Palliative Efficacy of High-Dose Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Painful Non-Spine Bone Metastases: A Propensity Score-Matched Analysis

Round 1

Reviewer 1 Report

In this work the authors analyzed the long-term pain relief effect of SBRT treatment of non-spine bone metastases comparing to the effect of conventional palliative EBRT. The material is well-structured, the conclusions are clear, however it is not surprising that the impact of the higher-dose modern RT technology (with greater PTV) is better, than the conventional (dose) palliative RT, considering the long-term local control and symptomatic effect (and having the experience in routine clinical treatment decision factors). Nevertheless it is recommended to consider for publication, since the findings successfully legitimate the previous general statement. The reviewer has only some comments and notifications:

Title: It would be worthy to think about the reconstruction of the title, since the higher biological dose/effect of SBRT seems really important in the final results (comparing to the technology effect). I suggest rather „high(er) dose” or „ablative (dose)” SBRT in this context.   

Line30: This sentence belongs to the „Results” part and not to „Conclusions”. 

Line46-47: „radioresistant tumours vs. other primary tumours” I recommend rather „more (radio)sensitive tumours”.

Line 69: From June 2018 SBRT was indicated to all good condition/prognosis patient. This treatment strategy predicts the final results/conclusion of the work, however the match-paired analysis tried to exclude the effect of this selection bias. I recommend some explanation/comment to this change in routine care.  

Line 85-87: It is interesting to the readers that the CTV expansion is higher in case of SBRT target delineation comparing to conventional EBRT treatment. Please explain it.

Line 118: The 6monthes OR rates were also analyzed. It would be worthy to overemphasize these really long-term results in the material (and in the abstract as well).

Figure2: Comment: considering EBRT treatment a great number of patients were excluded because of early re-RT, death-lost of follow-up, and the absence of symptom evaluation. These findings really explain the selection procedure for SBRT/EBRT.

Line 187-189. It would be worthy to talk some words the long-term OS effect as well.    

Author Response

RESPONSES TO REVIEWER’S COMMENTS

We would like to sincerely thank the reviewer for taking time to review our manuscript and provide insightful comments and suggestions. We have revised the manuscript based on the comments, and believe that they have helped to improve the manuscript considerably. Here is a point-by-point response to the reviewer’s comments and concerns.

 

**************************************************************************

 

Reviewer 1

In this work the authors analyzed the long-term pain relief effect of SBRT treatment of non-spine bone metastases comparing to the effect of conventional palliative EBRT. The material is well-structured, the conclusions are clear, however it is not surprising that the impact of the higher-dose modern RT technology (with greater PTV) is better, than the conventional (dose) palliative RT, considering the long-term local control and symptomatic effect (and having the experience in routine clinical treatment decision factors). Nevertheless, it is recommended to consider for publication, since the findings successfully legitimate the previous general statement. The reviewer has only some comments and notifications:

 

Title: It would be worthy to think about the reconstruction of the title, since the higher biological dose/effect of SBRT seems really important in the final results (comparing to the technology effect). I suggest rather „high(er) dose” or „ablative (dose)” SBRT in this context.  

Response: We thank the reviewer for the constructive comment. We have revised the title according to reviewer’s comment to “Palliative Efficacy of High-dose Stereotactic Body Radiotherapy versus Conventional Radiotherapy for Painful non-Spine Bone Metastases: A Propensity Score-Matched Analysis.”

 

Line30: This sentence belongs to the „Results” part and not to „Conclusions”.

Response: We thank the reviewer for pointing this out. We have moved the sentence to the Results subsection of the Abstract (Lines 30-31 of the revised manuscript).

 

Line46-47: „radioresistant tumours vs. other primary tumours” I recommend rather „more (radio)sensitive tumours”.

Response: We thank the reviewer for the suggestion and have changed it to the following: “…it is less effective against radioresistant tumors than more radiosensitive primary tumors…” (Line 48 of the revised manuscript).

 

Line 69: From June 2018 SBRT was indicated to all good condition/prognosis patient. This treatment strategy predicts the final results/conclusion of the work, however the match-paired analysis tried to exclude the effect of this selection bias. I recommend some explanation/comment to this change in routine care. 

Response: We thank the reviewer for the suggestion. Although we had performed SBRT only for oligometastases, SBRT for all painful non-spine bone metastases started in June 2018 as a clinical trial [11]. As the outcomes of the prospective study were demonstrated to be excellent, we have offered SBRT for all painful lesions even after the completion of the clinical trial.

We have added the necessary explanation (Lines 71-72 of the revised manuscript).

 

Line 85-87: It is interesting to the readers that the CTV expansion is higher in case of SBRT target delineation comparing to conventional EBRT treatment. Please explain it.

Response: We thank the reviewer for highlighting this important point.

The large CTV margin (20–30 mm) in SBRT was determined based on a previous analysis about patterns of intraosseous recurrence [12]. Out-of-field recurrences in the same bone were observed in more than 40% of cases treated via SBRT with a CTV margin of 5–10 mm, and the mean distance to the recurrent tumor from the initial bone metastasis was 34 mm (range, 15–55 mm) [12].

As pointed out by the reviewer, the target of SBRT was larger than that of cEBRT. On the contrary, the irradiated volume of cEBRT was often larger than that of SBRT owing to the poor dose concentration of cEBRT (like the case in Figure 1). Therefore, it was difficult to determine the correlation between pain relief effect and target size in this study.

We have incorporated this information in the Discussion (Lines 272–280 of the revised manuscript).

 

Line 118: The 6monthes OR rates were also analyzed. It would be worthy to overemphasize these really long-term results in the material (and in the abstract as well).

Response: We have added the 6-month OR rates in the Abstract on lines 30–31 according to the reviewer’s comment.

“A noteworthy finding of our study is that the OR rate even at 6 months after SBRT was significantly higher than that after cEBRT (and 72.2% vs. 48.0%; p < 0.01).”

 

Figure2: Comment: considering EBRT treatment a great number of patients were excluded because of early re-RT, death-lost of follow-up, and the absence of symptom evaluation. These findings really explain the selection procedure for SBRT/EBRT.

 

Line 187-189. It would be worthy to talk some words the long-term OS effect as well.   

Response: We thank the reviewer for this constructive comment. We have added the long-term OS effects in the Discussion (Lines 287–295 of the revised manuscript) as follows:

“We performed bone SBRT for patients in a good general condition. Contrastingly, cEBRT was provided to patients with all statuses of general condition. Hence, we selected only those patients with a good general condition among the cEBRT cohort and matched them to the SBRT group. Therefore, the finding of no significant difference in OS among the two groups may be attributed to PSM. However, OS in the SBRT group was comparatively longer than that in the cEBRT group. The high OR rate and low local failure rate of SBRT may have contributed to maintenance of general condition and activities and subsequent prolongation of survival (alternatively, the longer OS may have been owing to a selection bias or advances in systemic therapy).”

 

 

There has been substantial modification to the paper in line with the reviewers’ suggestions, and I hope that the paper will benefit from these revisions. Once again, we thank you for the time you put in reviewing our paper and look forward to meeting your expectations.

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors of this interesting manuscript address a hot topic in radiotherapy, namely the comparison between the efficacy of stereotaxic radiotherapy and palliative radiotherapy in pain relief in patients with bone metastases. The results of their analysis, based on the propensity score-matching method, show a significant superiority of stereotaxic radiotherapy. This report, while within the limits of a non-randomized comparison, may be useful in stimulating further research and in providing further data on this topic.

I have only a few minor observations:

* abstract: I would suggest moving the results in terms of local control from the conclusions to the "results" section

* line 67: "lesion pain", perhaps it would be useful to clarify / specify better;

* the definition of the SBRT CTV is not very clear; have two different CTV been defined ?; however the 2 cm expansion between GTV and CTV does not sound usual; perhaps the authors can further comment in the discussion section;

* although in the discussion the authors provide arguments regarding the fact that the different definition of CTV can hardly explain the different pain response, the fact remains that the CTV irradiated with SBRT is wider than that of palliative radiotherapy (if I understand correctly) ; this aspect should be mentioned among the limitations of the study;

* in table 1 the authors differentiate primary tumors between radioresistant and radiosensitive; did they refer to any specific classification?

* in their randomized study, Pielkenrood BJ et al (Int J Radiat Oncol Biol Phys 2021; 110: 358) arrive at opposite conclusions with respect to this analysis; I would recommend citing that paper and discussing the results.

Author Response

RESPONSES TO REVIEWER’S COMMENTS

We would like to sincerely thank the reviewer for taking time to review our manuscript and provide insightful comments and suggestions. We have revised the manuscript based on the comments, and believe that they have helped to improve the manuscript considerably. Here is a point-by-point response to the reviewer’s comments and concerns.

 

**************************************************************************

Reviewer 2

The authors of this interesting manuscript address a hot topic in radiotherapy, namely the comparison between the efficacy of stereotaxic radiotherapy and palliative radiotherapy in pain relief in patients with bone metastases. The results of their analysis, based on the propensity score-matching method, show a significant superiority of stereotaxic radiotherapy. This report, while within the limits of a non-randomized comparison, may be useful in stimulating further research and in providing further data on this topic.

 

I have only a few minor observations:

* abstract: I would suggest moving the results in terms of local control from the conclusions to the "results" section

Response: We thank the reviewer for pointing this out. We have moved the sentence to the Results subsection of the Abstract (Lines 30–31 of the revised manuscript).

 

* line 67: "lesion pain", perhaps it would be useful to clarify / specify better;

Response: We have revised the term to “index pain” for clarification (line 69 of the revised manuscript).

 

* the definition of the SBRT CTV is not very clear; have two different CTV been defined?; however the 2 cm expansion between GTV and CTV does not sound usual; perhaps the authors can further comment in the discussion section;

Response: Only one CTV was determined for each case.

As pointed out by the reviewer, this large CTV margin is different from experts’ recommendations [PMID: 34509549]. The basis for the large margin has been added in the Discussion (Lines 272–280 of the revised manuscript).

 

* although in the discussion the authors provide arguments regarding the fact that the different definition of CTV can hardly explain the different pain response, the fact remains that the CTV irradiated with SBRT is wider than that of palliative radiotherapy (if I understand correctly) ; this aspect should be mentioned among the limitations of the study;

Response: As pointed out by the reviewer, the target of SBRT was larger than one of cEBRT. Contrastingly, however, the irradiated volume of cEBRT was often larger than that of SBRT due to the poor dose concentration of cEBRT (as shown in the case in Figure 1). Therefore, it was difficult to consider the correlation between pain relief effect and target size in the present study.

We have incorporated this information in the Discussion (Lines 272–280 of the revised manuscript).

 

* in table 1 the authors differentiate primary tumors between radioresistant and radiosensitive; did they refer to any specific classification?

Response: To the best of our knowledge, there is not distinctive definition to distinguish between radioresistance or radiosensitivity of tumors. We have classified them based on References #16–18.

 

* in their randomized study, Pielkenrood BJ et al (Int J Radiat Oncol Biol Phys 2021; 110: 358) arrive at opposite conclusions with respect to this analysis; I would recommend citing that paper and discussing the results.

Response: We thank the reviewer for raising this important point.

We have added the following sentences in the Discussion (Lines 228–237 of the revised manuscript).

“Although the present study demonstrated the superiority of SBRT for pain palliation, randomized controlled trials comparing pain-relieving effects between SBRT and cEBRT for bone metastases have reported paradoxical results: superiority of SBRT [10, 22] and non-superiority [23–27]. Consequently, the superior effectiveness of SBRT is still uncertain. Additionally, although, the reasons for the discrepancy in results are unclear, we postulate that the following factors may have contributed to the difference: (i) difference of prescribed SBRT dose; (ii) spine or non-spine bone; (iii) unbalanced allocation to each group (e.g., PS, radiation sensitivity); and (iv) intent-to-treat or per-protocol analyses (owing to a high death rate and loss of follow-up).”

 

There has been substantial modification to the paper in line with the reviewers’ suggestions, and I hope that the paper will benefit from these revisions. Once again, we thank you for the time you put in reviewing our paper and look forward to meeting your expectations.

Reviewer 3 Report

This is  a well-written paper that is of interest to clinicians who seek evidence about the value of SBRT versus sEBRT in patients with bone metastases. 

Author Response

Reviewer 3

This is a well-written paper that is of interest to clinicians who seek evidence about the value of SBRT versus cEBRT in patients with bone metastases.

 

Response: We would like to sincerely thank the reviewer for taking time to review our manuscript.

Reviewer 4 Report

This is a very good clinical paper. It compares the benefit of SBRT to conventional radiotherapy in patients with painful non-spine bone metastases using a propensity score-matched method. The limitations of this study are described in a compact and precise manner in Discussion.

Please consider the following responses to the details.

1. The pain response over time shown in Table 2 is the key result of this paper. In addition to Table, please consider illustrating the graph using the Kaplan-Meier method as Figure. 

2. Please add the p-value to Figure3.

Author Response

RESPONSES TO REVIEWER’S COMMENTS

We would like to sincerely thank the reviewer for taking the time to review our manuscript and providing insightful comments and suggestions. We have revised the manuscript based on these comments and believe that they have helped us improve our manuscript.

 

**************************************************************************

 

Reviewer 4

This is a very good clinical paper. It compares the benefit of SBRT to conventional radiotherapy in patients with painful non-spine bone metastases using a propensity score-matched method. The limitations of this study are described in a compact and precise manner in Discussion.

 

Please consider the following responses to the details.

 

1. The pain response over time shown in Table 2 is the key result of this paper. In addition to Table, please consider illustrating the graph using the Kaplan-Meier method as Figure.

Response: We thank the reviewer for the constructive comment.

However, it is difficult to show pain events as time-to-event outcomes because often, the pain observed is temporary. For example, a patient experienced pain progression due to a pain flare 1 week after radiotherapy, but the pain disappeared after 1 month. Another patient experienced pain progression due to a fracture 3 months after radiotherapy, but the pain disappeared spontaneously after 6 months. Therefore, pain response is judged at a specific time (such as 1 month, 3 months, and 6 months).

We apologize for not being able to add the illustration as per your suggestion.

 

2. Please add the p-value to Figure3.

Response: We thank the reviewer for this suggestion. We added the p-value in Figure 3 according to the reviewer’s recommendation.