A Phase III Multi-Centre Randomised Trial comparing adjuvant versus early salvage Radiotherapy following a Radical Prostatectomy: Results of the TROG 08.03 and ANZUP “RAVES” Trial

Abstract

Adjuvant radiotherapy (ART) has been shown to nearly halve the risk of biochemical failure (BF) for high risk post prostatectomy patients. The RAVES trial aimed to test the hypothesis that observation with early salvage radiotherapy (SRT) is not inferior to ART with respect to biochemical failure in patients with high risk disease after radical prostatectomy (RP). Eligible patients needed to have either extraprostatic extension, seminal vesicle invasion (SVI) or positive surgical margins (PSM) and have a postoperative PSA ≤0.10ng/ml. Patients were randomised 1:1 to either ART commencing within 6 months of RP or close observation with early SRT triggered by a PSA level of ≥0.20ng/ml. RT plans were reviewed in real time and utilised 3D CRT or IMRT/VMAT to a dose of 64Gy/32# to the prostate bed alone without androgen deprivation (AD). Primary aim was to exclude a 10% inferiority in Freedom from Biochemical Failure (FFBF) in the SRT arm corresponding to 5-year FFBF rates of 74% (ART) and 64% (SRT) and a hazard ratio (HR) of 1.48. BF was defined as a PSA rise to 0.40 or higher or commencement of AD after RT. Analysis was on an intention to treat basis. 333 patients were randomised (n=166 ART; n=167 SRT) across 32 institutions in Australia and New Zealand between March 2009 and December 2015. Median follow up was 6.1 years. The Independent Data Monitoring Board recommended that enrolment close early based on interim analyses showing that further recruitment to reach the target of 470 was unlikely to substantially increase power due to an unexpectedly low event rate. Mean age in both arms was 63 years. 16% in ART had a high Gleason Score (8-10) compared with 15% in SRT. SVI was seen in 19% of ART and 20% with SRT. PSM occurred in 66% of ART and 68% of the SRT groups. 84 SRT patients (50.3%) had their PSA rise to 0.2, triggering SRT, of which 80 received SRT. The 5 year FFBF rates were 86% (95% CI [79%, 91%]) in the ART arm compared with 88% (95% CI [82%, 92%]) in the SRT arm. The 8 year rates were 79% with ART (95% CI [68%, 87%]) and 76% (95% CI [65%, 84%]) with SRT. The hazard ratio for the SRT arm was 1.03 (90% CI [0.65, 1.63], p=0.91). The corresponding 90% range in absolute difference between SRT and ART at 5 years was from SRT 5.8% inferior to SRT 5.1% superior. Six percent of patients in the ART arm developed evidence of local, regional or distant failure by 8 years compared with 5% in the SRT group. The grade 2+ GU toxicity rate was lower in the SRT arm (OR 0.34, 95% CI [0.17, 0.68], p=0.002) with no significant difference in grade 2+ GI toxicity rate (OR 0.48, 95% CI [0.047, 4.88], p=0.53). Similar FFBF rates were shown between ART and SRT, but we did not meet the protocol defined level set for non-inferiority. SRT spares approximately half of men from pelvic radiotherapy, and is associated with significantly lower levels of GU toxicity.