Conventional Versus Hypofractionated Radiation Therapy for Localized Prostate Cancer: A Meta-analysis of Randomized Noninferiority Trials

Trevor Joseph Royce, Dong Hoon Lee, NaNa Keum, Nitipong Permpalung, Calvin J Chiew, Sherise Epstein, Kristen M Pluchino, Anthony V D'Amico

Whether hypofractionated radiation therapy (RT) compared with conventionally fractionated RT provides comparable or possibly improved cancer control without increased toxicity in localized prostate cancer (PC) remains unknown. Realizing from the CHHiP trial that outcomes are highly sensitive to the dose fractionation schedule and number of treatments, we conducted a systematic review and meta-analysis selecting only the randomized noninferiority trials, because the randomized arms closely approximated one another in terms of the dose fractionation schedule, and compared cancer control and toxicity of hypofractionated RT with conventionally fractionated RT for localized PC. Randomized noninferiority trials evaluating hypofractionated (2.4-4Gy daily fractions for 15-30 treatments) versus conventionally fractionated RT (1.8-2Gy daily fractions for 40-45 treatments) in men with localized PC were selected. Studies that were not noninferiority trials, used extreme hypofractionation, or treated metastatic disease were excluded. Three studies were retained for analysis. Data were pooled using a random-effects model to determine hazard ratio (HR) and risk ratio (RR). Heterogeneity was assessed via chi-square test, I2 statistics, and metaregression. The primary outcome was disease-free survival (DFS), defined as death from any cause or biochemical, local, regional, or distant progression. Of the 5484 men, 3553 (64.8%) had intermediate-risk PC. Hypofractionated RT as compared with conventionally fractionated RT was associated with significantly improved DFS (HR 0.869; 95% confidence interval [CI], 0.757, 0.998; p=0.047), whereas overall survival was not (HR 0.84; 95% CI, 0.66, 1.07; p=0.16). Acute grade 2 or higher gastrointestinal toxicity was significantly increased with hypofractionation (RR 1.42; 95% CI 1.15, 1.77; p=0.002); however, this did not translate into late grade 2 or higher gastrointestinal toxicity. An increase in late grade 2 or higher genitourinary complications was observed (RR 1.18; 95% CI 0.98, 1.43; p=0.08). Hypofractionated RT as compared with conventionally fractionated RT could improve DFS in men with intermediate-risk PC and, therefore, would be reasonable to consider in men who do not have risk factors for late genitourinary complications. Treatment with a shorter course of radiation, using higher doses per treatment over fewer days, may be the preferred approach in appropriately selected patients with localized prostate cancer.