Sex differences in osteosarcoma survival across the age spectrum: A National Cancer Database analysis (2004–2016)

Background: Osteosarcoma displays a bimodal peak in incidence in adolescence and later adulthood. Males are more frequently diagnosed with osteosarcoma in both periods. Males have worse survival than females, which is generally poor at 30–70% 5-years post diagnosis, depending on age, but treatment received is often unaccounted for in survival analyses. Methods: Therefore, we estimated sex differences in survival for children and adults stratifying by treatment received and other disease characteristics using the National Cancer Database (2004–2016, n=9017). We estimated sex differences in long-term survival using Kaplan Meier survival curves and Log-Rank p-values. We also estimated hazard ratios (HR) and 95% confidence intervals (CIs) as the measure of association between sex and death using Cox regression. Results: In all age groups, cases were predominantly male (52–58%). In Kaplan-Meier analyses, males had worse overall survival than females for 0–19, 20–39, and ≥60-year-olds (Log-Rank p<0.05). Females had higher 5- and 10-year survival percentages in all age groups. In adjusted Cox models, males had a higher risk of death among 0–19-year-olds (HR_overall: 1.24, 95% CI: 1.06–1.44; HR_{non-metastatic disease}: 1.35, 95% CI: 1.12, 1.63, HR_{lower limb tumors}: 1.31, 95% CI: 1.09–1.59). Among 20–39-year-olds, males had an increased risk of death when receiving surgery only (HR: 4.67, 95% CI: 1.44, 15.09). Among those ≥60-year-olds, males had a suggestive increased risk of death overall (HR: 1.17, 95% CI: 0.99–1.39) and a higher risk of death based on some tumor locations, (HR_{upper limb}: 2.52, 95% CI: 1.24, 5.11; HR_midline: 1.36, 95% CI: 1.02, 1.82). Conclusions: Our findings suggest that the worse survival among young males compared to females with osteosarcoma persisted after accounting for many major disease characteristics, including treatment received. Collectively, our work points toward other unexplored mechanisms beyond treatment, potentially biologic or otherwise, which may be driving the observed sex differences in long-term survival.