As reported in The Lancet by Christopher C. Parker, MD, and colleagues, initial findings in the phase III RADICALS-RT trial have shown no biochemical progression-free survival benefit and no difference in freedom from nonprotocol hormone therapy with adjuvant radiotherapy vs salvage radiotherapy after radical prostatectomy for prostate cancer.

Christopher C. Parker, MD

Study Details

In the open-label trial, 1,396 patients from sites in Canada, Denmark, Ireland, and the United Kingdom were randomly assigned between November 2007 and December 2016 to receive adjuvant radiotherapy (n = 697) or to an observation policy with salvage radiotherapy prompted by prostate-specific antigen (PSA) progression (n = 699) after radical prostatectomy. Patients had to have at least one risk factor for biochemical progression, including pathologic T stage 3 or 4, Gleason score of 7 to 10, positive margins, or preoperative PSA ≥ 10 ng/mL. Random assignment was stratified by Gleason score, margin status, planned radiotherapy schedule (52.5 Gy in 20 fractions or 66 Gy in 33 fractions), and center. Salvage radiotherapy was prompted by PSA ≥ 0.1 ng/mL or three consecutive rises. 

The primary outcome measure was freedom from distant metastases. Data on freedom from distant metastases are not yet mature. The current report provides findings on biochemical progression-free survival and freedom from nonprotocol hormone therapy.

Biochemical progression-free survival events were defined as PSA of ≥ 0.4 ng/mL following postoperative radiotherapy, PSA > 2.0 ng/mL at any time, clinical progression, initiation of nonprotocol hormone therapy, and death from any cause.

Biochemical Progression-Free Survival

Median follow-up was 4.9 years. A total of 649 patients (93%) in the adjuvant radiotherapy group underwent radiotherapy within 6 months of surgery. A total of 228 patients (33%) in the salvage radiotherapy group underwent radiotherapy within 8 years after random assignment. Among patients assigned to the salvage radiotherapy policy, 58 (8%) met the protocol definition of PSA biochemical progression during follow-up but had not started radiotherapy at time of analysis.

A total of 169 biochemical progression-free survival events were observed, including 87 in the adjuvant radiotherapy group and 82 in the salvage radiotherapy group. At 5 years, biochemical progression-free survival was 85% in the adjuvant radiotherapy group vs 88% in the salvage radiotherapy group (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 0.81–1.49, P = .56). Among 382 vs 384 patients at intermediate risk on the basis of CAPRA-S (Cancer of the Prostate Risk Assessment postsurgical) score of 3 to 5, the hazard ratio was 1.13 (95% CI = 0.70–1.81, P =.62). Among 260 vs 257 patients at high risk on the basis of CAPRA-S score ≥ 6, the hazard ratio was 1.00 (95% CI = 0.66–1.52, P = 1.0).

Among patients with a biochemical progression-free survival event, 91 (54%) of 169 initiated nonprotocol hormone therapy, including 42 of 87 (48%) in the adjuvant radiotherapy group and 49 of 82 (60%) in the salvage radiotherapy group. Freedom from nonprotocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group vs 92% for those in the salvage radiotherapy group (HR = 0.88, 95% CI = 0.58­–1.33, P = .53).

Regarding long-term efficacy outcome measures, data for the primary outcome measure of freedom from distant metastasis were not yet mature at the time of analysis. Patients assigned to salvage radiotherapy were observed to have a freedom from distant metastasis rate of 91% at 9 years. Data for overall survival were also immature. Death occurred in a total of 26 patients (4%) in the salvage radiotherapy group, with 8 deaths being attributed to prostate cancer.

Toxicity

Grade 1 or 2 diarrhea, proctitis, cystitis, hematuria, and urethral stricture were significantly more common in the adjuvant radiotherapy group vs the salvage radiotherapy group at < 2 years and at ≥ 2 years after random assignment. Grade 3 or 4 hematuria was reported in 3% vs < 1% of patients at < 2 years and in 4% vs < 1% at ≥ 2 years. Grade 3 or 4 urethral stricture within 2 years was reported in 6% vs 4% of patients (P = .020). A total of 33 vs 13 serious adverse events were reported, with 3 considered treatment-related. Self-reported urinary incontinence was worse at 1 year among patients in the adjuvant radiotherapy group (mean score = 4.8 vs 4.0, P = .0023).

The investigators concluded, “These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy.”

Matthew R. Sydes, MSc, of the MRC Clinical Trials Unit at UCL, London, is the corresponding author for The Lancet article.  

Disclosure: The study was funded by Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society. For full disclosures of the study authors, visit thelancet.com.