The Role of Dosimetric Parameters in Radiation Pneumonitis: A Functional Approach in Adjuvant Treatment of Malignant Pleural Mesothelioma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The current study evaluates the predictive value of conventional and functional dosimetric parameters for radiation pneumonitis risk in patient receiving adjuvant radiotherapy in malignant pleural mesothelioma. The current study is evaluating an interesting aspect to add to currently used methods in evaluating radiotherapy plan.

Overall, the study is well structured with proper presentation of aim of study, methods, and results.

Minor suggestions:

In the abstract: the term FCL was introduced in the abstract, but it was not explained prior to its appearance. This need to be explained in the abstract body to avoid confusion.

Introduction section: well-organized but would expect to state a clear hypothesis of the study opposite to how it is mentioned in the document. The purpose of the study explains comparing between to parameters but not clearing stating what is the null/alternative hypothesis.

Method section: Well-organized and stating properly the inclusion criteria, radiotherapy protocol, delineation of functional lung volume and proper statistical method. Again, here the term (FCL) was mentioned as abbreviation which was identify what does it represents but it is named fully prior to the abbreviation --- this need to be modified.

Results: well-organized but no mention of volume of the structure contoured in term of conventional and functional lung. Also, it seems these patients could have underlying lung conditions, but it was never mentioned if patients have any conditions and if they are receiving any treatment during radiation for these conditions. It would be beneficial to know such information

Author Response

We​‍​‌‍​‍‌ thank the Reviewer for the valuable comments, which have greatly facilitated the improvement of the manuscript's clarity and completeness. Here are our point-by-point replies:

• Abstract – FCL abbreviation: We entirely agree with the Reviewer. We have changed the term FCL_V20, and its full definition ("functional contralateral lung volume receiving ≥20 Gy") has been provided before the abbreviation is used in the abstract.
• Introduction – Hypothesis statement: We have made the hypothesis of the study clearer to the reader by putting it at the end of the Introduction section. The hypothesis now clearly implies that functional dosimetric parameters might have greater predictive value for radiation pneumonitis than anatomical ones.
• Methods – Abbreviation definition: The abbreviation “FCL” was incorrectly used twice without a full explanation. Correction has been made throughout the Methods section, making sure that the term is fully written before the abbreviation is used.
• Results – Lung volumes and comorbidities: We have described the volumes of the conventional and functional lungs that were contoured, including median values, in the Results section.
• Also, respiratory comorbidities (e.g., COPD, emphysema) were recorded and are now clearly mentioned in the Results. Pulmonary comorbidities were detected in 10 patients (13.2%) in total. Since the study was retrospective, the data on the medical treatments given during radiotherapy were not always available.

The changed manuscript with all changes is ​‍​‌‍​‍‌enclosed.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors in the present article have discussed the predictive value of conventional and functional dosimetric parameters in assessing RP risk in MPM patients, which was attempted to be evaluated.

Points of concern are that need to be addressed.

1. Can the authors provide information on the clinical stage for the patients and the smoking status if recorded? Is there any correlation between the parameters and RP?
2. Can the authors please explain how this study is novel and provide more information that the already published article “Dosimetric Correlates of Pulmonary Toxicity in Patients with Malignant Pleural Mesothelioma Receiving Radiation Therapy to the Intact Lungs” and others already referred to in the article?
3. Please highlight the work's translational importance.
4. Check for language and grammatical errors.

Comments on the Quality of English Language

Check for grammatical errors.

Author Response

We​‍​‌‍​‍‌ are grateful to the Reviewer for the helpful comments that have allowed us to improve the manuscript. Our detailed written responses to each of your comments can be found below. In line with this, a rewritten version of the manuscript has been sent to the journal.
Clinical stage and smoking status: Data on the clinical stage were gathered and can now be seen in the revised Results section. According to the IMIG classification, the majority of patients were stage III.
Unfortunately, smoking status was not always recorded in the retrospective records and therefore, it has not been included. However, we have now made this point clearer in the Methods.
A logistic regression analysis examining the relationship between the main dosimetric parameters and radiation pneumonitis (RP) is part of the updated Results.
Novelty of the study: We have explained in the Discussion how our study contributes to the knowledge base. Unlike previous studies (e.g., Rosenzweig et al.), this paper is about a uniform group of MPM patients treated with IMRT after pleurectomy/decortication (P/D), and it directly compares conventional and functional dosimetric parameters (FCL_V20), presenting ROC-based thresholds for prediction of RP. These features demonstrate the paper’s originality.
The​‍​‌‍​‍‌ paragraph on the translational implications has been extracted from the Discussion as a separate paragraph and it clarifies that lung dose functional maps can be used to determine the treatment of patients with pre-existing lung conditions thus the care can be more individualized and safer.
Language and grammar:
The paper has been language and clarity-wise very carefully checked and a few minor stylistic changes have been made to help the reader go smoothly through the ​‍​‌‍​‍‌text.