RE: Effect of chemotherapy and surgery timing on mortality in upper and lower extremity osteosarcoma

Since the 1970s, multiagent chemotherapy has clinically improved the survival of patients with osteosarcoma, with 5-year survival rates increasing from 10%-20% to 60%-70%.¹ Although the current standard of care recommends preoperative chemotherapy to shrink tumors and thereby increase the likelihood of limb-sparing surgery, evidence has been presented that the survival benefit of preoperative chemotherapy is not significant.² It was with great interest that we read the recently published study by Danese et al.³ in this issue of the Journal. The study compared the difference in 5-year survival between 2 strategies—surgery first and chemotherapy first—by analyzing data from the Surveillance, Epidemiology, and End Results (SEER) database of patients with osteosarcoma of the extremities between 2000 and 2020.³ The study provides new observational data on treatment strategies for osteosarcoma, particularly by analyzing data from a large SEER sample, and further validates the survival benefit of the surgery-first strategy for patients under certain conditions. The study found that the 5-year survival rate in the surgery-first group was 74% compared with 67% in the chemotherapy-first group, a 6.9% improvement in survival, although the difference was not statistically significant. However, there are several points in the study that need to be clarified.

First, the chemotherapy variables in the SEER database are binary and do not provide detailed records of the type of chemotherapy regimen, specific drug combinations, dose intensity, and duration of treatment. This oversimplification may affect the true assessment of chemotherapy effectiveness because different chemotherapy regimens may differ clinically in terms of efficacy and side effects. For example, dose-intensive chemotherapy differs from standard chemotherapy in terms of efficacy and toxicity, and such differences, which were not differentiated in the data analysis, may lead to an overestimation or underestimation of efficacy in chemotherapy-referred groups. In addition, actual clinical details such as completion of postoperative chemotherapy, treatment interruptions, and dose reductions were not captured in the data, and these factors may affect the long-term survival of patients.

Second, the timing of a patient’s diagnosis may result in inconsistent follow-up periods. Patients diagnosed earlier will have longer follow-up, whereas patients diagnosed later may have insufficient follow-up, which could affect the assessment of long-term survival. In addition, the data cutoff date of December 2020 also means that some patients diagnosed later may have been incorrectly considered “alive” during the follow-up period. Inconsistent follow-up may introduce bias between the 2 survival datasets, making comparisons of 5-year survival less reliable.

Third, although the study attempted to control for confounding factors such as age, sex, tumor size, and stage, other important factors influencing treatment decisions were not documented in the SEER database. For example, health status, surgical risk, economic conditions, and family support may influence a physician‘s choice of treatment and patient compliance. These factors may affect the effectiveness of implementation of treatment strategies and may also differ clinically between the surgery-preferred and chemotherapy-preferred groups, which could affect the results of the survival comparison.

Finally, studies have focused only on differences in overall survival but have not performed detailed subgroup analyses for specific subgroups (eg, tumor stage, tumor size, pathology type). For example, patients with advanced stage disease may be better suited to a surgery-first strategy, whereas patients with early stage disease may be better suited to a chemotherapy-first strategy. Failure to refine patient subgroups may have masked differences in the effectiveness of treatment strategies among patients with different characteristics, limiting the generalizability of the results. Future studies could explore the conditions under which surgery-first or chemotherapy-first strategies provide the best outcomes by analyzing different subgroups, allowing for more precise treatment decisions.

Author contributions

Liang Liu, MD (Conceptualization; Methodology), Yan Xiao, MD (Investigation; Writing—original draft), ShengYao Liu, MD (Validation; Visualization; Writing—review & editing), Zufeng Ye, PhD, MD (Funding acquisition; Project administration; Resources), and Wei Liu, PhD, MD (Formal analysis; Investigation; Writing—original draft).

Funding

Hunan Provincial Department of Science and Technology Xiangkeji [2023] No. 18 Key R&D Program: 2023SK2044; Hunan Provincial Natural Science Foundation Upper-level Project: 2022JJ30546; Hengyang Science and Technology Innovation Program Basic Research Project: 202150063656; Scientific Research Project of Hunan Provincial Department of Education: 19C1567.

Conflicts of interest

All authors declare no conflicts of interests for this study.

Data availability

Our article does not cover the data.

Author notes

L. Liu and Y. Xiao contributed equally to this article.