A Retrospective Comparative Analysis of Outcomes and Prognostic Factors in Adult and Pediatric Patients with Osteosarcoma

Round 1

Reviewer 1 Report

Dear authors,

Thank you for your interesting and well-written manuscript. I believe that the results you present here are of great interest to the osteosarcoma research community, especially regarding the usefullness of methotrexate in the adult population.

Regarding the lesser extent of tumour necrosis in the adult cohort compared to the pediatric cohort, I wonder if this is a reflection of the MAP vs AP protocol? Could it be that the MAP regime leads to more tumour necrosis? Is there a way to look at tumour necrosis only in adults receiving MAP and compare those to the pediatric population? I think that this would be interesting to look at. While I do not think it is necessary to add this in order to approve the manuscript for acceptance, I do think it is of interest to other researchers.

Kind Regards

Author Response

Dear reviewer,

Thank you for your thoughtful comments and review of our manuscript.

We have tried to answer the question you posed regarding comparison of tumor necrosis between adult patients treated with MAP and pediatric patients treated with MAP and added this data to the manuscript. Based on our results, adult patients treated with MAP have a significantly lower mean tumor necrosis compared to pediatric patients treated with MAP. 

Kind Regards,

Stefano Testa, MD
Stanford University Department of Medicine

Reviewer 2 Report

In their manuscript, Testa and collaborators performed a restrospective analysis of 112 patients with osteosarcoma treated at Stanford University between 1989 and 2019. The authors analyzed OS and PFS in adult and pediatric patients with ≥90% necrosis vs <90% necrosis, and in patients treated with methotrexate-doxorubicin-cisplatin vs doxorubicin-cisplatin. While they observed a better OS and PFS in pediatric patients that had ≥90% necrosis compared to <90% necrosis, the authors didn’t find any difference in the adult population. Likewise, the addition of methotrexate didn’t improve OS or PFS. The authors conclude that in pediatric patients, the percentage of tumor necrosis after neoadjuvant therapy could be used as a prognostic factor for OS and PFS.

The manuscript is very well written and highlights important information about the use of methotrexate in combined therapies. The English is perfect and the manuscript doesn’t contain any major flaw with the exception of the limited number of patients in this study. Yet, the authors highlight the limitations of certain comparisons due to a low number of patients.

Author Response

Dear Reviewer, 

Thank you very much for your thoughtful comments and review of our manuscript. 

We appreciate your time and attention. 

Sincerely,

Stefano Testa, MD
Stanford University Department of Medicine 

Reviewer 3 Report

This is a retrospective analysis of a cohort of pediatric and adult patients with osteosarcomas treated in two institutions.

To be honest, I don't understand the main aim of this study, because pediatric and adult osteosarcomas should be treated as separate diseases. The biology and behavior of adult osteosarcoma are different than pediatric osteosarcoma. Then clinical factors are also different (see Tab. 1 and Tab. 2). Retrospective description of those two groups in one publication (comparison of conclusions/findings?), especially regarding treatment efficacy is very controversial. 

The severely-biased retrospective study (long period, non-homogenous groups, incomplete data, etc.) with a small sample size (only 45 participants in the "adults arm") cannot provide an answer to the raised questions, namely therapeutic value of methotrexate in adult patients with osteosarcoma and correlation of outcomes with post-treatment necrosis. This issue should be a matter of multi-institutional or international randomized study focused only on adult patients, preferably over 40 y.o.

The efficacy of MAP is well-known in pediatric osteosarcoma (and investigated/discussed several times). The justification for adding methotrexate in adult patients is still unsolved and this study does not provide any relevant data on this topic. The issue of survival could be found in other articles as well as in SEER-related publications.

Author Response

Dear Reviewer,

Thank you for your thoughtful comments and review of our manuscript.

Below we are providing detailed replies to your comments.

1) “To be honest, I don't understand the main aim of this study, because pediatric and adult osteosarcomas should be treated as separate diseases. The biology and behavior of adult osteosarcoma are different than pediatric osteosarcoma. Then clinical factors are also different (see Tab. 1 and Tab. 2). Retrospective description of those two groups in one publication (comparison of conclusions/findings?), especially regarding treatment efficacy is very controversial.”

• Given the scarcity of studies directly comparing pediatric and adult patients with osteosarcoma we took advantage of the close collaboration between the adult and pediatric osteosarcoma groups at our institution to carry out a direct comparative analysis of patient-related and treatment-related variables between adult and pediatric patients with osteosarcoma. Our aim was to point out any differences between the two populations that could inform clinical decision-making and/or lay the basis for further larger prospective studies in either population.

2) The severely-biased retrospective study (long period, non-homogenous groups, incomplete data, etc.) with a small sample size (only 45 participants in the "adults arm") cannot provide an answer to the raised questions, namely therapeutic value of methotrexate in adult patients with osteosarcoma and correlation of outcomes with post-treatment necrosis. This issue should be a matter of multi-institutional or international randomized study focused only on adult patients, preferably over 40 y.o.

• With this revision we more clearly describe in the discussion which are the limitations of this study. Here we do not provide definitive answers to the questions we have posed given the limitations of our study. However, our results offer the basis for hypotheses that should be tested in larger, multi-institutional prospective randomized studies as your rightfully pointed out.

3) The efficacy of MAP is well-known in pediatric osteosarcoma (and investigated/discussed several times). The justification for adding methotrexate in adult patients is still unsolved and this study does not provide any relevant data on this topic. The issue of survival could be found in other articles as well as in SEER-related publications.

• In this study we did not find any differences in outcomes between adult patients that received MAP compared to those that received AP. Based on our results, and the limitations of this study, we cannot conclude that methotrexate does not provide any benefits in adult patients with osteosarcoma. Rather, our results indicates that further larger prospective studies are still needed to try answering this question.

Sincerely,

Stefano Testa, MD
Stanford University Department of Medicine