In a phase III noninferiority trial (RAVES) reported in The Lancet Oncology, Kneebone et al found that salvage radiotherapy did not meet noninferiority criteria for biochemical progression vs adjuvant radiotherapy, but was associated with nearly identical biochemical control rates and reduced genitourinary toxicity among high-risk patients undergoing radical prostatectomy.
The trial included 333 patients from sites in Australia and New Zealand who had undergone radical prostatectomy. They were randomly assigned between March 2009 and December 2015 to receive adjuvant radiotherapy within 6 months (n = 166) or salvage radiotherapy prompted by a prostate-specific antigen (PSA) level of ≥ 0.20 ng/mL (n = 167). Patients had to have pathologic staging showing high-risk features—defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion—and a postoperative PSA level of ≤ 0.10 ng/mL. Radiotherapy in both groups was 64 Gy in 32 fractions. The primary endpoint was freedom from biochemical progression, defined as PSA of ≥ 0.40 ng/mL and rising from the previous value, in the intent-to-treat population. Noninferiority of salvage radiotherapy was considered to be achieved if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy (hazard ratio [HR] for salvage radiotherapy vs adjuvant radiotherapy of 1.48).
Median follow-up was 6.1 years. An independent data monitoring committee recommended early closure of enrollment due to unexpectedly low event rates. The study was underpowered for noninferiority. Overall, 84 patients (50%) in the salvage radiotherapy group underwent radiotherapy.
Freedom from biochemical progression at 5 years was 86% in the adjuvant radiotherapy group vs 87% in the salvage radiotherapy group (stratified HR = 1.12, 95% confidence interval [CI] = 0.65–1.90, P for noninferiority = .15). Rates at 8 years were 80% vs 75%.
Among 158 patients in the adjuvant radiotherapy group and 151 in the salvage radiotherapy group included in per-protocol analysis, 5-year freedom from biochemical progression was 86% vs 89% (stratified HR = 0.97, 95% CI = 0.53–1.78, P for noninferiority = .086). Rates at 8 years were 80% vs 77%.
Grade ≥ 2 genitourinary toxicity occurred in 54% of patients in the salvage radiotherapy group vs 70% of patients in the adjuvant radiotherapy group (odds ratio [OR] = 0.34, P = .0022). Grade ≥ 2 gastrointestinal toxicity occurred in 10% vs 14% (OR = 0.48, P = .53). Grade ≥ 2 erectile dysfunction occurred in 96% vs 98% of patients.
The investigators stated, “The RAVES trial shows similar biochemical control rates between adjuvant radiotherapy and early salvage radiotherapy with 5-year freedom from biochemical progression of 86% in the adjuvant radiotherapy group compared with 87% in the salvage radiotherapy group. Although the study was underpowered for noninferiority, these findings support our hypothesis that salvage radiotherapy does not have a freedom from biochemical progression rate that is more than 10% inferior to adjuvant radiotherapy.”
They concluded, “Salvage radiotherapy did not meet trial specified criteria for noninferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity.”
Andrew Kneebone, MBBS, of the Department of Radiation Oncology, Royal North Shore Hospital, Sydney, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the New Zealand Health Research Council, Australian National Health Medical Research Council, and others. For full disclosures of the study authors, visit thelancet.com.