Conversion in a Resectable Tumor after Denosumab Neoadjuvant in a Large Dorsal Giant Cells Tumor: A Case Report and a Literature Review

Round 1

Reviewer 1 Report

The authors Sereno and colleagues present the case of a 39-yo male with mild symptoms who revealed a large mass near the lungs at the x-ray exam. The patient was dinged with primary bone tumor and biopsy identified the presence of giant cells. Neoadjuvant treatment with denosumab was initiated and after 6 months the mass significantly shrinked, allowing surgical intervention. Two months later, Ct scan showed no persistence nor recurrence of disease. 

The manuscript is of interest since it presents an unusual case of an unresectable vertebral giant cell tumor with very few symptoms , which became surgically operable after six months of denosumab administration.

However, few suggestions are provided below to improve the overall quality of the paper. 

1) Besides denosumab, also multitarget tyrosine-kinase inhibitor proved to be effective in treatment of unresectable bone tumor. Indeed, recently it has been showed that lenvatinib can exert antitumor efficacy in bone sarcomas including osteosarcoma and chondrosarcoma in combination with pembrolizumab (NCT04784247) or with etoposide plus ifosfamide - in the latter case showing an enhanced efficacy of chemotherapy mediated by lenvatinib, with no new safety issues in patients (doi.org/10.1016/S1470-2045(21)00387-9). It is known that angiogenesis is one of the major hallmarks of tumorigenesis, and the involvement of VEGFR has been described in supporting RANKL-induced osteoclastogenesis in giant cell tutors of bone (doi:10.1038/labinvest.2012.108, doi:10.1016/S0024-3205(03)00434-X). In this regard, a recent translational study reported that lenvatinib, either alone or in combination with denosumab, was more effective compared to denosumab alone in patient-derived primary cultures of GCTB (doi: 10.3390/biomedicines10020372). Please add this topic with relevant references for proper discussion. 

2) In Introduction section, the authors mention palliative treatments such as embolization as an option when surgery and radiotherapy are not feasible. However, also high-intensity focused ultrasound technique represents an option for treating RT-resistant bone lesions. Indeed, several studies showed its ability to achieve effective pain control within a couple of weeks (10.1016/j.clon.2017.12.023, doi: 10.1245/s10434-008-0011-2, oi: 10.1007/s00520-022-06990-y) and in some cases also HIFU seems to be effective also in tumor control with a high rate of partial response recorded (doi: 10.1097/RLI.0b013e318285bbab, doi: 10.1080/02656736.2019.1655593). Please add this treatment option with relevant references for proper discussion. 

Author Response

Reviewer 1

• Besides denosumab, also multitarget tyrosine-kinase inhibitor proved to be effective in treatment of unresectable bone tumor. Indeed, recently it has been showed that lenvatinib can exert antitumor efficacy in bone sarcomas including osteosarcoma and chondrosarcoma in combination with pembrolizumab (NCT04784247) or with etoposide plus ifosfamide - in the latter case showing an enhanced efficacy of chemotherapy mediated by lenvatinib, with no new safety issues in patients (doi.org/10.1016/S1470-2045(21)00387-9). It is known that angiogenesis is one of the major hallmarks of tumorigenesis, and the involvement of VEGFR has been described in supporting RANKL-induced osteoclastogenesis in giant cell tutors of bone (doi:10.1038/labinvest.2012.108, doi:10.1016/S0024-3205(03)00434-X). In this regard, a recent translational study reported that lenvatinib, either alone or in combination with denosumab, was more effective compared to denosumab alone in patient-derived primary cultures of GCTB (doi: 10.3390/biomedicines10020372). Please add this topic with relevant references for proper discussion. 

 

Re: Ok. We have included this. Thank you very much for the information

 

• In Introduction section, the authors mention palliative treatments such as embolization as an option when surgery and radiotherapy are not feasible. However, also high-intensity focused ultrasound technique represents an option for treating RT-resistant bone lesions. Indeed, several studies showed its ability to achieve effective pain control within a couple of weeks (10.1016/j.clon.2017.12.023, doi: 10.1245/s10434-008-0011-2, oi: 10.1007/s00520-022-06990-y) and in some cases also HIFU seems to be effective also in tumor control with a high rate of partial response recorded (doi: 10.1097/RLI.0b013e318285bbab, doi: 10.1080/02656736.2019.1655593).Please add this treatment option with relevant references for proper discussion. 

Re: Thank you very much. We have included it. Very interesting.

Reviewer 2 Report

This article is a case report of thoracic spinal giant cell tumor completely removed after  neoadjuvant denosumab treatment. This is an excellent report of a good outcome, however the following points should be addressed for publish.

 

This paper is classified as a case report.

The introduction is too long and should be properly shorter.

The postoperative follow-up period should be clearly indicated.

There is a description of the histological findings for the surgically removed tissue, however a figure image need to be shown.

Was postoperatively denosumab administered to prevent recurrence? The question of whether to administer postoperatively needs to be discussed.

In discussion section, reports of previous literature are listed and difficult to read, and it would be better to summarize them in a table.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The paper has been improved and not could be considered for publication.

Reviewer 2 Report

I conclude that the work is not worthy of publication because it has not been sufficiently revised to address the points I have pointed out.

Author Response

This article is a case report of thoracic spinal giant cell tumor completely removed after neoadjuvant denosumab treatment. This is an excellent report of a good outcome, however the following points should be addressed for publish.

 

This paper is classified as a case report.

Re: Thank you very much for the commentary. Yes, it is a case report and review of the literature. There was not an alternative section for these types of paper

 

The introduction is too long and should be properly shorter.

Re: Ok, we have shorten it.

 

The postoperative follow-up period should be clearly indicated.

Re: Ok, we have clarified the postoperative follow-up

 

There is a description of the histological findings for the surgically removed tissue, however a figure image need to be shown.

Re: The patient was operated to another center. We have tried to contact the pathologist on several occasions to obtain an image of the postoperative pathology without success. The colleague has been on medical leave for a prolonged period of time. For this reason we were unable to include the image. Indeed, it would have been very enriching to obtain it, but after several attempts we gave up.

 

Was postoperatively denosumab administered to prevent recurrence? The question of whether to administer postoperatively needs to be discussed.

Re: In this case, the benefit with complete response and after a considerable number of preoperative denosumab cycles is unclear. In addition, different studies show high response rates with Denosumab in case of relapse. We have already added this commentary in the manuscript

 

In discussion section, reports of previous literature are listed and difficult to read, and it would be better to summarize them in a table.

Re: Ok, we have made a new table. Thank you for the idea.

 

Round 3

Reviewer 2 Report

This revised manuscript answers the reviewers’ questions and addresses their concerns. It deserves attention and is worthy of publication in this journal.