Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Shoji Nagao's article, "The New Era of Intraperitoneal Carboplatin in Ovarian Cancer: From Biological Basis to Clinical Implementation," is a synthesis of 19 references. The authors conclude that intraperitoneal carboplatin therapy is a versatile option in the modern management of ovarian cancer. This report, although divided into five parts (apart from the introduction and conclusion), lacks a "Materials and Methods" section. This omission makes the results and impact of the carboplatin/PARP inhibitor combination difficult to interpret. Various gynecological oncology group (GOG) databases are used, but they need to be more detailed. Statistical analysis and a clear conclusion are lacking, thus hindering a better understanding of the topic. Without this data, this report is far from ready for publication.

Author Response

Comment 1

The manuscript lacks a “Materials and Methods” section.

Response: We agree that clarification of the review methodology improves transparency. A short “Review methodology” paragraph has been added to the Introduction section, describing the literature search approach and the selection of key clinical trials and pharmacokinetic studies. This manuscript is a narrative review synthesizing previously published clinical and pharmacological evidence; therefore, no original statistical analysis was performed.

Comment 2

GOG database usage should be clarified.

Response: We have clarified that the review focuses on pivotal randomized GOG/NRG trials and prospective IP carboplatin studies, and this explanation has been incorporated into the revised manuscript.

Comment 3

Statistical analysis and a clearer conclusion are needed.

Response: Because this manuscript is a narrative review, no new statistical analysis was conducted. However, the Conclusion section has been shortened and refocused to clearly distinguish: findings supported by randomized trials, hypothesis-generating concepts, and future research directions.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a thoughtful synthesis of the biological rationale, pharmacokinetics, and evolving clinical evidence supporting intraperitoneal carboplatin in ovarian cancer. The narrative is largely coherent, the key trials are well discussed, and the authors make a convincing case for revisiting IP carboplatin in the modern therapeutic landscape. However, several interpretative, structural, and clarity issues need to be addressed to strengthen balance, transparency, and clinical applicability. Overall, I warrant minor revision before it can be published.

• In Section 2, the pharmacokinetic discussion is strong but repetitive. The concepts of “hybrid systemic delivery” and “bidirectional exposure” are restated multiple times across paragraphs. These should be consolidated into a single, clearly defined conceptual framework introduced once and referenced later, rather than re-explained.
• In Section 3 (lines 115–147), statements suggesting that IP platinum benefit extends beyond minimal residual disease should be more cautiously worded. Specifically, the sentence implying efficacy in larger residual tumors should explicitly note that supporting evidence is largely retrospective or subgroup-based and not powered for this question.
• The discussion of treatment completion as a determinant of benefit (lines 118–121 and 145–147) should be sharpened by explicitly stating that completion is a post-randomization variable and may reflect patient fitness rather than treatment superiority. Consider adding one sentence explaining why this limits causal inference.
• In the comparison between iPocc and GOG-252 (Section 4), the authors should more clearly acknowledge that these trials were conducted in different eras, populations, and geographic settings. A short paragraph explicitly stating that cross-trial comparisons are hypothesis-generating would improve scientific rigor.
• The proposed explanation that bevacizumab “diluted” the benefit of IP carboplatin (lines 175–180) is speculative. This should be clearly labeled as a hypothesis, and the wording should be softened to avoid implying a proven biological interaction.
• The PFS benefit reported for iPocc (lines 182–185) should include a brief comment on absolute magnitude and clinical relevance, not only statistical significance, to help readers contextualize the result.
• In Section 5.2, the lack of biomarker stratification is appropriately identified as a limitation, but the authors should explicitly state that no conclusions can currently be drawn regarding differential benefit in HRD or BRCA-mutant tumors, rather than implying potential advantage.
• In Section 6.3, the discussion of PARP inhibitors should be tightened to clearly separate biological plausibility from evidence. Phrases suggesting that IP carboplatin may “optimize” PARP inhibitor benefit should be revised to emphasize that this remains untested and speculative.
• In Section 6.4, the rationale for favoring ddTCip over bevacizumab-containing regimens would benefit from a clearer summary sentence explicitly stating in which clinical scenarios one approach might reasonably be preferred over the other, based on existing data.
• Practical considerations related to catheter placement and management (Section 6.5) should include at least one sentence quantifying complication rates reported in iPocc or prior trials, rather than remaining purely descriptive.
• The Conclusions section largely repeats earlier arguments. It should be shortened and refocused on two to three key take-home messages, explicitly distinguishing what is supported by randomized evidence versus what remains investigational.
• Minor editorial issues include inconsistent abbreviation use, occasional redundancy in trial descriptions, and minor typographical errors that should be corrected with careful proofreading.

Author Response

Reviewer 2

    We thank the reviewer for the detailed and constructive suggestions.

Comment 1

Pharmacokinetic discussion is repetitive.

Response: We agree with the reviewer’s suggestion. The conceptual framework of “hybrid systemic delivery” and “bidirectional exposure” is now introduced once in Section 2, and repeated explanations in later sections have been removed .

Comment 2

Interpretation regarding larger residual tumors should be cautious.

Response: The wording has been revised to clarify that evidence in this setting is primarily retrospective or subgroup-based and should be interpreted cautiously.

Comment 3

Treatment completion bias should be clarified.

Response: We added the following clarification: Treatment completion represents a post-randomization variable and may reflect patient fitness and tumor biology rather than treatment efficacy alone.

Comment 4

Cross-trial comparison (iPocc vs GOG-252).

Response: We added a paragraph explicitly stating that cross-trial comparisons are hypothesis-generating and limited by differences in population, geography, and treatment era.

Comment 5

Bevacizumab interaction is speculative.

Response: The relevant section has been revised to clearly label this as a hypothesis rather than a proven mechanism.

Comment 6

Clinical relevance of PFS benefit in iPocc.

Response: We added a statement noting that the absolute PFS improvement was modest despite statistical significance, to provide clinical context.

Comment 7

HRD/BRCA subgroup interpretation.

Response: We clarified that no conclusions can currently be drawn regarding molecular subgroup benefit.

Comment 8

PARP inhibitor section should distinguish hypothesis vs evidence.

Response: This section has been revised to clearly separate biological plausibility from clinical evidence.

Comment 9

Dose dense TCip vs bevacizumab strategy clarification.

Response: A summary sentence was added to Section 7.4 clarifying clinical scenarios where each strategy may be considered.

Comment 10

Catheter complication rates.

Response: We added a sentence quantifying reported catheter-related complication rates from prior IP trials.

Comment 11

Conclusion should be shorter

Response: The Conclusion has been substantially shortened and focused on key take-home messages.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive and timely narrative review on the evolving role of intraperitoneal (IP) carboplatin in epithelial ovarian cancer. The authors present a clear biological and pharmacokinetic rationale for IP platinum therapy and thoughtfully reframe IP carboplatin as a hybrid strategy combining intensified peritoneal exposure with effective systemic delivery. The discussion of the iPocc trial in relation to earlier GOG studies, particularly GOG-252, is well structured and conceptually strong, and the manuscript is of clear interest to clinicians and researchers in gynecologic oncology.

The manuscript is generally well written, scientifically sound, and appropriately referenced. The English language is clear and of high quality, with correct terminology and an appropriate academic tone. No major language editing is required; however, minor stylistic polishing, particularly shortening some long and complex sentences, could further improve readability.

Several points would benefit from clarification or more cautious interpretation.

First, while the iPocc trial results are discussed in detail, the clinical benefit observed (particularly in terms of progression-free survival) is modest, and overall survival data remain immature. Although the authors appropriately acknowledge potential selection bias related to treatment completion, further moderation of conclusions regarding broad clinical applicability would strengthen the manuscript.

-Second, the proposed integration of IP carboplatin with modern maintenance strategies, particularly PARP inhibitors, is biologically appealing but remains speculative. This should be more clearly framed as a hypothesis-generating concept, as no prospective data currently validate this approach. Similarly, the discussion on the interaction between bevacizumab and IP chemotherapy is interesting but largely theoretical and should be presented with appropriate caution.

-Finally, the generalizability of IP carboplatin outside specialized, high-volume centers deserves further emphasis, given the ongoing issues related to port placement, catheter-related complications, and institutional expertise.

Overall, this is a high-quality review that offers valuable insights into the contemporary and potential future role of IP carboplatin in ovarian cancer. With minor revisions focused on balancing interpretation and improving clarity, the manuscript would make a meaningful contribution to the field.

Comments on the Quality of English Language

The English language is clear and of high quality, with correct terminology and an appropriate academic tone. No major language editing is required; however, minor stylistic polishing, particularly shortening some long and complex sentences, could further improve readability.

Author Response

Reviewer 3

We thank the reviewer for the positive evaluation of the manuscript.

Comment 1

Clinical benefit modest; OS immature.

Response: We agree and have added wording emphasizing that PFS benefit is modest and OS data remain immature

Comment 2

PARP inhibitor integration remains speculative.

Response: This section has been revised to clearly frame the concept as hypothesis-generating.

Comment 3

Generalizability outside high-volume centers.

Response: We expanded the discussion in Section 5.4 to emphasize: port management expertise, institutional infrastructure, and real-world reproducibility (Line 243-244).