Dear Dr. Nagao,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Major Comments:

Relation to recent GOG studies:

Two recent GOG phase II trials (Gynecol Oncol. 2025;195:50–58, 59–65) have explored fertility-sparing strategies combining conization and lymphadenectomy. These should be cited and discussed to contextualize the study design and highlight differences or innovations in your protocol.

Dual experimental approach:

The concurrent use of NAC and fertility-sparing surgery represents a “double experimental” design. The rationale for combining these interventions should be explicitly justified, and the potential risks of this approach discussed.

Oncologic staging:

The protocol does not include a pre-treatment sentinel lymph node biopsy (SLNB) , which is critical for accurate baseline staging. Please justify this omission or consider including SLNB (with ultrastaging) as a criterion for eligibility (pN0, macro- or micrometastasis).

Endpoints and limitations:

The primary endpoint (uterine preservation) is clinically meaningful but should be interpreted within the constraints of a short 2-year follow-up, single-center design, and very small sample size (n=10). These limitations should be emphasized in the Discussion.

Statistical plan:

Include more detail regarding missing data handling, adjustment for confounders, and justification for the sample size (even if feasibility-based).

Novelty and contribution:

The use of dose-dense paclitaxel/carboplatin (dd-TC) NAC prior to fertility-sparing surgery could represent a distinctive contribution. Please emphasize this and clearly state how this approach differs from previous reports.

Clinical implications:

The Discussion should better outline how this feasibility study can inform future multicenter trials and guideline development.

Minor Comments:

Clarify imaging modalities for determining lymph node status (PET-CT vs. CT).

Specify how tumor size is measured and reviewed (MRI criteria, double reading).

Correct minor grammatical inconsistencies.

Add line numbering for easier reference during revision.

==============================

Please submit your revised manuscript by Dec 15 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Kazunori Nagasaka

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Figures 1 and 2 in the "study_protocol_E.docx" SI file were provided in non-English language. Please provide an updated “study_protocol_E.docx” with Figures 1 and 2 in English language.

3. Thank you for stating the following financial disclosure:

“Okayama University Hospital Clinical Research Incentive Grant”

Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

4. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

5. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Additional Editor Comments:

Dear Authors,

This manuscript presents a prospective, single-arm phase II trial evaluating fertility-sparing treatment with neoadjuvant dose-dense paclitaxel and carboplatin followed by conization and laparoscopic pelvic lymphadenectomy for FIGO stage IB2–IB3 cervical cancer. The study is well organized and clinically meaningful, addressing a highly relevant but challenging area in gynecologic oncology.

However, several important revisions are required before publication. The protocol should be better contextualized with recent literature, particularly the two GOG phase II studies published in Gynecologic Oncology (2025;195:50–58, 59–65), which explored similar fertility-sparing strategies. A comparative discussion is needed to clarify the novelty of the present trial.

The study combines two experimental elements—neoadjuvant chemotherapy and conservative surgery—and the rationale for this dual approach should be explained more clearly, including safety considerations. The lack of sentinel lymph node biopsy before treatment is a notable limitation that may affect staging accuracy; justification or modification should be discussed.

While the primary endpoint (uterine preservation) is clinically appropriate, the small sample size (n=10), single-center design, and short follow-up substantially limit generalizability. The statistical plan requires more detail, including handling of missing data, adjustment for confounders, and justification for sample size, even if based on feasibility.

The Discussion should emphasize the distinctiveness of the dose-dense paclitaxel/carboplatin regimen and elaborate on how this feasibility study could inform future multicenter or randomized trials.

Minor grammatical corrections and line numbering are also recommended.

Overall, this is a promising and well-structured clinical protocol that addresses an important gap in fertility preservation for cervical cancer.

With the above revisions, it would make a stronger and more rigorous contribution.

Sincerely,

Plos One Editorial Office

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

Reviewer #5: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Partly

Reviewer #2: No

Reviewer #3: Partly

Reviewer #4: No

Reviewer #5: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: No

Reviewer #5: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: No

Reviewer #5: Yes

**********

5. 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

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: This manuscript presents a prospective, single-arm phase II trial investigating fertility-sparing treatment with neoadjuvant chemotherapy (NAC) followed by conization and laparoscopic pelvic lymphadenectomy for women with FIGO stage IB2–IB3 cervical cancer. The focus on oncologic safety alongside reproductive outcomes is clinically meaningful, and the detailed description of endpoints is commendable.

Nevertheless, several concerns should be addressed to strengthen the manuscript:

1. Relation to recent GOG studies: Two recent GOG trials (Gynecol Oncol. 2025;195:50-58, 59-65) investigated fertility-sparing strategies using conization and laparoscopic lymphadenectomy. These important studies are not cited, and their omission limits the contextualization of the current work. The authors should clearly compare their design with the GOG protocols, highlighting similarities and differences.

2. Dual experimental approach: The trial combines two experimental elements: (i) NAC as induction therapy and (ii) fertility-sparing surgery (conization plus lymphadenectomy). While each strategy has some supporting evidence, their concurrent use introduces complexity and potential risk. It will be important for the authors to acknowledge this “double experimental arm” and to discuss whether observed outcomes can be attributed to NAC, the surgical approach, or their combination. A clear rationale and safety considerations for using both interventions simultaneously should be explicitly stated.

3. Endpoints and limitations: The primary endpoint of successful uterine preservation is clinically relevant, but its adequacy must be interpreted in the context of long-term oncologic outcomes. The relatively short follow-up period (2-year RFS) and the single-center nature of the trial are significant limitations that need to be clearly recognized.

4. Novelty and contribution: The incorporation of dose-dense paclitaxel/carboplatin NAC before fertility-sparing surgery could represent a unique contribution compared with prior trials, but the authors should emphasize this distinction more strongly.

5. Clinical implications: The discussion should elaborate on how this trial may inform future multicenter investigations or guideline development, particularly if preliminary safety and feasibility are confirmed.

In summary, this is a timely and clinically relevant protocol. However, the manuscript should integrate recent GOG findings, acknowledge the dual experimental nature of the intervention, and clarify the trial’s novelty, limitations, and future implications.

Reviewer #2: This clinical protocol describes a Phase II clinical trial (n=10) to evaluate a fertility-preserving treatment for women aged ≤40 years with FIGO stage IB2–IB3 cervical cancer. The primary objective is uterine preservation, with secondary outcomes including recurrence-free survival, overall survival, reproductive outcomes, and quality of life. The study investigates whether neoadjuvant dose-dense chemotherapy can downstage tumors larger than 2 cm, enabling safe conservative surgery in patients who would otherwise require radical treatment.

Minor Revisions Suggested:

1. Include a more detailed statistical analysis plan, addressing missing data handling, confounding variables, and sensitivity analyses.

2. Provide justification for the sample size, even if based on feasibility rather than formal hypothesis testing.

3. Add line numbering to the manuscript to facilitate peer review.

Limitations and Areas for Improvement:

1. Small Sample Size: The planned enrollment of 10 patients is suitable for a pilot feasibility study but limits statistical power and generalizability. No formal power calculation is provided to justify this sample size. Additionally, the small sample size is insufficient to reliably estimate outcomes related to the secondary objectives.

2. Lack of Control Group: As a single-arm study, the absence of a comparator group restricts the ability to assess relative efficacy or draw causal conclusions.

3. Handling of Missing Data: The protocol does not specify strategies for managing missing data, which is particularly important for longitudinal outcomes such as quality of life and reproductive metrics.

4. No Adjustment for Confounders: There is no mention of multivariate analysis or adjustment for potential confounding factors (e.g., tumor histology, age, baseline fertility status), which may affect outcome interpretation.

5. Limited Statistical Detail: The statistical analysis section lacks detail regarding the software to be used, assumptions underlying Kaplan–Meier analysis, and plans for subgroup or exploratory analyses.

Reviewer #3: This study addresses an important clinical challenge—balancing oncologic control and fertility preservation in younger women with cervical cancer. However, its single-arm, single-center design with a very small sample size significantly limits the strength of conclusions that can be drawn. The lack of a control arm prevents comparative effectiveness assessment. The stringent inclusion criteria and complex intervention pathway may also limit applicability.

The lack of routine pre-treatment sentinel lymph node biopsy is a major limitation of the current study protocol. It compromises accurate baseline staging, risks undertreatment, and may lead to unnecessary procedures with associated morbidity and psychological distress. Incorporating SLNB before initiating chemotherapy and surgery would enhance patient selection, improve oncologic safety, and optimize fertility preservation outcomes. Addressing this gap is essential for ensuring the study’s clinical relevance and ethical soundness.

To enhance robustness, the study could benefit from:

- Include laparoscopic pelvic Sentinel-Node Biopsy (with Ultrastaging) as a pre-treatment criteria

- Study Inclusion Criteria: pN0 (macro and micrometastasis)

- Including a matched control group or historical controls for comparison.

- Expanding sample size and considering multicenter involvement.

- More direct fertility-related endpoints (pregnancy/live birth rates).

- Clearer criteria for intervention discontinuation and handling non-responders.

- More detailed patient support to manage psychological impact.

Despite these limitations, as an early Phase II feasibility study, it is a reasonable first step toward defining fertility-preserving strategies in cervical cancer, provided its findings are interpreted cautiously.

Reviewer #4: Dear authors, I congratulate you on your idea, but it needs to be better contextualised in order to start the study protocol.

The main problem is related to tumour staging.

1- You need to clarify how you determine lymph node negativity (with PET? With lymphadenectomy? At what times and in what manner?)

2- You must specify how you will determine tumour size (double blind MRI review?).

3- You must specify whether you will exclude patients who have undergone conisation as a diagnostic procedure.

4- You must specify how you will deal with negative prognostic histological factors (invasion of lymphovascular spaces, deep stromal infiltration, g3, etc.).

5- The sample size presented is insufficient. Please set yourself an outcome to observe and build a sample size based on your objectives.

5- The conceptual part is outdated and should be updated with the latest knowledge on the subject (PMID: 37261562; PMID: 36064991).

Only after these necessary corrections have been made can the study be considered for publication.

Reviewer #5: Dear Author,

I have reviewed your article entitled: “Fertility-sparing surgery with neoadjuvant chemotherapy in early and locally advanced cervical cancer: A clinical protocol”. This manuscript describes a well-structured Phase II, single-arm, single-center clinical protocol investigating the feasibility and oncologic safety of fertility-sparing surgery following neoadjuvant dose-dense paclitaxel and carboplatin (dd-TC) in patients with FIGO 2018 stage IB2–IB3 cervical cancer. The topic is clinically relevant and of potential high impact, as fertility preservation in cervical cancer remains an unmet need for women with tumors larger than 2 cm.

I have some consideration:

• Do you perform PET-CT or CT scans for all patients? Could you clarify it?

• Extending or clarifying the reproductive follow-up period would improve the study’s relevance

• Minor grammatical consistency is recommended.

• I suggest to add some references like these: PMID: 39531915; PMID: 38471373

**********

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

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Reviewer #1: Yes:  Tsukasa Baba

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes:  Carlo Ronsini

Reviewer #5: No

**********

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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

Dear Dr. Nagao,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jan 26 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Kazunori Nagasaka

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Dear Prof. Nagao,

The manuscript has improved, but several issues require revision.

As mentioned by Reviewer 1, the description of SLNB availability in Japan is outdated; RI-based SLN mapping has been reimbursed since 2023, and ICG-guided SLNB will be covered in 2025.

This should be corrected and discussed in relation to the choice of full lymphadenectomy. Redundancy between sections remains, and the Discussion should focus more clearly on risks and decision criteria when combining NAC with fertility-sparing surgery. The limitations should also note the lack of pathological nodal staging before NAC.

We look forward to receiving your revised manuscript soon.

Sincerely,

Kazunori Nagasaka

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #5: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: The authors have made substantial improvements in their revised manuscript. The integration of recent GOG trial data, clarification of methodological details, and enhanced justification for fertility-sparing treatment in bulky IB2–IB3 disease are appreciated. However, several important issues remain before the manuscript is suitable for publication.

1. Sentinel Lymph Node Biopsy (SLNB): inaccurate and outdated statements

The revised manuscript states that sentinel lymph node biopsy is not widely available or insured in Japan.

This is no longer accurate. Current status in Japan (important for this protocol)

Since 2023, SLN mapping using radioisotope tracers (RI) has been covered by national insurance.

From summer 2025, indocyanine green (ICG)-guided SLN mapping will also be reimbursed, allowing SLN detection without radiation exposure.

As a result, SLNB using ICG fluorescence is expected to become widely feasible, especially in young and fertility-oriented patients.

Given these developments, the authors’ statements underestimate the current and near-future accessibility of SLNB in Japan.

Required revisions

Correct the description of insurance status for SLNB (RI and ICG).

Update the Discussion to reflect how the availability of radiation-free ICG mapping may influence future iterations of the protocol.

Comment briefly on why full pelvic lymphadenectomy was selected despite these recent changes, and how SLNB + ultrastaging could reduce morbidity in fertility-sparing candidates.

This correction is essential for methodological accuracy and for aligning the protocol with evolving clinical practice.

2. Redundancy between Introduction and Discussion

Several sections still repeat the same information:

(a) Tumors ≤2 cm and evidence from SHAPE / ConCerv / GOG-278

These data are described extensively in both Introduction and Discussion. In the Discussion, they should appear only to support interpretation of the protocol’s design—not as repeated background.

(b) Rationale for dd-TC chemotherapy

Response rates and pCR values appear in both sections almost unchanged.

Recommendation

Streamline the Discussion by removing repeated background and focusing on how these external results inform safety expectations and feasibility for IB2–IB3 tumors.

3. Dual Experimental Approach: more explicit interpretation needed

The authors now acknowledge that the protocol combines two investigational elements:

(1) NAC for tumor downstaging, and

(2) fertility-sparing surgery.

However, the Discussion still leans heavily on general evidence supporting each modality rather than explaining:

Which specific risks remain unknown when both interventions are combined

How response criteria, conization pathology, and radiologic reassessment mitigate those risks

What constitutes a safety threshold to abandon fertility preservation and proceed to standard treatment

Explicitly stating these points will improve transparency and strengthen the scientific rationale.

4. Limitations section: incomplete

Although sample size, single-center design, and short follow-up are discussed, one limitation requires clearer acknowledgment:

Lack of pathological nodal staging prior to NAC may create staging uncertainty, because chemotherapy can suppress but not eradicate nodal metastases.

Given the increasing availability of SLNB (RI and ICG), the omission should be explicitly recognized as a limitation.

5. Length and focus of the Discussion

The Discussion remains relatively long and contains extensive summaries of prior trials.

A more effective structure would emphasize:

What new insights the feasibility study aims to generate

How the design specifically addresses the safety of fertility preservation in bulky IB2–IB3 tumors

How the results could inform future multicenter studies or guideline development

Reducing narrative background and highlighting the protocol’s unique contribution will enhance readability.

6. Strengths of the revision

Several improvements should be acknowledged:

Clearer surgical criteria and pathological evaluation

Strengthened description of adverse event monitoring

Integration of recent GOG trial literature

Better explanation of the intended contribution to fertility-sparing oncologic management

These revisions have significantly improved the manuscript.

Overall Recommendation

The manuscript has improved, but additional revision is still required.

In particular:

Update the description of SLNB insurance coverage in Japan, including the 2025 adoption of ICG fluorescence mapping, which eliminates radiation exposure.

Reduce redundancy between sections.

Clarify limitations and sharpen the rationale for the dual experimental design.

Addressing these points will greatly enhance the accuracy, clarity, and scientific rigor of the protocol.

Reviewer #2: All comments have been adequately addressed.

Reviewer #3: The questions were responded and the improvements were done.

Aim is clear

Study design description is accurate

Eligibility criteria clear

ddTC regimen description acceptable

Primary and Secondary endpoints are appropriate

AE reporting (CTCAE v5.0) is standard

Reviewer #5: I would like to thank the authors for answering the various issues. They have response to all of issue.

**********

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 #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #5: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

Dear Dr. Nagao,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Feb 01 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Kazunori Nagasaka

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Dear Dr.Nagao,

Thank you for submititng your manuscript to Plos One.

A reviewer has commented to your revised manuscript.

Please revise the content accordingly, and we look forward to receiving your manuscript soon.

Sincerely,

Kazunori Nagasaka

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: The authors have carefully and thoroughly revised the manuscript in response to the previous reviewer comments. The revised version shows clear improvement in structure, clarity, and methodological transparency. In particular, the updated description of sentinel lymph node biopsy in the Japanese clinical context, the streamlined Discussion, and the explicit definition of safety criteria and interim analysis substantially strengthen the protocol.

Overall, this is a well-designed and clearly presented Phase II feasibility study addressing an important and clinically relevant unmet need in young women with cervical cancer who desire fertility preservation. The manuscript is suitable for publication after minor revisions aimed at further clarification rather than substantive modification.

1. Interpretation of the primary endpoint

The use of uterine preservation as the primary endpoint is appropriate for a feasibility study. However, a brief clarification of how this endpoint should be interpreted alongside oncologic outcomes (e.g., short-term RFS) would improve clinical interpretability.

Suggested action: Add one or two sentences in the Discussion clarifying that uterine preservation is evaluated in conjunction with oncologic safety endpoints, rather than as an isolated success measure.

2. Imaging-based assessment after neoadjuvant chemotherapy

The manuscript appropriately explains the rationale for relying on post-NAC imaging and subsequent pelvic lymphadenectomy. For balance, it would be helpful to briefly acknowledge the inherent limitations of imaging-based response assessment, including the possibility of occult residual disease.

Suggested action: Add a short statement in the Discussion noting this limitation.

3. Sample size justification

The feasibility nature of this study and the small sample size are acceptable. A short explanation of the practical or ethical considerations that informed the choice of a target sample size of 10 patients would enhance transparency.

Suggested action: Provide a brief clarification in the Sample Size or Discussion section.

4. Ethical transparency

Given the dual experimental nature of the proposed strategy, the ethical framework is generally well described. A brief statement emphasizing that patients are explicitly informed of the non-standard and exploratory aspects of this approach would further strengthen the protocol.

Suggested action: Add a single sentence to the Ethical Considerations section.

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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: Yes:  Tsukasa Baba

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Fertility-sparing surgery with neoadjuvant chemotherapy in early and locally advanced cervical cancer: A clinical protocol

PONE-D-25-48071R3

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,

Kazunori Nagasaka

Academic Editor

PLOS One

Additional Editor Comments (optional):

Dear Prof. Nagao,

Congratulations.

I am pleased to inform you that your manuscript has been accepted for publication in PLOS ONE.

The revisions have clearly strengthened the clarity, methodological transparency, and ethical rigor of the study.

I wish you continued success in your important research endeavors.

Warmest congratulations to you and your team.

Sincerely,

PLOS ONE

Kazunori Nagasaka

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: The authors have responded to all reviewer comments in a thorough, thoughtful, and transparent manner. Each point has been appropriately addressed with concise revisions that improve the clarity, interpretability, and ethical transparency of the manuscript without altering its feasibility-focused intent.

Specifically, the added clarification regarding the interpretation of uterine preservation in conjunction with oncologic safety endpoints strengthens the clinical relevance of the primary endpoint. The acknowledgment of the limitations of imaging-based assessment after neoadjuvant chemotherapy provides appropriate balance, and the revised explanation of the sample size justification enhances methodological transparency. In addition, the explicit statement regarding informed consent and the exploratory nature of the strategy further reinforces the ethical rigor of the study.

Overall, these revisions meaningfully improve the manuscript. I have no further substantive comments and recommend acceptance of the manuscript in its current form.

Reviewer #2: All comments have been adequately addressed.

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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 #1: Yes:  Tsukasa Baba

Reviewer #2: No

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