The Role of Denosumab for Surgical Outcomes in Patients with Giant Cell Tumour of Bone: A Systematic Review

Round 1

Reviewer 1 Report

This article is interesting and well written article but it has some limitations:

1. Authors need to organize not only the manuscript but also the abstract  around 2-4 clearly articulated questions (or research purposes), and pose those questions or purposes in terms of explicit study variables. This way, when you answer them, the reader walks away with 2-4 explicit "take home" points, and they are the ones you think most important. These questions or purposes would be stated in the appropriate section of the Abstract, as theiy are in the last paragraph of the Introduction.
2. Expand background and methods in the abstract by following the introduction and methods in the text. 
3. Please avoid acronyms in the abstract.
4. Can authors clarify what is wrong with the previous systematic review. If it showed a benefit, why do we need another study?
5. Avoid the terms “significant” and its relatives. If something is significantly larger than something else, just say it’s larger. If it is “larger” but not “significantly so”, please say that it is no different. For no-difference findings that are not, say something like “previous study found no difference between A and B (data, stats, p)”.
6. I do not think that distant metastases should be included in the paragraph "Adverse effects" in association with malignant transformation. This association creates confusion as distant metastases may be present in the benign GCT. This paragraph is interesting and the topic controversial. The authors should better analyze the literature data on the possible secondary malignant transformation of the GCT with or without denosumab treatment.

Author Response

Dear Reviewer 1.,

Thank you very much for your careful review and very helpful comments. We have revised our manuscript based on your and the other two reviewers’ comments. We believe that the quality of this manuscript has improved after revision. The followings are our point-by-point responses to your comments.

Kind regards,

All the co-authors

This article is interesting and well written article but it has some limitations:

1. Authors need to organize not only the manuscript but also the abstract  around 2-4 clearly articulated questions (or research purposes), and pose those questions or purposes in terms of explicit study variables. This way, when you answer them, the reader walks away with 2-4 explicit "take home" points, and they are the ones you think most important. These questions or purposes would be stated in the appropriate section of the Abstract, as they are in the last paragraph of the Introduction.

---We have revised as requested.

1. Expand background and methods in the abstract by following the introduction and methods in the text. 

---We have revised as requested within the 200 word count limit.

1. Please avoid acronyms in the abstract.

---We have deleted all the acronyms in the abstract.

1. Can authors clarify what is wrong with the previous systematic review. If it showed a benefit, why do we need another study?

--- The following has been added to the Introduction section and Abstract section:

“One previous systematic review addressed only one outcome—disease recurrence; therefore we undertook this new systematic review to address the above five outcomes.”

---We also have added two sentences to explain why we needed to search the primary literature as below on page 6:

“However, this eligible systematic review only reported one (i.e., disease recurrence) of five outcomes that we were interested in. Thus, we undertook this new systematic review to address all five outcomes.”

1. Avoid the terms “significant” and its relatives. If something is significantly larger than something else, just say it’s larger. If it is “larger” but not “significantly so”, please say that it is no different. For no-difference findings that are not, say something like “previous study found no difference between A and B (data, stats, p)”.

---We have deleted the term of “significant” on page 8 and page 10 under Results section.

1. I do not think that distant metastases should be included in the paragraph "Adverse effects" in association with malignant transformation. This association creates confusion as distant metastases may be present in the benign GCT. This paragraph is interesting and the topic controversial. The authors should better analyze the literature data on the possible secondary malignant transformation of the GCT with or without denosumab treatment.

---We have clarified that the outcome that was assessed lung metastases of benign histology was not related to denosumab treatment. We present all of the comparative data available on page 9. On page 11 under Discussion section, we stated that “short follow-up time (median 27 to 85 months) may be insufficient to accurately report malignant transformation of GCTB or osteonecrosis of jaw.” We hope that more studies with sufficient follow-up time will investigate this point clearly in the near future.

Reviewer 2 Report

Dear Editor:

  Thank you for the opportunity to review the manuscript by Gupta et al entitled “The Role of Denosumab for Surgical Outcomes in Patients with Giant Cell Tumour of Bone: A Systematic Review”.  This is a small review of a small literature on GCTB.  This is a rare tumor and the data is limited.  Overall, their conclusion is that there is insufficient evidence to make any conclusions based on their analysis.

Prior to publication, the authors should address the following concerns.

1. Minor DENO is never defined before first use
2. In the statement “A 26 shorter mean operating time was found in patients with both adjuvant and 27 neoadjuvant DENO administration when compared with patients receiving no 28 DENO or receiving adjuvant DENO, but the difference was not statistically 29 significant”. If it isn’t statistically significant that the statement must state this clearly. There is not a statistically significant difference in operating time.  This is in both in the abstract and the discussion verbatim.
3. The authors should re-read for redundancies.

Author Response

Reviewer 2.

Dear Reviewer 2.,

Thank you very much for your careful review and very helpful comments. We have revised our manuscript based on your and the other two reviewers’ comments. We believe that the quality of this manuscript has improved after revision. The followings are our point-by-point responses to your comments.

Kind regards,

All the co-authors

Dear Editor:

  Thank you for the opportunity to review the manuscript by Gupta et al entitled “The Role of Denosumab for Surgical Outcomes in Patients with Giant Cell Tumour of Bone: A Systematic Review”.  This is a small review of a small literature on GCTB.  This is a rare tumor and the data is limited.  Overall, their conclusion is that there is insufficient evidence to make any conclusions based on their analysis.

Prior to publication, the authors should address the following concerns.

1. Minor DENO is never defined before first use

---On page 3, we have clarified the acronym for denosumab (DENO).

1. In the statement “A both adjuvant and neoadjuvant DENO administration when compared with patients receiving no DENO or receiving adjuvant DENO, but the difference was not statistically significant”. If it isn’t statistically significant that the statement must state this clearly. There is not a statistically significant difference in operating time.  This is in both in the abstract and the discussion verbatim.

---We have revised as follows: “Neoadjuvant DENO administration was associated with a shorter (not statistically significant) mean operating time than patients receiving no DENO.” on page 10.

1. The authors should re-read for redundancies.

---Thank you very much for this comment. We have reviewed the whole manuscript and reworded several sentences.

Reviewer 3 Report

In this manuscript by Gupta et al., the authors have provided a systematic review on the role of Denosumab for surgical outcomes in
patients with Giant Cell Tumour of Bone. A review of the literature was conducted at  MEDLINE, EMBASE, PubMed, and Cochrane Database of Systematic Reviews databases. Based on their search, the authors had concluded that there is insufficient evidence to understand the value of
DENO in the peri-operative setting in patients with GCTB. This is a significant study. However, the authors should address the below points before reconsidering the manuscript for publication.

1. The authors should re-check the grammar and flow of the manuscript to make it better to read.
2. The novelty of the study should be clearly emphasized in the abstract and introduction sections.
3.   The summary of the pain rate of denosumab from the baseline until the first follow up should be added. 
4. The data on the summary of other adverse effects of denosumab from the baseline until the first follow will improve the manuscript.

Author Response

Reviewer 3.

Dear Reviewer 3.,

Thank you very much for your careful review and very helpful comments. We have revised our manuscript based on your and the other two reviewers’ comments. We believe that the quality of this manuscript has improved after revision. The followings are our point-by-point responses to your comments.

Kind regards,

All the co-authors

In this manuscript by Gupta et al., the authors have provided a systematic review on the role of Denosumab for surgical outcomes in
patients with Giant Cell Tumour of Bone. A review of the literature was conducted at  MEDLINE, EMBASE, PubMed, and Cochrane Database of Systematic Reviews databases. Based on their search, the authors had concluded that there is insufficient evidence to understand the value of
DENO in the peri-operative setting in patients with GCTB. This is a significant study. However, the authors should address the below points before reconsidering the manuscript for publication.

1. The authors should re-check the grammar and flow of the manuscript to make it better to read.

---We have reviewed and revised the manuscript as suggested.

1. The novelty of the study should be clearly emphasized in the abstract and introduction sections.

-The following has been added to the Introduction section and Abstract section:

“One previous systematic review addressed only one outcome—disease recurrence; therefore we undertook this new systematic review to address the above five outcomes.”

3. The summary of the pain rate of denosumab from the baseline until the first follow up should be added. 

---One of our five outcomes is “pain control”, but no studies addressed this outcome. Therefore the following point is made in the Results and Discussion sections:

 “There were no studies that evaluated pain control in patients receiving DENO versus no DENO.”

1. The data on the summary of other adverse effects of denosumab from the baseline until the first follow will improve the manuscript.

---Other less common adverse effects of denosumab were not assessed in this study as the five outcomes listed were the focus of this systematic review.

Round 2

Reviewer 3 Report

The authors have addressed all the comments and the manuscript may be accepted for publication.