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

Abstract

Background 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. Methods 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). Results 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. Conclusion 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.

The Influence of Gene Aberrations on Survival in Resected IDH Wildtype Glioblastoma Patients: A Single-Institution Study

“…The best outcomes for glioma patients are achieved through aggressive multimodal therapy involving safe and maximal resection followed by chemoradiotherapy [ 28 ]. In the studied cohort, every eligible patient who had undergone defined resection was reevaluated for oncotherapy suitability.…”

Implementing targeted therapies in the treatment of glioblastoma: Previous shortcomings, future promises, and a multimodal strategy recommendation

“…Consequently, the widespread use of historic controls is a commonly mentioned explanation for the failed transitions between phase II and phase III trials. 23 All experimental agents that completed efficacy assessments in Phase II and thus transitioned onto a phase III trial have universally failed since 2005. 1 , 9 The drawback of single-arm studies with historic controls is that skipping contemporary controls might overestimate the effect of the experimental drug, especially if the survival of the control population has risen over time.…”

“… 1 , 9 The drawback of single-arm studies with historic controls is that skipping contemporary controls might overestimate the effect of the experimental drug, especially if the survival of the control population has risen over time. 23 However, these trials tend to be favored by clinicians as they require fewer recruited patients. 24 Generally, randomization can dismiss this risk of false positive results and mitigate confounders, although as mentioned they often require large sample sizes and are costly.…”

Next Steps for Immunotherapy in Glioblastoma

“…Many have deemed the use of historical controls as suboptimal due to potential differences in patient, disease, and therapeutic characteristics that subsequently confound results. Furthermore, historical controls face different survival trends when matched to contemporary patients, likely as a result of evolving therapeutic options [ 67 , 68 , 69 ]. Moving forward, the reliability of historical controls should continue to be kept in mind when designing clinical trials.…”