Impact of chronotherapy and time-of-day on surgical and adjuvant outcomes in glioblastoma and mixed high-grade glioma patients: a systematic review.

[BACKGROUND] Circadian rhythms regulate DNA repair, cell-cycle progression, metabolism, and immune function processes central to glioblastoma (GBM) treatment response. Aligning therapy with intrinsic biological timing ("chronotherapy") may improve efficacy without increasing toxicity. This systematic review evaluated the impact of treatment time-of-day on outcomes in GBM, focusing on temozolomide (TMZ) administration, radiotherapy (RT) scheduling, and surgical timing.

[METHODS] Following PRISMA 2020 guidelines, PubMed, Embase, and Google Scholar were searched through October 2025 for original human studies of adults with GBM or high-grade glioma comparing outcomes by time-of-day exposure (PROSPERO-CRD420251185806). Eligible endpoints included overall survival (OS), progression-free survival (PFS), postoperative complications, and length of stay (LOS). Randomized and observational studies were assessed using RoB 2 and ROBINS-I tools, respectively, and synthesized narratively due to heterogeneity.

[RESULTS] Six studies met inclusion criteria: three on TMZ timing, two on RT timing, and one on surgical timing. Morning TMZ was associated with longer OS in a retrospective cohort (median 1.43 vs 1.13 years; HR 0.67, 95% CI 0.46-0.98) and a similar trend in a feasibility trial (20.3 vs 16.4 months), though a large pooled analysis from two EORTC trials showed no OS/PFS difference but higher myelosuppression with morning dosing. Afternoon RT improved OS (25.6 vs 18.5 months, p = 0.014) and PFS (20.6 vs 13.3 months, p = 0.022) in a circadian-synchronized cohort, while other RT and surgical studies reported no time-dependent effects.

[CONCLUSION] Available evidence suggests that treatment time-of-day may be associated with modest and context-dependent differences in adjuvant therapy outcomes in glioblastoma. Signals favoring morning temozolomide administration and afternoon radiotherapy are biologically plausible but inconsistent, while current data do not support a clinically meaningful effect of surgical timing. These findings should be considered hypothesis-generating, underscoring the need for prospective, biomarker-guided chronotherapy trials before clinical implementation.