Three randomized trials and a meta-analysis of the trials failed to show a significant effect of adjuvant radiotherapy on biochemical progression or combined clinical events after radical prostatectomy for early, high-risk prostate cancer.
In the largest of the three trials, salvage radiotherapy was associated with a 3% absolute advantage for biochemical progression-free survival (bPFS) at 5 years, although the difference did not reach statistical significance. One of the smaller trials showed absolute difference in bPFS of 1% at 6 years in favor of salvage therapy, whereas the other showed a nonsignificant 2% higher event-free survival (EFS) with salvage radiotherapy.
The meta-analysis, which included 2,153 randomized patients, yielded a 5-year EFS of 89% with adjuvant radiotherapy and 88% with salvage therapy, also not significant.
The largest of the trials and the meta-analysis were published simultaneously in the Lancet, and the two smaller trials in the Lancet Oncology.
Collectively, the trials had some limitations and potential confounders that left the door open for a beneficial effect of adjuvant radiotherapy in selected patients, according to the authors of an accompanying commentary. For example, one of the randomized trials included patients who normally would skip radiotherapy because of low clinical risk, while another trial had a potential time bias for assessment of bPFS after salvage radiotherapy. Also, use of hormonal therapy varied.
“Nonetheless, the four studies represent an important step forward and support the use of early salvage as opposed to adjuvant radiotherapy for many patients after radical prostatectomy, with the possible exception of those at high risk for progression…which comprised less than 20% of men in the three randomized trials, and for whom shared patient and clinician decision making should be considered,” wrote Derya Tilki, MD, of University Hospital Hamburg-Eppendorf in Germany, and Anthony V. D’Amico, MD, PhD, of Dana Farber Cancer Institute in Boston.
Follow-up continues in the RADICALS-RT randomized trial, which has a primary endpoint of metastasis-free survival. However, as previously reported, the analysis of bPFS showed no significant benefit with adjuvant radiotherapy. The trial included 1,396 patients with localized prostate cancer associated with at least one high-risk characteristic (pathologic T-stage 3 or 4, Gleason score 7-10, positive surgical margins, or preoperative PSA ≥10 ng/mL).
All patients underwent radical prostatectomy and were randomized to early adjuvant radiotherapy or to a watch-and-wait strategy of salvage irradiation. In the adjuvant group, radiation therapy was delivered within 6 months in 93% of patients, whereas a third of patients in the salvage group received radiotherapy within 8 years of surgery.
The 5-year bPFS was 85% with adjuvant therapy and 88% with salvage therapy, representing a nonsignificant 10% increase in the risk of biochemical progression in the adjuvant group (95% CI 0.81-1.49, P=0.56). Additionally, adjuvant radiation therapy was associated with a higher incidence of urinary morbidity, reported Matthew R. Sydes, MD, of University College London, and colleagues.
Conducted in Australia and New Zealand, data analysis for the phase III RAVES trial included 333 patients with high-risk features. The trial had a median follow-up of 6.1 years, and enrollment closed prematurely because of slow enrollment, reported Andrew Kneebone, MD, of Royal North Short Hospital in Sydney, and colleagues.
Patients were randomized to adjuvant radiotherapy within 6 months of radical prostatectomy or to salvage irradiation triggered by a rise in PSA of 0.20 ng/mL or more. The trial had statistical power to demonstrate noninferiority of salvage radiotherapy, defined as a 5-year bPFS within 10% of the rate for adjuvant radiotherapy.
The results showed a 5-year bPFS of 86% with adjuvant radiotherapy versus 87% with salvage radiotherapy (HR 1.12, 95% CI 0.65-1.90, P=0.15). Patients allocated to adjuvant radiation therapy had a higher incidence of grade ≥2 genitourinary toxicity.
Although the trial failed to meet prespecified statistical criteria for noninferiority, “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,” the authors concluded.
The GETUG-AFU17 randomized trial included 424 patients enrolled at 46 hospitals in France. The trial closed early because of a lower-than-expected clinical event rate. Following radical prostatectomy, all patients received standardized hormonal therapy and were randomized to immediate or delayed radiotherapy. The primary endpoint was EFS, defined as disease relapse (locoregional or metastatic), biochemical progression, or death.
After a median follow-up of 75 months, the adjuvant group had a 5-year EFS of 92% versus 90% for the patients allocated to delayed radiation therapy (HR 0.81, 95% CI 0.48-1.36, P=0.42). Late grade ≥2 genitourinary toxicities and genitourinary adverse events occurred in about three times as many patients in the adjuvant arm, reported Paul Sargos, MD, of Institut Bergonie in Bordeaux, and colleagues.
The meta-analysis of the three trials had the statistical power to determine whether adjuvant radiotherapy improved EFS as compared with salvage treatment. The analysis included an expanded definition of EFS: biochemical progression, clinical or radiologic progression, initiation of nonstudy treatment, prostate cancer death, or a PSA increase ≥2 ng/mL at any time after randomization.
The analysis “showed no evidence that event-free survival was improved with adjuvant radiotherapy compared with early salvage radiotherapy,” concluded Claire L. Vale, PhD, of University College Hospital in London, and colleagues. The 1% absolute difference in EFS represented a nonsignificant 5% difference in the hazard ratio in favor of adjuvant therapy (95% CI 0.75-1.21, P=0.70). Results were consistent across the trials, which were judged to have a low risk of bias.
Last Updated September 29, 2020
RADICALS-RT was supported by Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society. Sydes disclosed relevant relationships with Astellas, Clovis Oncology, Novartis, Pfizer, Sanofi, and Eli Lilly.
The meta-analysis was supported by the UK Medical Research Council. Vale disclosed no relevant relationships with industry.
RAVES was supported by multiple governmental, professional, and nonprofit organizations in Australia and New Zealand. Kneebone disclosed no relevant relationships with industry.
GETUG-AFU17 was supported by the French Health Ministry and Ipsen. Sargos disclosed relevant relationships with Astellas, Bayer, Bouchara, Ferring, Ipsen, Janssen, Sanofi, and Takeda.
Tilki and D’Amico disclosed no relevant relationships with industry.