Dose-escalated radiotherapy for clinically localized and locally advanced prostate cancer.

Background: Treatments for clinically localized prostate cancer include radical prostatectomy, external beam radiation therapy, brachytherapy, active surveillance, hormonal therapy, and watchful waiting. For external beam radiation therapy, oncological outcomes may be expected to improve as the dose of radiotherapy (RT) increases. However, radiation-mediated side effects on surrounding critical organs may also increase.

Objectives: To assess the effects of dose-escalated RT in comparison with conventional dose RT for curative treatment of clinically localized and locally advanced prostate cancer.

Search Methods: We performed a comprehensive search using multiple databases including trial registries and other sources of grey literature, up until 20 July 2022. We applied no restrictions on publication language or status.

Selection Criteria: We included parallel-arm randomized controlled trials (RCTs) of definitive RT in men with clinically localized and locally advanced prostate adenocarcinoma. RT was dose-escalated RT (equivalent dose in 2 Gy [EQD] ≥ 74 Gy, lesser than 2.5 Gy per fraction) versus conventional RT (EQD < 74 Gy, 1.8 Gy or 2.0 Gy per fraction). Two review authors independently classified studies for inclusion or exclusion.

Data Collection And Analysis: Two review authors independently abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of the evidence of RCTs.

Main Results: We included nine studies with 5437 men in an analysis comparing dose-escalated RT versus conventional dose RT for the treatment of prostate cancer. The mean participant age ranged from 67 to 71 years. Almost all men had localized prostate cancer (cT1-3N0M0). Primary outcomes Dose-escalated RT probably results in little to no difference in time to death from prostate cancer (hazard ratio [HR] 0.83, 95% CI 0.66 to 1.04; I = 0%; 8 studies; 5231 participants; moderate-certainty evidence). Assuming a risk of death from prostate cancer of 4 per 1000 at 10 years in the conventional dose RT group, this corresponds to 1 fewer men per 1000 (1 fewer to 0 more) dying of prostate cancer in the dose-escalated RT group. Dose-escalated RT probably results in little to no difference in severe RT toxicity of grade 3 or higher late gastrointestinal (GI) toxicity (RR 1.72, 95% CI 1.32 to 2.25; I = 0%; 8 studies; 4992 participants; moderate-certainty evidence); 23 more men per 1000 (10 more to 40 more) in the dose-escalated RT group assuming severe late GI toxicity as 32 per 1000 in the conventional dose RT group. Dose-escalated RT probably results in little to no difference in severe late genitourinary (GU) toxicity (RR 1.25, 95% CI 0.95 to 1.63; I = 0%; 8 studies; 4962 participants; moderate-certainty evidence); 9 more men per 1000 (2 fewer to 23 more) in the dose-escalated RT group assuming severe late GU toxicity as 37 per 1000 in the conventional dose RT group. Secondary outcomes Dose-escalated RT probably results in little to no difference in time to death from any cause (HR 0.98, 95% CI 0.89 to 1.09; I = 0%; 9 studies; 5437 participants; moderate-certainty evidence). Assuming a risk of death from any cause of 101 per 1000 at 10 years in the conventional dose RT group, this corresponds to 2 fewer men per 1000 (11 fewer to 9 more) in the dose-escalated RT group dying of any cause. Dose-escalated RT probably results in little to no difference in time to distant metastasis (HR 0.83, 95% CI 0.57 to 1.22; I = 45%; 7 studies; 3499 participants; moderate-certainty evidence). Assuming a risk of distant metastasis of 29 per 1000 in the conventional dose RT group at 10 years, this corresponds to 5 fewer men per 1000 (12 fewer to 6 more) in the dose-escalated RT group developing distant metastases. Dose-escalated RT may increase overall late GI toxicity (RR 1.27, 95% CI 1.04 to 1.55; I = 85%; 7 studies; 4328 participants; low-certainty evidence); 92 more men per 1000 (14 more to 188 more) in the dose-escalated RT group assuming overall late GI toxicity as 342 per 1000 in the conventional dose RT group. However, dose-escalated RT may result in little to no difference in overall late GU toxicity (RR 1.12, 95% CI 0.97 to 1.29; I = 51%; 7 studies; 4298 participants; low-certainty evidence); 34 more men per 1000 (9 fewer to 82 more) in the dose-escalated RT group assuming overall late GU toxicity as 283 per 1000 in the conventional dose RT group. Based on long-term follow-up (up to 36 months), dose-escalated RT may result or probably results in little to no difference in the quality of life using 36-Item Short Form Survey; physical health (MD -3.9, 95% CI -12.78 to 4.98; 1 study; 300 participants; moderate-certainty evidence) and mental health (MD -3.6, 95% CI -83.85 to 76.65; 1 study; 300 participants; low-certainty evidence), respectively.

Authors' Conclusions: Compared to conventional dose RT, dose-escalated RT probably results in little to no difference in time to death from prostate cancer, time to death from any cause, time to distant metastasis, and RT toxicities (except overall late GI toxicity). While dose-escalated RT may increase overall late GI toxicity, it may result, or probably results, in little to no difference in physical and mental quality of life, respectively.