Variation over time and interdependence between disease progression and death among patients with glioblastoma (GBM) on RTOG 0525.

2017 Background: We assessed the longitudinal hazard characteristics for death and progression in newly diagnosed GBM patients, evaluated the impact of prognostic factors and treatment on the hazard within different time intervals to determine if effects are time-variant, and quantified the prognostic influence of disease progression on survival. METHODS Among patients randomized to Radiation Therapy Oncology Group (RTOG) 0525 comparing dose-dense (dd) with standard dose (sd) temozolomide (TMZ), we estimated the death and failure (death or progression) hazards over time, compared the hazard difference between subgroups within time intervals, and assessed the effect of disease progression on survival. RESULTS In the entire group, the peak hazard of death occurred from 9 to 24 months with a slow decline after that; the average monthly hazards are 2.9%, 6.07%, and 3.71%, respectively for three intervals: prior to 9, 9-24 and after 24 months; the hazard of progression/death reached a peak around 6 months (interval of 0 to prior to 9 months) with the average monthly hazard of 11.06% and decreased dramatically thereafter. Patients with better prognosis (MGMT methylated tumor and RPA III) had a lower hazard at all intervals. The relative benefit (longer survival) of MGMT methylated vs unmethylated was substantial in the first 2.5 years, but was diminished thereafter. The relative benefit (longer progression-free survival) of dd over sd TMZ occurred in the first 6 months (hazard ratio (HR): 0.70; 95% CI: 0.58-0.86); p<0.001), although it was diminished thereafter. After adjusting RPA class and MGMT methylation status, the HR of death for patients who had progressed over non-progressors was 6.59 (95% CI: 5.12-8.43, p<0.001). CONCLUSIONS Hazards over time reveal changes in the risk that may have biologic and therapeutic relevance. After the peak hazard of death between 9 and 24 months, a consistently high hazard remains, but it is lower than in the peak period. The rate of dying after progression is about 6.59 times the rate for non-progressors; suggesting that progression free survival is a relevant clinical endpoint. Supported by NCI U10 CA 21661 and U10 CA37422.