前列腺癌时间治疗学：治疗时间对放疗疗效和生活质量的影响

Circadian-controlled genes influence numerous physiologic processes, including hormone regulation. Emerging evidence across cancer types suggests that aligning therapy delivery with circadian cycle (chronotherapy) may optimize efficacy and reduce toxicity. Given the hormone-sensitive nature of prostate cancer (PCa) and frequent use of androgen deprivation therapy (ADT) combined with external beam radiation therapy (EBRT), the timing of EBRT relative to circadian phase may modulate treatment response. Thus, we investigated whether time-of-day (TOD) of EBRT delivery is associated with PCa outcomes overall and by ADT status. Patients with localized PCa enrolled in the Center for Prostate Disease Research Multicenter National Database Study (2007-2023) were eligible for inclusion if treated with EBRT. TOD of EBRT was categorized as morning (≥80% of sessions before 10AM), afternoon (≥80% of sessions after 10AM), or mixed. Clinical endpoints included biochemical recurrence (BCR), metastasis, and death. Quality of life was longitudinally evaluated over 36 months via the Expanded Prostate Cancer Index Composite (EPIC). Cox proportion hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between TOD of EBRT and PCa outcomes. Kaplan-Meier analyses were used to examine survival. Among 339 included patients, 156 received morning EBRT, 137 afternoon EBRT, and 46 mixed TOD EBRT. On average, patients were 69.9 years old, had clinical stage T1 disease (78.8%), and had a PSA of 9.0 ng/mL at EBRT initiation. ADT was more often administered to afternoon (55.5%) and mixed TOD patients (58.7%) than morning patients (38.5%). Afternoon EBRT was not associated with death (HR=1.24, 95% CI 0.66-2.33) or BCR/metastasis (HR=1.37, 95% CI 0.66-2.85) relative to morning EBRT. Results were similar when stratified by ADT status. There were no differences in BCR-free, metastasis-free, or overall survival by TOD or ADT status. Overall, morning and afternoon patients reported similar EPIC scores; sexual function and bother scores were notably lower than other scores. Among those who received ADT, afternoon patients reported worse urinary bother (UB) and sexual bother (SB) scores ( p-values : UB month 36=0.04; SB month 18=0.01; SB month 30=0.04) than morning patients. Scores were similar among morning and afternoon patients who did not receive ADT. Within an equal-access healthcare setting, TOD of EBRT was not associated with oncologic outcomes for localized PCa. However, the combination of ADT and afternoon EBRT was associated with worse urinary and sexual quality of life, suggesting potential interaction between circadian regulated hormone signaling, ADT, and treatment timing. This study provides evidence that ADT may interact with TOD of PCa therapy and that further research in circadian biology, ADT timing, and chronotherapeutic optimization in PCa is warranted.