A Systematic Review of Adjuvant Chemotherapy in Localized Dedifferentiated Chondrosarcoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an exciting meta-analysis and provides a very good review of the adjuvant therapy and the DDCS.

The methods are very well explained, and the results are presented clearly.

While the study aims to analyse adjuvant chemotherapy, the authors could further discuss the genomics of DDCS or other sarcomas, like osteosarcoma. For osteosarcoma, many genomics papers are available (one example PMID: 25496518) describing the potential of genomic profiling for these rare tumours. The genomics should be discussed. This is especially relevant because the chemotherapy did not have any additional benefit to the surgical therapy, indicating that existing chemotherapy options are exhausted. A new approach is needed, and genomics can open this new avenue for cancer therapies.

Author Response

Responses to the Reviewers

Thank you for your detailed and thoughtful comments regarding our manuscript. We believe that our paper has markedly improved as a result of your valuable comments and feedback.

Reviewer's comments:

Reviewer: 1

Comment

This is an exciting meta-analysis and provides a very good review of the adjuvant therapy and the DDCS.

The methods are very well explained, and the results are presented clearly.

While the study aims to analyse adjuvant chemotherapy, the authors could further discuss the genomics of DDCS or other sarcomas, like osteosarcoma. For osteosarcoma, many genomics papers are available (one example PMID: 25496518) describing the potential of genomic profiling for these rare tumours. The genomics should be discussed. This is especially relevant because the chemotherapy did not have any additional benefit to the surgical therapy, indicating that existing chemotherapy options are exhausted. A new approach is needed, and genomics can open this new avenue for cancer therapies.

Response:

Thank you for your valuable comments. We added the following sentences in the “Discussion” section; “In recent years, research has been conducted on the mechanisms of DDCS development and therapeutic targets. The BCL2 and TGFβ have been investigated as potential gene targets in DDCS [46]. Van Oosterwijk et al. used a microarray containing 42 dedifferentiated chondrosarcomas and performed immunohistochemistry to study the expression of growth plate signaling molecules. High expression of SOX-9 and FGFR-3 was observed, along with abnormal cellular localization of heparan sulfate proteoglycans [46]. TGFβ signaling through p-SMAD2 and PAI-1 was highly active, suggesting that TGFβ inhibitors may be a therapeutic option for DDCS [46]. Anti-apoptotic proteins (Bcl-2 and/or Bcl-xL) were also highly expressed in DDCS. Using an inhibitor with the BH-3 mimetic ABT-737 rendered the dedifferentiated chondrosarcoma cell lines sensitive to doxorubicin or cisplatin [46].

TP53 gene mutations are found in 20% of conventional chondrosarcomas and DDCS [47]. Studies have found a correlation between the overexpression of TP53 or its point mutations and tumors with a higher histological grade. This suggests a role for this gene in tumor progression [48]. Other frequently mutated genes in chondrosarcomas are related to the cell cycle process and control, including MDM2 and cyclin-dependent kinase 4 (CDK4), which inhibit p53 and are overexpressed in chondrosarcomas [49]. High expression of CDK4 and MDM2 correlated with a higher histological grade [50]. MDM2 overexpression has also been observed in DDCS [19]. The second most important pathway alteration involved in high-grade chondrosarcoma is in the retinoblastoma protein (pRB) pathway [50]. Deletion of CDKN2A/p16/INK4A, caused by the deletion of the 9p21 region, occurs more frequently in high-grade chondrosarcomas and DDCS [50,51]. This suggests the potential efficacy of CDK4 inhibitors [50].

Amplification of the c-MYC oncogene is present in approximately 20% of DDCS and correlates with poor prognosis, and molecular targeting of MYC expression may be useful in DDCS [52]. The heterozygous loss and homozygous deletion of exostosin 1/2 (EXT1/EXT2) genes have been reported in peripheral chondrosarcomas [47,53,54]. EXT mutations are also found in osteochondromas and are much more frequent than in peripheral chondrosarcomas, suggesting an EXT-independent pathogenesis of secondary peripheral chondrosarcomas [55].

Genomic profiling has revealed telomerase reverse transcriptase (TERT) gene amplification and ATRX mutations, in addition to TERT promoter mutations, in approximately 20% of high-grade chondrosarcomas and DDCS. These telomere gene abnormalities are accompanied by IDH1/IDH2 mutations, CDKN2A/2B deletions, and TP53 mutations, suggesting a possible association and synergistic effect between these genes in chondrosarcoma progression [56]. Therefore, treatments targeting telomerase may be effective for treating DDCS [57]. “

Reviewer 2 Report

Comments and Suggestions for Authors

This systematic review compared the 5-year survival rates between patients with localized dedifferentiated chondrosarcoma (DDCS) who underwent surgery plus adjuvant chemotherapy versus surgery alone. The results showed similar 5-year survival rates between the two groups (28.2% vs 24.0%), suggesting a limited effect of adjuvant chemotherapy on improving prognosis. The main issues with this article are as follows:

1.      The author's literature search strategy was confined to searching for "dedifferentiated chondrosarcoma" exclusively within titles and abstracts. This approach may lead to the omission of literature that comprehensively evaluates various pathological subtypes of chondrosarcoma. Such literature may not specifically mention dedifferentiated chondrosarcoma in their titles and abstracts.

2.      All included studies were retrospective non-randomized studies, which have inherent biases.

3.      The results of this study were negative, consistent with the current mainstream opinions, and did not yield any new conclusions.

4.      The two subtypes of DDCS (central and peripheral) were not analyzed separately due to the lack of sufficient outcome data based on subtypes. However, previous studies suggested potential biological differences between subtypes.

Author Response

Responses to the Reviewers

Thank you for your detailed and thoughtful comments regarding our manuscript. We believe that our paper has markedly improved as a result of your valuable comments and feedback.

Reviewer: 2

Comment

This systematic review compared the 5-year survival rates between patients with localized dedifferentiated chondrosarcoma (DDCS) who underwent surgery plus adjuvant chemotherapy versus surgery alone. The results showed similar 5-year survival rates between the two groups (28.2% vs 24.0%), suggesting a limited effect of adjuvant chemotherapy on improving prognosis. The main issues with this article are as follows:

1. The author's literature search strategy was confined to searching for "dedifferentiated chondrosarcoma" exclusively within titles and abstracts. This approach may lead to the omission of literature that comprehensively evaluates various pathological subtypes of chondrosarcoma. Such literature may not specifically mention dedifferentiated chondrosarcoma in their titles and abstracts.

Response:

Thank you for your pointing out. Among the articles that do not mention dedifferentiated chondrosarcoma in the title and abstract, it is unlikely that there is an article that specifies all of the following factor. The number of patients who received surgery and (neo-)adjuvant chemotherapy for localized dedifferentiated chondrosarcoma and how many of them survived for 5 years, and the number of patients who received only surgery for localized dedifferentiated chondrosarcoma and how many of them survived for 5 years. In addition, cited references were thoroughly examined by hand search. There are no missing articles.

Comment

2. All included studies were retrospective non-randomized studies, which have inherent biases.

Response:

We agree with you. This is stated in the limitaion. Ideally, an RCT would be necessary, however as dedifferentiated chondrosarcoma is a rare cancer, RCTs are expected to be difficult. We think a retrospective study with minimized bias is realistic.

Comment

3. The results of this study were negative, consistent with the current mainstream opinions, and did not yield any new conclusions.

Response:

Thank you for your valuable comments. We have added reports on basic research that may provide therapeutic targets for new treatments. We added the following sentences in the “Discussion” section; “In recent years, research has been conducted on the mechanisms of DDCS development and therapeutic targets. The BCL2 and TGFβ have been investigated as potential gene targets in DDCS [46]. Van Oosterwijk et al. used a microarray containing 42 dedifferentiated chondrosarcomas and performed immunohistochemistry to study the expression of growth plate signaling molecules. High expression of SOX-9 and FGFR-3 was observed, along with abnormal cellular localization of heparan sulfate proteoglycans [46]. TGFβ signaling through p-SMAD2 and PAI-1 was highly active, suggesting that TGFβ inhibitors may be a therapeutic option for DDCS [46]. Anti-apoptotic proteins (Bcl-2 and/or Bcl-xL) were also highly expressed in DDCS. Using an inhibitor with the BH-3 mimetic ABT-737 rendered the dedifferentiated chondrosarcoma cell lines sensitive to doxorubicin or cisplatin [46].

TP53 gene mutations are found in 20% of conventional chondrosarcomas and DDCS [47]. Studies have found a correlation between the overexpression of TP53 or its point mutations and tumors with a higher histological grade. This suggests a role for this gene in tumor progression [48]. Other frequently mutated genes in chondrosarcomas are related to the cell cycle process and control, including MDM2 and cyclin-dependent kinase 4 (CDK4), which inhibit p53 and are overexpressed in chondrosarcomas [49]. High expression of CDK4 and MDM2 correlated with a higher histological grade [50]. MDM2 overexpression has also been observed in DDCS [19]. The second most important pathway alteration involved in high-grade chondrosarcoma is in the retinoblastoma protein (pRB) pathway [50]. Deletion of CDKN2A/p16/INK4A, caused by the deletion of the 9p21 region, occurs more frequently in high-grade chondrosarcomas and DDCS [50,51]. This suggests the potential efficacy of CDK4 inhibitors [50].

Amplification of the c-MYC oncogene is present in approximately 20% of DDCS and correlates with poor prognosis, and molecular targeting of MYC expression may be useful in DDCS [52]. The heterozygous loss and homozygous deletion of exostosin 1/2 (EXT1/EXT2) genes have been reported in peripheral chondrosarcomas [47,53,54]. EXT mutations are also found in osteochondromas and are much more frequent than in peripheral chondrosarcomas, suggesting an EXT-independent pathogenesis of secondary peripheral chondrosarcomas [55].

Genomic profiling has revealed telomerase reverse transcriptase (TERT) gene amplification and ATRX mutations, in addition to TERT promoter mutations, in approximately 20% of high-grade chondrosarcomas and DDCS. These telomere gene abnormalities are accompanied by IDH1/IDH2 mutations, CDKN2A/2B deletions, and TP53 mutations, suggesting a possible association and synergistic effect between these genes in chondrosarcoma progression [56]. Therefore, treatments targeting telomerase may be effective for treating DDCS [57]. “

Comment

4. The two subtypes of DDCS (central and peripheral) were not analyzed separately due to the lack of sufficient outcome data based on subtypes. However, previous studies suggested potential biological differences between subtypes.

Response:

We agree with you. After many articles have been published that analyze central and peripheral dedifferentiated chondrosarcoma separately, it is necessary to perform a systematic review again and perform a meta-analysis separately for central and peripheral dedifferentiated chondrosarcoma. However, the current evidence is limited to what is shown in this manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors Thanks for submitting your manuscript I only have one main question/ comment Given the rarity of this diagnosis, do the authors feel a randomized control trial of only patients with dedifferentiated chondrosarcoma is feasible? Are there other options available to improve the current understanding of systemic therapy for this disease? eg. prospective multicentre registry or similar

Author Response

Responses to the Reviewers

Thank you for your detailed and thoughtful comments regarding our manuscript. We believe that our paper has markedly improved as a result of your valuable comments and feedback.

Reviewer: 3

Comment

Thanks for submitting your manuscript I only have one main question/ comment Given the rarity of this diagnosis, do the authors feel a randomized control trial of only patients with dedifferentiated chondrosarcoma is feasible? Are there other options available to improve the current understanding of systemic therapy for this disease? eg. prospective multicentre registry or similar

Response:

We agree with you. We think RCT will be difficult because dedifferentiated chondrosarcoma is a rare cancer. We suggest that dedifferentiated chondrosarcoma patients should be prospectively registered at multiple institutions after determining an adjuvant chemotherapy regimen, and then compare the treatment results with historical controls after minimizing bias by matching.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

After my second review, I find two additional issues that must be addressed.

First, over 40% patients enrolled in this study were from a single study by Grimer et al. This study should be excluded, or discussed seperately. 

Second, the authors omitted conducting subgroup analysis for unexpected heterogeneity and neglected to perform sensitivity analysis. Thus, they failed to investigate the sources of heterogeneity.

Author Response

Responses to the Reviewers

Thank you for your detailed and thoughtful comments regarding our manuscript. We believe that our paper has markedly improved as a result of your valuable comments and feedback.

Reviewer's comments:

Reviewer: 2

Comment

After my second review, I find two additional issues that must be addressed.

First, over 40% patients enrolled in this study were from a single study by Grimer et al. This study should be excluded, or discussed seperately.

Second, the authors omitted conducting subgroup analysis for unexpected heterogeneity and neglected to perform sensitivity analysis. Thus, they failed to investigate the sources of heterogeneity.

Response

We don't think it makes sense to conduct a separate meta-analysis of studies with a large number of patients just because they have a large number of patients. We added a discussion on the research by Grimer et al. “Grimer et al. reported that many patients were unexpectedly diagnosed as DDCS after curettage or marginal resection of what was thought to be atypical cartilaginous tumors [9]. Positive surgical margins were associated with poor prognosis [9]. Early diagnosis of DDCS before treatment is important to improve patient prognosis [9]. The dedifferentiation rate of atypical cartilaginous tumors has been reported to be 4–6% [53,54]. Studies have reported medium-term follow-up safety for atypical cartilaginous tumors of the long bone with active surveillance [46–48,50]. For active surveillance of atypical cartilaginous tumors of the long bone, magnetic resonance imaging (MRI) is recommended every 1 to 2 years [46–52]. A systematic review found that compared to atypical cartilaginous tumors, high-grade chondrosarcoma may more frequently exhibit the following MRI features: loss of entrapped fatty marrow, cortical　breakthrough, and extraosseous soft tissue expansion [55]. Therefore, if the above findings are observed on follow-up MRI, biopsy should be considered before surgery.”

Since the I² value indicating heterogeneity was 2%, heterogeneity was low, the collected studies were homogeneous, and the reliability of the pooled results was high. Please refer to Cochrane Handbook for Systematic Reviews of Interventions, Chapter 10: Analysing data and undertaking meta-analyses, https://training.cochrane.org/handbook.

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

I don't quite understand why there are numerous negative values for the odds ratios (OR), which should inherently range from 0 to positive infinity. Additionally, sensitivity analysis has not been conducted even in this particular scenario.

Author Response

Responses to the Reviewer

Thank you for your detailed and thoughtful comments regarding our manuscript. We believe that our paper has markedly improved as a result of your valuable comments and feedback.

Reviewer's comments:

Reviewer:

Comment

I don't quite understand why there are numerous negative values for the odds ratios (OR), which should inherently range from 0 to positive infinity. Additionally, sensitivity analysis has not been conducted even in this particular scenario.

Response

There was an input error in the statistical software. We have corrected the results and Figures 3 and 4. The odds ratio is now a positive number. We replaced the previous sentence with “The overall pooled odds ratio was 1.25 (95% confidence interval: 0.80–1.94; p = 0.324), and heterogeneity I² was 2%.” in the “Abstract” and “Results” section.

We performed sensitivity analysis and added it to the “Results” section. We have revised our conclusions accordingly.

We replaced the previous sentence with “However, when limited to peripheral DDCS, adjuvant chemotherapy was associated with prolonged survival (p = 0.03). The effect of adjuvant chemotherapy for localized central DDCS may be limited, however adjuvant chemotherapy for localized peripheral DDCS may be effective.” in the “Abstract” section.

We added the following sentence in the “Results” section; “Next, we limited the eligibility criteria to studies that distinguish between central or peripheral DDCS [8,9]. NAC was not associated with prolonged survival in localized central DDCS (p = 0.88) (Table 1) [8]. On the other hand, NAC was associated with prolonged survival in localized peripheral DDCS (p = 0.03) (Table 1) [9].”

We replaced the previous sentence with “However, there is only one study that investigated the effect of NAC on only peripheral DDCS, and according to that study, NAC was associated with prolonged survival in localized peripheral DDCS [9]. Hence, the effect of NAC for localized central DDCS may be limited, however NAC for localized peripheral DDCS may be effective.” in the “Discussion” section.

We replaced the previous sentence with “The effect of NAC for localized central DDCS may be limited, however NAC for localized peripheral DDCS may be effective.” in the “Conclusion” section.