Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data

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Background It is unclear whether adjuvant or early salvage radiotherapy following radical prostatectomy is more appropriate for men who present with localised or locally advanced prostate cancer. We aimed to prospectively plan a systematic review of randomised controlled trials (RCTs) comparing these radiotherapy approaches. Methods We used a prospective framework for adaptive meta-analysis (FAME), starting the review process while eligible trials were ongoing. RCTs were eligible if they aimed to compare (immediate) adjuvant radiotherapy (ART) versus early salvage radiotherapy (SRT), following radical prostatectomy in men with intermediate or high-risk, localised or locally advanced prostate cancer. We searched trial registers and conference proceedings until April 2019 to identify eligible RCTs. By establishing the ARTISTIC collaboration with relevant trialists, we were able to anticipate when eligible trial results would emerge, and we developed and registered a protocol prior to knowledge of the trial results (CRD42019132669). We included a harmonised definition of PSA-driven, event-free survival (EFS), and predicted when we would have sufficient power to assess whether ART was superior to SRT. Investigators supplied results for EFS, both overall and within pre-defined patient subgroups. Hazard ratios (HRs) for the effects of radiotherapy timing on EFS and subgroup interactions were combined using fixed-effect meta-analysis. Findings We identified 3 eligible trials and were able to obtain updated EFS results for 2153 men (100% of those randomised). Median follow-up ranged from 60 to 78 months. 1075 men were randomised to receive ART and 1078 to a policy of SRT, of whom, 421 (39%) had commenced treatment at the time of analysis. Patient characteristics were balanced within trials and overall. Men had median age of around 65 years and most (78%) had a Gleason sum score of 7. All trials were assessed as having low risk of bias. Based on 270 EFS events, the meta-analysis showed no evidence that EFS was improved with ART compared to a policy of SRT (HR=0.95, 95% CI=0.75-1.21, p=0.70), with only a 1% change in 5-year EFS (89% vs. 88%). Results were consistent across trials (heterogeneity p=0.18; I2=42%). Although power is limited, we did not see any strong evidence of a difference in the treatment effect according to any of the patient or disease characteristics assessed. Interpretation This collaborative, and prospectively-designed systematic review and meta-analysis suggests that ART does not improve EFS in men with localised or locally advanced prostate cancer. Until data on long-term outcomes are available, early salvage treatment would seem the preferable treatment policy as it offers the opportunity to spare many men from RT and its associated side-effects. Funding This work is funded by the UK Medical Research Council study (MC_UU_12023/25)