Accelerated Hypofractionated Magnetic Resonance Guided Adaptive Radiation Therapy for Ultracentral Lung Tumors

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The idea of the work is very good, but in my opinion, unfortunately, the work is statistically problematic and it is necessary to re-conduct and summarize the research with a larger number of patients (over 50 people Including women, men and children).

Author Response

Manuscript ID: Tomography-2674764

 

" Accelerated Hypofractionated Magnetic Resonance Guided Adaptive Radiation Therapy for Ultracentral Lung Tumors "

 

Response to Comments

We greatly appreciate the thoughtful feedback from the editors and reviewers during the peer review process, and we have carefully addressed each of the points raised in the following point-by-point responses. We believe that the comments from the reviewers and our corresponding revisions have significantly improved the quality of the manuscript.

 

As a result of these revisions, and to address the comments from the reviewers for additional sections to add, we found it essential to augment the number of references in our submission. It is our hope that it is now acceptable for publication in its revised form.

 

 

 

 

 

 

 

 

 

Reviewer #1

 

 

Comment #1

The idea of the work is very good, but in my opinion, unfortunately, the work is statistically problematic, and it is necessary to re-conduct and summarize the research with a larger number of patients (over 50 people Including women, men and children).

 

Answer: Thank you for your thoughtful review of our manuscript. We appreciate your positive acknowledgment of the work's underlying idea. We would like to address your concern regarding the limited number of patients included in the study.

Despite the relatively small sample size of 13 patients, it's essential to note that our analysis encompass a comprehensive examination of 195 individually delivered fractions. This approach allowed us to gain a nuanced and detailed understanding of the need for adaptation in our proposed intervention (Page 9; lines 302-305). By thoroughly analyzing each fraction, we were able to discern patterns and potential complications, particularly in the context of broncho-vascular fistula.

While we acknowledge the value of larger sample sizes for statistical robustness, the focus on individual fractions provided us with substantial data points for a thorough investigation. The findings presented in the manuscript aim to shed light on the critical aspects of adaptation and its potential impact on mitigating complications. We believe that the detailed analysis of the delivered fractions adds depth to our work and contributes significantly to the field.

Reviewer 2 Report

Comments and Suggestions for Authors

The overall effort is commendable, but several areas require attention to enhance the paper's clarity, comparability, and overall impact.

I have the following concerns : 

Institutional Definitions:

It would be beneficial for the authors to expound on the rationale behind the chosen institutional definition. Discussing potential variations and limitations in definitions will contribute to a more nuanced understanding.

Pictorial Evidence:

Enhancing the image size and quality will significantly improve the manuscript's visual impact and aid the target audience.

 Comparator Table:

Instead of an exhaustive table listing every study, I would suggest a concise comparator table. This should focus on relevant data such as comparing mean distances or some objective measure of organs at risk, total dosing, and mean dose per schedule of your patient population versus other relevant studies, which will facilitate a better understanding of why your methodology merits further investigation.

Discussion/Conclusion Section:

The discussion section requires further development to articulate why the chosen protocol and methodology in this study offer advantages over existing data. I am not certain that the trials you cite are directly comparable to your patient population. 

 

Consideration of Contributory Factors:

The inclusion of a section addressing contributory factors would be useful. For example, comparative age, anticoagulation use, pre-existing esophageal/vascular or other relevant conditions when discussing complications and toxicities is a must, when you state that your  level of treatment toxicity is lower. 

 

Comprehensiveness of Explanation:

Ultimately, a more comprehensive explanation is needed to elucidate why the chosen protocol and procedure merit further investigation. I would suggest that you clearly articulate the advantage and innovation of your protocol and the potential clinical implications thereof. 

Best regards

 

Author Response

The overall effort is commendable, but several areas require attention to enhance the paper's clarity, comparability, and overall impact.

We appreciate the positive comments on our submission.

Comment #1: Institutional Definitions. It would be beneficial for the authors to expound on the rationale behind the chosen institutional definition. Discussing potential variations and limitations in definitions will contribute to a more nuanced understanding.

Answer: We appreciate this comment from the reviewer and in the revised version, have provided additional clarification for accuracy and clarity.

 

Page 2, lines 85-89 “The rationale for this ultracentral definition stems from the proximity to critical structures and potential impact on treatment planning and outcomes. It's important to acknowledge potential variations and limitations in definitions, which will be further discussed.”

 

 

Comment #2: Pictorial Evidence. Enhancing the image size and quality will significantly improve the manuscript's visual impact and aid the target audience.

 

Answer: We appreciate this comment from the reviewer and in the revised version, to enhance clarity for readers, we have increased the image size and quality (please see below).

 

Figure 1, page 4:

 

 

Comment #3: Comparator Table. Instead of an exhaustive table listing every study, I would suggest a concise comparator table. This should focus on relevant data such as comparing mean distances or some objective measure of organs at risk, total dosing, and mean dose per schedule of your patient population versus other relevant studies, which will facilitate a better understanding of why your methodology merits further investigation.

 

Answer: Thank you for your thoughtful suggestion regarding the comparator table/figure. We've taken your feedback into consideration and have incorporated a figure that compares treatment-related toxicities across various studies. We believe this visual representation provides a comprehensive overview. Additionally, recognizing the value of detailed information for reference, we have included an extensive table as supplementary material (Supplementary Table 1). This supplementary table aims to offer a more in-depth exploration of the relevant data, including mean distances, objective measures of organs-at-risk, total dosing, and mean dose per fractionation schedule. We hope that these additions enhance the clarity and comprehensiveness of our methodology section. Your input has been invaluable, and we appreciate your thorough review.

 

Page 7; Figure 3:

“Figure 3. Treatment-related toxicities associated to hypofractionated schedules from this study and other case series, showing the median total dose and median number of fractions for each study. *Current study. fract=fractions. Gy=Gray”

 

 

 

Comment #4. Discussion/Conclusion Section. The discussion section requires further development to articulate why the chosen protocol and methodology in this study offer advantages over existing data. I am not certain that the trials you cite are directly comparable to your patient population. 

 

Answer: We agree with this comment. To elaborate on the advantages of our chosen protocol and methodology, we have address in the revised manuscript as follows:

 

Page 7, lines 197-206: “SBRT has established itself as a safe and effective treatment for peripheral lung tumors, showing minimal grade 4 and higher toxicities.  [11] However, when extending the application to central tumors within the "no-fly zone" defined by the Radiation Therapy Oncology Group (RTOG), particularly with aggressively hypofractionated schedules, the landscape changes, leading to unacceptably high rates of high-grade toxicity.[12] Even less aggressively hypofractionated schedules have demonstrated modestly high rates of toxicities, especially concerning centrally-located OARs. The HILUS trial further underscores the challenges, reporting a high risk of treatment-related death, particularly hemoptysis, reaching 15% for tumors situated 1 cm from the proximal bronchial tree (PBT) when treated with a hypofractionated schedule of 56 Gy in 8 fractions (7 Gy per fraction).”

 

Page 7, lines 213-216: “Notably, two prior retrospective series detailed their experience with a more conservative hypofractionation schedule, administering a total of 60 Gy in 12 fractions (5 Gy per fraction), utilizing daily cone-beam computerized tomography (CBCT) for online setup and position verification.”

 

Page 7, lines 225-231: “In our series, we adopted a more prolonged hypofractionation schedule, delivering 60 Gy in 15 fractions, a departure from the more aggressive regimens in prior studies. Crucially, our treatment methodology involved mid-inspiration breath hold, ensuring alignment between planning constraints and the delivered dose to central OARs. This approach stands in contrast to radiotherapy delivery methods that aim to reduce respiratory excursion, potentially leading to a dose cloud surpassing OAR constraints during treatment”

 

Page 8, lines 247-249: “The implementation of daily on-table MRgART imaging and recontouring uncovered noteworthy variations in PBT, trachea, and esophagus doses, surpassing the original planning directives in 57.4%, 14.4%, and 55.4%, respectively, of the total daily fractions.”

 

Comment #5: Consideration of Contributory Factors.­ The inclusion of a section addressing contributory factors would be useful. For example, comparative age, anticoagulation use, pre-existing esophageal/vascular or other relevant conditions when discussing complications and toxicities is a must, when you state that your level of treatment toxicity is lower. 

Answer: We agree with this comment and has been addressed in the reviewed version of the manuscript. In fact, in comparison to other series, we had elderly patients, a large majority who were current or former smokers, a small percentage who had already had prior radiotherapy to the chest, and approximately 40% on anti-platelets or anti-coagulants. This has been added to the manuscript.

 

Page 8, lines 237-246: “Moreover, in the context of discussing contributory factors to treatment complications, this cohort was a relatively old population (median age of 70 years), with a large treatment volume for radiation (up to 211.81 cc), with a significant portion being smokers or ex-smokers (77%). Our study population reflects a demographic profile commonly associated with increased vulnerability to side effects. Additionally, a subset of patients with a history of prior RT to the thoracic region (15.4%), pre-existing lung diseases (15.4%), and a substantial proportion on antiplatelets or anticoagulants (38.5%) introduces further complexity to our analysis. These risk factors, collectively considered, underscore the importance of a nuanced interpretation of treatment outcomes, as the interplay of these variables could potentially contribute to variations in observed toxicities.”

Page 5: We have added new columns for smoking status, antiplatelets/anticoagulant treatments and lung diseases (COPD, asthma or other) to Table 1.

 

 

Comment #6: Comprehensiveness of Explanation. Ultimately, a more comprehensive explanation is needed to elucidate why the chosen protocol and procedure merit further investigation. I would suggest that you clearly articulate the advantage and innovation of your protocol and the potential clinical implications thereof. 

 

Answer: We agree with this comment and has been addressed in the revised manuscript.

Pages 9-10, lines 310-320: “In our institutional study, the use of accelerated hypofractionated MRgART for ultracentral lung tumors has yielded highly promising outcomes. The application of a meticulously designed dose and fractionation schedule of 60 Gy in 15 fractions, coupled with daily online adaptation, demonstrated a remarkable absence of high-grade toxicities. This innovative approach not only ensured the safety of the treatment but also facilitated a more precise total dose calculation for OARs. The unique capability of MRgART to dynamically adapt to the anatomical shifts of internal structures and changes in target volumes throughout the treatment timeline played a crucial role. This adaptability not only improved target volume coverage but also effectively mitigated potential adverse effects on surrounding tissues, setting a new standard for the comprehensive and patient-centric management of ultracentral lung tumors.”

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

While thanking the authors, unfortunately, in my opinion, more samples should be considered and the test statistics on this number of patients are not enough. I hope the authors pay more attention to adding the statistics of patients and this suggestion is very necessary to increase the quality of the work and the accuracy of the results.

Author Response

We sincerely appreciate your constructive feedback on our manuscript titled "Accelerated Hypofractionated Magnetic Resonance Guided Adaptive Radiation Therapy for Ultracentral Lung Tumors" (Manuscript ID: Tomography-2674764). Your input is valuable, and we have carefully considered your concerns regarding the sample size and statistical robustness.

In response to your suggestion for including more patient samples and enhancing statistical analysis, we would like to underscore several key aspects that contribute to the uniqueness and significance of our work:

1. Comprehensive Evaluation: Our study meticulously analyzes all fractional data from 13 patients undergoing a 15-fraction of radiotherapy course for ultracentral primary tumors and involved regional lymph nodes. This dataset comprises 195 fractions, with 69.2% of patients concurrently receiving systemic therapy. Through daily recontouring of target volumes and organs-at-risk, our approach provides critical insights into fractionation variations resulting from set-up and motion uncertainties, as well as daily anatomical variations. Notably, we observed increases in doses exceeded treatment planning constraints in over half of the fractions for two key organs-at-risk: proximal bronchial tree and esophagus.

 

2. Comparative Analysis: To contextualize our findings, we highlight that only two MR-guided series for ultra-central lung tumors have been published to date (Regnery et al. [1] and Sandoval et al. [2]). Our series stands out due to the following reasons:
   44. Inclusion criteria: While existing studies include both central and ultracentral tumors (Regnery et al. 44.4%, and Sandoval et al. 80.9%), our focus is solely on ultracentral tumors (100%).
   45. Dose and Fractionation Schedules: We present a uniform 15-fraction course (total dose of 60 Gy) for all patients, contrasting with the varied schedules in existing studies (shown in below Table).
   46. Concomitant Systemic Therapy: Our study reports concurrent systemic therapy in a substantial proportion of patients, providing a unique perspective compared to prior works.
       1. Regnery et al. reported concurrent tyrosine kinase inhibitors (TKI) in only 1 patient.
       2. Sandoval et al. reported concurrent systemic therapy in a minority (4 out of 47 patients), including central and ultracentral cases, with concurrent immunotherapy (non-specified).
   47. Margin Differences: Variations in margins used across patients in existing studies are highlighted, emphasizing the standardized approach in our series.
       1. Regnery et al. Gross tumor volume (GTV) was expanded by 2 mm to obtain the clinical target volume (CTV), and by another 3 mm to obtain the planning target volume (PTV).
       2. Sandoval et al. The 3-mm isotropic expansion of the GTV to create the PTV.
   48. Adaptive Approach: Unlike prior studies, our methodology involves daily recontouring of both targets and organs-at-risk, ensuring a comprehensive adaptive process for all patients.
       1. Regnery et al.: “the treating team manually adapted the GTV contours and the OAR contours in a spherical region around the PTV (PTVexpand concept).” 91% of the total fractions delivered were adapted (including all, central and ultracentral tumors [36 patients])
       2. Sandoval et al. only 34% of the patients (central and ultracentral) underwent a daily treatment adaptation.

Considering these distinctions, our work represents the only MR-guided radiotherapy series for ultra-central lung tumors in which all patients were treated with a 15-fractions course, with daily adaptations for both targets and organs-at-risk. This makes it the largest consecutive series of its kind, warranting consideration for publication.

We hope the journal and editors recognize the unique nature of our study and consider it for publication.

Thank you for your time and thoughtful review.

 

 

 

References

1. Regnery, S.; Katsigiannopulos, E.; Hoegen, P.; Weykamp, F.; Sandrini, E.; Held, T.; Deng, M.; Eichkorn, T.; Buchele, C.; Rippke, C.; et al. To fly or not to fly: Stereotactic MR-guided adaptive radiotherapy effectively treats ultracentral lung tumors with favorable long-term outcomes. Lung Cancer 2023, 179, 107175, doi:10.1016/j.lungcan.2023.03.011.
2. Sandoval, M.L.; Sim, A.J.; Bryant, J.M.; Bhandari, M.; Wuthrick, E.J.; Perez, B.A.; Dilling, T.J.; Redler, G.; Andreozzi, J.; Nardella, L.; et al. Magnetic Resonance-Guided Stereotactic Body Radiation Therapy/Hypofractionated Radiation therapy for Metastatic and Primary Central and Ultracentral Lung Lesions. JTO Clin Res Rep 2023, 4, 100488, doi:10.1016/j.jtocrr.2023.100488.

Author Response File: Author Response.pdf