Impact of High DosE rAdioTherapy (HEAT) in Localized Prostate Cancer: An Individual Patient Data (IPD) Meta-Analysis of 15 Randomized Trials.

PURPOSE/OBJECTIVE(S) Radiotherapy (RT) dose escalation for localized prostate cancer has not demonstrated improvement in overall survival (OS) from individual trials. It is unclear if the use of androgen deprivation therapy (ADT) effects the potential benefit of dose escalation. Therefore, to achieve sufficient power to answer this question, we performed a meta-analysis of randomized trials evaluating the benefit of RT dose escalation in localized prostate cancer. MATERIALS/METHODS The Meta-Analysis of Randomized clinical trials in Cancer of the Prostate (MARCAP) Consortium was formed to obtain IPD from multiple randomized controlled trials. Patients were categorized based on RT dose and use and duration of ADT. Short-term ADT (STADT) was defined as ≤6 months, long-term ADT (LTADT) as 18-36 months, and low and high dose RT as < or ≥74 Gy EQD2. IPD from 15 trials (n = 13,864 patients) were used. The primary endpoint of all analyses was OS, with metastasis-free survival (MFS) and the incidence of biochemical recurrence (BCR) as secondary endpoints. Sensitivity analyses using only trials with direct and relevant randomization (10 trials; n = 9,775 patients) were used to perform a network meta-analysis (NMA). RESULTS The median follow-up was 8.5 years (IQR 5.6-11.2). Escalating dose in the absence of ADT did not improve OS (HR 0.92, 95% CI 0.79-1.08) or MFS (HR 0.91, 95% CI 0.78-1.07). In the presence of STADT, high dose RT significantly improved OS (HR 0.79, 95% CI 0.67-0.94) and MFS (HR 0.80, 95% CI 0.68-0.94), as well as in the presence of LTADT for OS (HR 0.64, 95% CI 0.50-0.82) and MFS (HR 0.71, 95% CI 0.57-0.89). On sensitivity analysis using the NMA, dose escalation did not significantly improve outcomes in the absence of ADT (OS: HR 1.00, 95% CI 0.75-1.34; MFS: HR 0.97, 95% CI 0.67-1.41) or in the presence of STADT (OS: HR 0.95, 95% CI 0.54-1.67; MFS: HR 0.89, 95% CI 0.46-1.70) or LTADT (OS: HR 0.75, 95% CI 0.38-1.47; MFS: HR 0.78, 95% CI 0.36-1.67). In both the pooled comparison and the NMA, dose escalation improved BCR without ADT (NMA HR 0.53, 95% CI 0.32-0.88) in the presence of STADT (NMA HR 0.37, 95% CI 0.16-0.84), but not in the presence of LTADT (NMA HR 0.46, 95% CI 0.18-1.21). CONCLUSION Dose-escalation alone does not improve MFS or OS. In the presence of STADT or LTADT, the impact of dose-escalation differed when pooling non-randomized comparisons (which is prone to selection bias) versus performing an NMA restricted to only direct randomized comparisons (which is affected by limited network connectivity). BCR was more consistently improved. Given the uncertain impact on survival and the potential for increased toxicity, future studies using biomarker selection are needed to better personalize which patients benefit most from dose escalation.