Dear Dr. Nagao,

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Kind regards,

Satyajeet Rath

Academic Editor

PLOS One

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Additional Editor Comments:

Although its a well thought out and well written article, issues regarding poor dosimetric data reporting, use of older treatment techniques like four-field box and lack of all these being mentioned in limitations need to be addressed adequately along with the queries raised by the reviewers.

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Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: Yes

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??>

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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: This paper describes a well-designed study to investigate the factors that influence PIF incidence after pelvic radiotherapy. The documentation of significant inter-institutional variation between patient outcomes will likely contribute to more informed management of these complex patients in the future. The writing is very clear and the data are straightforward and fairly interpreted.

Reviewer #2: This manuscript reports a retrospective multicenter cohort study evaluating the incidence and risk factors of pelvic insufficiency fractures following definitive radiotherapy for cervical cancer. The topic is clinically relevant, as long-term survivorship issues and late skeletal toxicity are increasingly important in gynecologic oncology. The multicenter design and attempt to standardize diagnostic criteria across institutions are notable strengths. However, the study’s conclusion is insufficiently substantiated by the current data. Several key methodological limitations, particularly the lack of dosimetric bone analysis, absence of baseline bone health assessment, and incomplete adjustment for center-level confounders, substantially weaken causal inference. Substantial methodological clarification and additional analyses are required before the manuscript can be considered for publication.

Major Issues

• The manuscript repeatedly implies a dose effect relationship between radiotherapy and PIFs, yet no quantitative dosimetric analysis of pelvic bones is provided. No dose–volume parameters are reported.

• The conclusion that institutional differences may reflect technical nuances is speculative without objective dosimetric evidence.

• At a minimum, the authors should either provide a comparative analysis of bone dosimetry across institutions or explicitly acknowledge that the absence of bone dose data precludes any mechanistic interpretation.

• Treating institution emerges as an “independent” risk factor; however, this variable likely functions as a proxy for unmeasured confounders, including differences in imaging surveillance intensity, variations in CT slice thickness or MRI protocols, thresholds for reporting asymptomatic fractures, and subtle planning or delivery differences not captured by protocol summaries. Without hierarchical modeling or more granular center-level variables, attributing risk to institution is methodologically weak.

• The manuscript should better contextualize this limitation and avoid overinterpretation of menopause as a dominant risk factor.

• The absence of baseline bone mineral density data represents a major limitation, given the well-established association between osteoporosis and pelvic insufficiency fractures. Menopausal status alone is an imprecise surrogate for bone health, and the very high hazard ratio reported for menopause raises concern for substantial residual confounding. Accordingly, the manuscript should more clearly contextualize this limitation and avoid overinterpreting menopause as a dominant independent risk factor.

• Pelvic insufficiency fractures is treated as a time-to-event outcome using Kaplan–Meier and Cox regression, yet death and disease progression are treated only as censoring events, despite being potential competing risks.

• Given the non-negligible risk of death or progression in this population, a competing-risk framework would be more appropriate or, at minimum, should be discussed.

• Most patients were treated with conventional four-field techniques and central shielding, with limited use of IMRT/VMAT.

• The applicability of the findings to modern image-guided IMRT-based cervical cancer radiotherapy is therefore restricted.

• This limitation should be emphasized more strongly in both the Discussion and Conclusions.

Minor Issues

• The diagnostic criteria for pelvic insufficiency fracture, while described, would benefit from a concise, standardized definition early in the Methods section.

• Clarify whether asymptomatic fractures detected incidentally were included and whether imaging was symptom-driven or routine.

• Tables summarizing institutional characteristics should clearly indicate which variables were statistically compared and which were descriptive only.

• Figures would benefit from clearer labeling of censoring and number at risk.

• Although the prevalence of osteoporosis medications was low, this information remains clinically relevant and could be summarized more clearly in a dedicated table or footnote.

• Some statements regarding “institutional quality control” and “technical nuances” are speculative and should be more cautiously phrased.

• The Discussion would benefit from clearer separation between findings supported by data and hypotheses requiring future validation.

• Overall language quality is good, but minor grammatical edits and sentence tightening are recommended, particularly in the Discussion section.

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Reviewer #1: No

Reviewer #2: No

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Incidence of pelvic fractures after definitive radiotherapy for cervical cancer: A retrospective multicenter cohort study (The IPFAR study)

PONE-D-25-43659R1

Dear Dr. Nagao,

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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Kind regards,

Satyajeet Rath

Academic Editor

PLOS One

Additional Editor Comments (optional):

I appreciate the replies of all the authors

Reviewers' comments: