Long-term trends in glioblastoma survival: implications for historical control groups in clinical trials

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Abstract
Historical controls continue to be used in early-phase brain tumor trials. We aim to show that historical changes in survival trends for glioblastoma (GBM) call into question the use of noncontemporary controls. We analyzed data from 46 106 primary GBM cases from the SEER database (1998-2016). We performed trend analysis on survival outcomes (2-year survival probability, median survival, and hazard ratios) and patient characteristics (age, sex, resection extent, and treatment type). In 2005-2016 (ie, the post–Stupp protocol era), fitting a parameter independently to each year, there was a demonstrable increase in median survival (R2 = 0.81, P < .001) and 2-year survival probability (R2 = 0.55, P = .006) for GBM. Trend analysis of the hazard ratio showed a significant time-dependent downward trend (R2 = 0.62, P = .002). When controlling, via multivariable Cox regression modeling, for age, sex, resection extent, and treatment type, there was a persistent downward trend in hazard ratios with increases in calendar time, especially in the most recent data. Contemporary GBM patients face a different overall hazard profile from their historical counterparts, which is evident in changes in measures of patient survival and parametric hazard modeling. Though there was a plateau in these measures before 2005 (pre–Stupp protocol), there is no evidence of a new plateau in recent years even when controlling for known prognostic factors (age, sex, resection extent, and treatment type), suggesting that it may be insufficient to match contemporary patients and noncontemporary controls on the basis of these factors.

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