Clinical Characteristics, Patterns of Care, and Treatment Outcomes of Radiation-Associated Osteosarcoma Compared to Spontaneous Osteosarcoma in a Large Single-Institution Series

Abstract

Second malignancies are among the most serious complications of radiation therapy (RT), but how their clinical behavior differs from primary malignancies of the same disease site remains incompletely understood. Osteosarcomas are among the most common radiation-associated malignancies. We sought to describe the clinical characteristics, patterns of care, and outcomes of radiation-associated osteosarcomas (RAOS) vs. spontaneous osteosarcomas (SOS). An institutional review board-approved single-institution retrospective cohort of 530 patients diagnosed with osteosarcoma between 1960 and 2015 was classified as having either RAOS (n = 56) or SOS (n = 474). Osteosarcomas were defined as radiation-associated if they occurred in a prior RT field at least 1 year after RT. Primary malignancies in patients who later developed RAOS occurred at a median age of 21 year (range: 2 mo-73 years) and included diverse histologies. Median time from primary malignancy to development of RAOS was 11 year (range: 1-41 year). Compared with SOS, RAOS occurred in older patients (median 46.5 year vs. 32 year, P = 0.029), were more centrally distributed (trunk 55.4% vs. 28.5%, extremity 19.6% vs. 53.4%, P = 0.00006), and were higher-grade (P = 0.049) but not later-stage (P = ns). Like SOS, RAOS were most commonly treated by surgery alone (53.6% vs. 58%, P = ns), with a significant minority receiving RT pre- and/or post-operatively (39.3% vs. 36.3%, P = ns). With a median follow-up of 44 mo, RAOS showed worse overall survival (OS; median = 3.5 years vs. 11.4 years; log-rank P = 0.003), progression-free survival (PFS, median 2.1 years vs. 4.1 years, P = 0.016), and local recurrence-free survival (LFS, median 4.6 years vs. not reached, P = 0.005). Among the 409 patients without distant metastatic disease at presentation, RAOS also showed worse distant metastasis-free survival (median 8.1 years vs. not reached, P = 0.04). On Cox multivariate analysis, RAOS vs. SOS remained significant for worse OS (HR = 2.10, 95% CI = 1.38-3.20, P = 0.0005), PFS (HR = 1.73, 95% CI = 1.17-2.56, P = 0.006), and LFS (HR = 2.02, 95% CI = 1.22-3.33, P = 0.006) after adjusting for other variables. Despite apparent similarity to SOS, RAOS in fact display distinct clinical characteristics and suffer worse outcomes. These findings suggest the need for further investigation into the biological basis of these differences as well as treatment strategies to address them.