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BACKGROUND: The histologic response of osteosarcoma to chemotherapy is commonly cited as a prognostic factor and typically graded as the percent necrosis of the tumor at the time of surgical resection. Few studies, to our knowledge, have examined the relationship of tumor necrosis relative to other factors. Existing studies are limited by prolonged enrollment periods or analysis of patient subsets without the strongest predictor of mortality: metastasis at diagnosis. Additionally, the definitive threshold value for a good histologic response is commonly set at more than 90% tumor necrosis with little evidence; some authors advocate other values. QUESTION/PURPOSES: (1) Are there alternative cutoff values for a good response to chemotherapy in a large, national cohort of contemporarily treated patients with osteosarcoma? (2) How does the association of histologic response to survival in osteosarcoma compare with other clinicopathologic factors? (3) What patient and clinical factors are associated with the histologic response? METHODS: We identified 2006 patients with osteosarcoma diagnosed between 2010 and 2015 in the National Cancer Database (NCDB), a registry that includes 70% of all new cancers diagnosed in the United States with 90% follow-up. Patients were excluded for missing documentation of percent tumor necrosis (21% 425 of 2006) or if definitive resection was not performed ( 0.05). Necrosis of less than 90% was associated with worse survival (HR 2.00 95% CI 1.58 to 2.52; p < 0.001 compared with more than 90% necrosis), and factors most associated with poor survival were metastasis (HR 2.85 95% CI 2.27 to 3.59; p < 0.001) and skip metastasis at the time of diagnosis (HR 2.52 95% CI 1.64 to 3.88; p < 0.001). On multivariate analysis, adjusting for demographic, clinicopathologic, and treatment factors, social determinants of health were negatively associated with percent necrosis of 90% or more, including uninsured status (OR 0.46 95% CI 0.23 to 0.92; p = 0.02 compared with private insurance) and lower socioeconomic status composite (OR for the lowest first and second quartiles were 0.63 95% CI 0.44 to 0.90; p = 0.01 and 0.70 95% CI 0.50 to 0.96; p = 0.03, respectively). Race other than White or Black (OR 0.61 95% CI 0.40 to 0.94; p = 0.02 compared with White race) was also negatively associated with percent necrosis of more than 90% after controlling for available covariates. CONCLUSION: This study suggests that a cutoff of 90% necrosis provides the best prognostic value for patients with osteosarcoma undergoing chemotherapy. Other threshold values did not show different survival benefits. Sociodemographic factors were associated with histologic response less than 90%. These associations must be carefully understood not as cause and effect but likely demonstrating the effects of health disparities and access to care. Although we controlled for multiple variables in our analysis, broad variables such as race may have been associated with histologic response due to unaccounted confounders. Medical providers should be aware of these associations to ensure equitable access and delivery of care because access to care may be responsible for these associations. Future studies should examine potential drivers of this observation, such as a delay in presentation or deviation from standard of care practices. LEVEL OF EVIDENCE: Level III, therapeutic study.
Richardson et al. (Tue,) studied this question.