Meta-analyses have demonstrated a dose-response relationship for prostate cancer and biochemical control.rr The Zaorksy meta-analysis of 12 randomised trials, including 6884 patients treated with EBRT, showed increasing biologically equivalent dose was associated with a 7.2% improvement in 10-year freedom from biochemical failure, for men with intermediate-risk prostate cancer. However, dose escalation has not been shown in any prospective studies to improve prostate cancer-specific survival or overall survival.
Evidence supporting moderate hypofractionation for intermediate-risk prostate cancer is not discussed within this protocol, but can be found in the evidence and efficacy sections of ID 3370 Prostate adenocarcinoma definitive EBRT hypofractionation.
Androgen Deprivation Therapy
Multiple randomised trials have demonstrated an improvement in disease outcomes when short-term ADT (4-6 months) was given in addition to radiation therapy.
- In RTOG 9408, 1979 patients (mainly low and intermediate-risk) were randomised to 66.6 Gy radiation therapy with or without 4 months of ADT (ADT commencing 2 months before radiation therapy). At a median follow-up of 9.1 years there was a benefit for short-term ADT and radiation therapy in 10-year overall survival (62% vs 57%, p = 0.03), disease-specific mortality (8% vs 4%, p = 0.001) and incidence of distant metastases.r
- D'Amico published a small study of 206 patients (75% with intermediate-risk disease) randomised to 70 Gy 3D CRT plus 6 months ADT.r The addition of ADT resulted in significantly higher overall survival and prostate cancer-specific survival, compared to radiation alone. 8-year overall survival rates were 74% (95% CI:64-82%) for radiation therapy plus ADT vs 61% (95% CI:49-71%) for radiation therapy alone.
The trials above used lower radiation doses than what is considered standard in contemporary practice. EORTC 22991 was a randomised study of 819 patients with intermediate (75%) or high-risk (25%) prostate cancer, comparing radiation therapy alone to radiation therapy plus 6 months ADT.r The radiation doses prescribed were 70 Gy, 74 Gy or 78 Gy, and ADT was given during and following radiation. After a median follow-up of 7.2 years, the addition of ADT to radiation therapy improved biochemical progression-free survival, compared to radiation alone (HR = 0.52, CI:0.41-0.66, p <0.001). Improvement in clinical progression-free survival was also statistically significant, 88.7% with radiation plus ADT vs 80.8% with radiation alone (HR = 0.63, 95% CI:0.48-0.84, p = 0.001). Overall survival data are not yet mature. In exploratory analysis, there was no statistically significant interaction between treatment effect and radiation dose.
In a network meta-analysis of 6 randomised trials comparing radiation therapy with or without ADT in 4663 men, the addition of ADT improved overall survival (HR = 0.70, 95% CI:0.62-0.81).r This analysis was repeated as a sensitivity analysis of the subset of randomised trials, treating mostly men with intermediate-risk prostate cancer, and found similar estimates (HR = 0.73, 95% CI:0.51-1.04).
Some patients may have a very small benefit from the addition of ADT. The risks versus benefits should be considered on an individual patient basis. For further information related to ADT agents and toxicities refer to eviQ medical oncology for urogenital cancers.