes

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

Reviewer #2: Yes

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Reviewer #2: (No Response)

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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 #2: No

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