Temozolomide chemotherapy for patients with newly diagnosed glioblastoma in the CENTRIC EORTC 26071-22072 and CORE trials: Does time of administration matter?

Background Preclinical work and retrospective studies suggest that temozolomide chemotherapy in glioblastoma may be more effective when administered in the morning rather than the evening. Here we examine the effect of timing in a large cohort of patients in 2 contemporaneous randomized clinical trials. Methods We assessed toxicity and survival data in patients with newly diagnosed glioblastoma enrolled in the CENTRIC EORTC 26071-22072 (n = 545, MGMT methylated) and CORE (n = 265, MGMT unmethylated) trials. We compared the outcome and toxicity of patients who took maintenance (adjuvant) temozolomide (TMZ) either in the morning (TMZ-m), afternoon (TMZ-a) or in the evening (TMZ-e). Results In CENTRIC and CORE, n = 102/260 (39%) and 50/198 (25%) received TMZ in the morning versus n = 35/260 (13%) and 34/198 (17%) in the evening. There was no difference in overall survival (OS) between the TMZ-m and TMZ-e groups (CENTRIC: adjusted mOS 20.6 months (95% confidence interval [CI], 18.4-23.4) TMZ-m vs 21.1 months (95% CI, 18.4-24.5) TMZ-e; adjusted hazard ratio (HR), 0.93 (95% CI, 0.63-1.39); P = .7; CORE: adjusted mOS, 10.9 months (95%CI, 9.7-11.8) TMZ-m vs 11.4 months (95%CI, 9.9-12.9) TMZ-e; adjusted HR, 0.87, 95%CI, 0.55-1.38); P = .6). The TMZ-m group had a higher proportion of bone marrow toxicity (CENTRIC: TMZ-m 33% vs TMZ-e 11%, P = .013, CORE: TMZ-m 24% vs TMZ-e 3%, P < .01). Conclusion In this post hoc analysis, we found no difference in outcome based on the time of TMZ administration. Bone marrow toxicity might occur more frequently when temozolomide is administered in the morning. Given the limitation to data from deceased patients only, these analyses should be viewed as exploratory only.