Long-Term Outcome of Intraoperative Radiotherapy for Early-Stage Breast Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

From a biostats and clinical epidemiology point of view, here are some comments for the Authors

• in general, this is a very well written manuscript, congrats to all of you!
• line 32, I totally agree with the Authors: ASTRO 2024 is the proper guideline for IORT treatments
• line 39, median follow-up of 7.1 years is very adequate and allows to make a serious forecasting
• you have fixed a 6-mos minimum follow-up to be included in the study cohort, why the last accrual comes from 2018?
• line 52, I suggest to include the updated epidemiological estimates coming from the GBD 2023 Study too, if possible; anyway, report age-std rates, more than all-ages ones
• continuous covariates have to be reported only as median/IQR, rather than range
• Firth-penalized Cox regression, have you decided to apply this model, due to the scarse number of events? Any other reasons? By which R package?
• KM curves quality is very very poor (one inside the other?), I warmly suggest to redo all of them, for a better clarity; moreover, there's no caption
• a dedicated table, showing the full results for all the univariate and multivariate survival models (LRFS, OS, MFS, is mandatory and needs to be added

Author Response

We sincerely thank the Academic Editor and the reviewers for their encouraging evaluation of our work and for their insightful comments, which have helped us further improve the manuscript.

From a biostats and clinical epidemiology point of view, here are some comments for the Authors

• in general, this is a very well written manuscript, congrats to all of you!
• line 32, I totally agree with the Authors: ASTRO 2024 is the proper guideline for IORT treatments
• line 39, median follow-up of 7.1 years is very adequate and allows to make a serious forecasting
• you have fixed a 6-mos minimum follow-up to be included in the study cohort, why the last accrual comes from 2018?

We thank the reviewer for raising this point.

Although the minimum follow-up for inclusion was set at 6 months, the study cohort itself was defined at the time of the initial data extraction and was not expanded thereafter.

Following this predefined cohort selection, additional time elapsed before final manuscript preparation, which provided a valuable opportunity to update and extend follow-up information for the originally included patients. Importantly, no new patients were added beyond the initial accrual period.

Although additional patients were treated with intraoperative radiation therapy after the accrual period, they were not included in the present analysis in order to preserve a fixed and internally consistent cohort.

This approach ensured internal consistency of the cohort and avoided post-hoc expansion, while allowing for a substantially longer and more mature follow-up. In this context, preserving cohort integrity was prioritized over maximal sample size.

As a result, the analysis reflects long-term outcomes in a stable population, which is particularly relevant for evaluating local control and late toxicity after intraoperative radiation therapy.

• line 52, I suggest to include the updated epidemiological estimates coming from the GBD 2023 Study too, if possible; anyway, report age-std rates, more than all-ages ones

As suggested, we included updated epidemiological estimates from the Global Burden of Disease 2023 Study in the Introduction and revised the text to emphasize age-standardized incidence rates.

• continuous covariates have to be reported only as median/IQR, rather than range

Thank you. We have revised the manuscript accordingly: continuous covariates are now reported as median (IQR) only (e.g., age and tumor size), and ranges have been removed for these variables.

For follow-up, we retained reporting as median (95% CI) estimated using the reverse Kaplan–Meier method, consistent with the Methods section. We also retained ranges for time-to-event outcomes (e.g., time to local recurrence) because they provide clinically interpretable context for the observed event timing. We hope this approach is acceptable.

• Firth-penalized Cox regression, have you decided to apply this model, due to the scarse number of events? Any other reasons? By which R package?

Yes, Firth-penalized Cox regression was used due to the limited number of recurrence events (low events-per-variable), to reduce small-sample bias and improve estimate stability. Models were fitted in R using the coxphf package (coxphf function).

• KM curves quality is very very poor (one inside the other?), I warmly suggest to redo all of them, for a better clarity; moreover, there's no caption

We thank the reviewer for this comment. All Kaplan–Meier curves have been redrawn to improve visual clarity, including removal of inset plots, adjusted y-axis scaling, and enhanced line differentiation. Detailed figure captions have been added.

• a dedicated table, showing the full results for all the univariate and multivariate survival models (LRFS, OS, MFS, is mandatory and needs to be added

We have added a dedicated table summarizing the complete results of the univariate and multivariable Cox proportional hazards models for LRFS, including hazard ratios with 95% confidence intervals and p-values for each covariate. For OS and MFS, only Kaplan–Meier analyses were performed; no univariate or multivariable Cox models were fitted.

We have added a previously missing p-value for involved surgical margins to the Results section (highlighted in the revised manuscript).

Reviewer 2 Report

Comments and Suggestions for Authors

This study evaluated retrospective review of IORT-treated patients to evaluate low-risk patients in response to ASTRO recommendations in 2023 recommending use of IORT in clinical trials.

N=358 does not change data from RCT on the subject.

Author Response

We sincerely thank the Academic Editor and the reviewers for their encouraging evaluation of our work and for their insightful comments, which have helped us further improve the manuscript.

Comments and Suggestions for Authors

This study evaluated retrospective review of IORT-treated patients to evaluate low-risk patients in response to ASTRO recommendations in 2023 recommending use of IORT in clinical trials.

N=358 does not change data from RCT on the subject.

We thank the reviewer for this important comment. We fully agree that our retrospective single-center cohort cannot replace randomized controlled trial evidence and is not intended to change conclusions derived from RCTs. We have revised the Discussion to clarify that the aim of this study is to provide real-world long-term outcomes in a contemporary IORT cohort and to evaluate how recurrence patterns align with risk stratification using ASTRO 2024 criteria, rather than to establish comparative efficacy versus whole-breast irradiation. We also emphasize the limitations inherent to a retrospective design (selection bias, lack of a control arm, and limited event counts) and frame our findings as hypothesis-generating and supportive of ongoing prospective evaluation.

Reviewer 3 Report

Comments and Suggestions for Authors

In the following manuscript entitled "Long-term outcome of intraoperative radiotherapy for early-stage breast cancer", the authors conducted a retrospective cohort study of intraoperative radiotherapy (IORT)-treated patients at their institution and made a comparison between whole-breast irradiation (WBI), and total mastectomy. They assessed local recurrence (LR), and prognosis using the 2024 American Society for Radiation Oncology (ASTRO) risk classification.

The article is well written, the research designed appropriately, and the methods adequately, and clearly described. I thus recommend publication in Cancers, at MDPI, after the following minor revisions have been applied:

The conclusion does not adequately reflect the article. It is too brief and needs to be further developed.

Use the good template for references. See at https://www.mdpi.com/authors/references

Author Response

We sincerely thank the Academic Editor and the reviewers for their encouraging evaluation of our work and for their insightful comments, which have helped us further improve the manuscript.

Comments and Suggestions for Authors

In the following manuscript entitled "Long-term outcome of intraoperative radiotherapy for early-stage breast cancer", the authors conducted a retrospective cohort study of intraoperative radiotherapy (IORT)-treated patients at their institution and made a comparison between whole-breast irradiation (WBI), and total mastectomy. They assessed local recurrence (LR), and prognosis using the 2024 American Society for Radiation Oncology (ASTRO) risk classification.

The article is well written, the research designed appropriately, and the methods adequately, and clearly described. I thus recommend publication in Cancers, at MDPI, after the following minor revisions have been applied:

The conclusion does not adequately reflect the article. It is too brief and needs to be further developed.

Thank you for this helpful suggestion. We agree that the original Conclusion was too brief. We have expanded the Conclusion to better reflect the scope and key messages of the study by (a) summarizing the long-term oncologic outcomes observed after IORT in our cohort, (b) integrating the findings on local recurrence and prognosis, (c) explicitly incorporating the interpretation and practical implications of the 2024 ASTRO risk classification for patient selection and outcome stratification, and (d) briefly acknowledging the main limitations inherent to a retrospective design and the need for further validation

Use the good template for references. See at https://www.mdpi.com/authors/references

Thank you. The reference list has been reformatted according to the MDPI reference style required by Cancers.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The Authors were able to fully solve the previous concerns, congrats!

My only remaining and minimal suggestion is to report table 2, using left columns for uv models, and right columns for the mv one

Author Response

 Thank you. We have revised Table 2 to improve readability by presenting univariable models results in the left columns and the multivariable model results in the right columns.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors The changes don't change the study design. I don't have comments for the authors that are different than my original review.  

Author Response

Thank you for the follow-up. We believe our revised Discussion is fully aligned with your original point: the manuscript does not challenge existing recommendations or suggest replacing randomized evidence. Rather, it reports long-term outcomes from a representative real-world IORT cohort in which this approach may be clinically relevant, and the results both (i) support adherence to current guideline-based patient selection (ASTRO 2024) and (ii) provide additional real-world evidence in areas where the guideline itself acknowledges limited randomized data. In this context, our findings are intended to complement - not substitute - randomized evidence, and to help motivate and inform future prospective studies and RCTs. As intended from the outset, the study was designed as a retrospective cohort and conducted and reported according to standards commonly used in peer-reviewed retrospective IORT series, including studies cited in our manuscript.