Chemotherapy Regimens for Non-Metastatic Conventional Appendicular Osteosarcoma: A Literature Review Based on the Outcomes

Round 1

Reviewer 1 Report (Previous Reviewer 1)

The authors have successfully addressed most corrections/suggestions.

Reviewer 2 Report (Previous Reviewer 2)

The authors have appropriately addressed the points raised by me, the reviewer, and have improved the manuscript. The revised manuscript has been improved to be worthy of publication.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The current manuscript addresses an interesting topic which is the superiority (or not) of using neoadjuvant vs adjuvant therapies for the treatment of osteosarcoma. Nevertheless, some issues should be addressed before acceptance for publication:

- The “conclusion” included in the Abstract section should be more complete;

- For people that are not completely informed about the topic, the meaning and differences between “adjuvant” and “neoadjuvant” therapy should be included;

- A schematic representation (image) should be made regarding current therapies for osteosarcoma, and their limitations;

- Figure 1 should be edited, since some interrogation marks “?” appear where they should not;

- What were the statistical software and tests that were performed? They should be stated in a section of their own.

Author Response

Reviewer #1

The current manuscript addresses an interesting topic which is the superiority (or not) of using neoadjuvant vs adjuvant therapies for the treatment of osteosarcoma. Nevertheless, some issues should be addressed before acceptance for publication:

- The “conclusion” included in the Abstract section should be more complete.

Reply: The authors tried to provide a more complete “conclusion” section within the abstract in the new version of the manuscript.

- For people that are not completely informed about the topic, the meaning and differences between “adjuvant” and “neoadjuvant” therapy should be included.

Reply: In order to provide a better understanding of the concepts “adjuvant” and “neoadjuvant” chemotherapy, the authors will introduce a simple explanation within the introduction in the new version of the manuscript.

- A schematic representation (image) should be made regarding current therapies for osteosarcoma, and their limitations.

Reply: A simple table (Table 1) summarizing current therapies for osteosarcoma and their limitations was introduced into the final manuscript.

- Figure 1 should be edited since some interrogation marks “?” appear where they should not.

Reply: Several reviewers mentioned this issue; however, the authors can’t find those problems in their file. The authors will send separately Figure 1 to be added into the final form of the manuscript if this problem persists.

- What were the statistical software and tests that were performed? They should be stated in a section of their own.

Reply: Due to the nature of this study, where only simple mathematics were used, we did not used any statistical software.

Author Response File: Author Response.docx

Reviewer 2 Report

This manuscript is a review article surveying several articles on conventional osteosarcoma arising in the extremities from the viewpoint of neoadjuvant chemotherapy (NAC) versus no NAC. The topic of this manuscript is of high clinical significance and has been discussed for a long time. I congratulate the authors for having examined so many papers on this topic.

#1. On the other hand, a meta-analysis seems necessary to conclude this issue. Since this manuscript claims to be a systematic review, a meta-analysis following the PRISMA statement should be attempted. If this is not possible, the reasons for this should be included. If meta-analysis is not feasible, reconstructing it as a narrative review article is one option. As the authors also stated, it is difficult to argue the superiority or inferiority of NAC with the results of Table 2 because of the significant differences between the two groups, such as differences in regimens. This paper is not a critical analysis, and its value is likely to be limited to that of a reference document.

#2. The title of the current paper makes it difficult to tell that this paper is an investigation in view of the presence or absence of NACs. Please consider revising it.

#3. In Figure 1, the text is garbled, and there are many question marks. This needs to be corrected.

#4. Both Tables 1 and 2 could be more accessible for readers. They need to be placed horizontally to be readable by the readers.

#5. The abbreviation "NACT" is uncommon and should be "NAC."

Author Response

Reviewer #2

This manuscript is a review article surveying several articles on conventional osteosarcoma arising in the extremities from the viewpoint of neoadjuvant chemotherapy (NAC) versus no NAC. The topic of this manuscript is of high clinical significance and has been discussed for a long time. I congratulate the authors for having examined so many papers on this topic.

#1. On the other hand, a meta-analysis seems necessary to conclude this issue. Since this manuscript claims to be a systematic review, a meta-analysis following the PRISMA statement should be attempted. If this is not possible, the reasons for this should be included. If meta-analysis is not feasible, reconstructing it as a narrative review article is one option. As the authors also stated, it is difficult to argue the superiority or inferiority of NAC with the results of Table 2 because of the significant differences between the two groups, such as differences in regimens. This paper is not a critical analysis, and its value is likely to be limited to that of a reference document.

Reply: The authors would like to thank reviewer #2 comments. To meet the requests of reviewer #2 the authors propose to present this manuscript solely as a review (and not as a systematic review) on the topic of chemotherapy regimens for conventional appendicular osteosarcoma, under a new title: Chemotherapy Regimens for Non-metastatic Conventional Appendicular Osteosarcoma: A Literature Review Based on the Outcomes

#2. The title of the current paper makes it difficult to tell that this paper is an investigation in view of the presence or absence of NACs. Please consider revising it.

Reply: As requested and as above mentioned, the authors proposed a new title to better suit the manuscript content: Chemotherapy Regimens for Non-metastatic Conventional Appendicular Osteosarcoma: A Literature Review Based on the Outcomes

#3. In Figure 1, the text is garbled, and there are many question marks. This needs to be corrected.

Reply: Several reviewers mentioned this issue; however, the authors can’t find those problems in their file. The authors will send separately a new Figure 1 to be added into the final form of the manuscript if this problem persists.

#4. Both Tables 1 and 2 could be more accessible for readers. They need to be placed horizontally to be readable by the readers.

Reply: The authors fully agree with the need to place horizontally tables 1 and 2, however, this issue need to be address together with the editorial team since that we only can place all the manuscript in vertical or in horizontal position. Ideally only the tables should be presented in horizontal position. To minimize immediately this issue, the authors modified the tables font and size.

#5. The abbreviation "NACT" is uncommon and should be "NAC."

Reply: The authors will correct throughout the manuscript this abbreviation (NACT to NAC).

Author Response File: Author Response.docx

Reviewer 3 Report

This manuscript is a comprehensive review encompassing studies published in English literature from 1980 to 2020. The MEDLINE/Pubmed and Scopus electronic databases were utilized for this purpose. The objective of this review was to assess the survival outcomes achieved through neoadjuvant chemotherapy or adjuvant chemotherapy approaches in the treatment of bone osteosarcoma. Additionally, this study aimed to evaluate the toxicity levels associated with various chemotherapeutic regimens utilized in this context.

Although there are inherent limitations, this systematic review reveals that there appears to be no significant difference in survival rates between neoadjuvant chemotherapy (NACT) and adjuvant chemotherapy (ACT) strategies. This finding highlights the need to critically examine our current treatment practices and explore new avenues to enhance the management of appendicular osteosarcoma.

With a wide range of evidence and a solid foundation, this comprehensive study proves its reliability and credibility. Considering the significant finding it has yielded, I believe that this study meets the necessary criteria for publication in this journal, in its current form.

Author Response

Reviewer 3

This manuscript is a comprehensive review encompassing studies published in English literature from 1980 to 2020. The MEDLINE/Pubmed and Scopus electronic databases were utilized for this purpose. The objective of this review was to assess the survival outcomes achieved through neoadjuvant chemotherapy or adjuvant chemotherapy approaches in the treatment of bone osteosarcoma. Additionally, this study aimed to evaluate the toxicity levels associated with various chemotherapeutic regimens utilized in this context. Although there are inherent limitations, this systematic review reveals that there appears to be no significant difference in survival rates between neoadjuvant chemotherapy (NACT) and adjuvant chemotherapy (ACT) strategies. This finding highlights the need to critically examine our current treatment practices and explore new avenues to enhance the management of appendicular osteosarcoma.

With a wide range of evidence and a solid foundation, this comprehensive study proves its reliability and credibility. Considering the significant finding it has yielded, I believe that this study meets the necessary criteria for publication in this journal, in its current form.

Reply: The authors would like to thank Reviewer #3 comments and support towards our manuscript and investigation goals.

Author Response File: Author Response.docx