As reported in The Lancet by Christopher C. Parker, MD, of Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, and colleagues, initial findings in the phase III RADICALS-RT trial have shown no biochemical progression-free survival benefit with adjuvant radiotherapy vs a policy of salvage radiotherapy after radical prostatectomy for prostate cancer.¹

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 had 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. Randomization 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 increases in PSA still below 0.1 ng/mL.

Christopher C. Parker, MD

The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. 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 PSA ≥ 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.

Median patient age was 65 years; median PSA at diagnosis was 7.9 ng/mL; Gleason score was < 7 in 7%, 3 + 4 in 49%, 4 + 3 in 27%, and ≥ 8 in 17%; and pathologic T stage was 2 in 24%, 3a in 57%, 3b in 18%, and 4 in 1%. Positive margins were present in 63%; lymph node stays were positive in 5% and negative in 51%, with no dissection in 44%; and CAPRA-S (Cancer of the Prostate Risk Assessment postsurgical) score was low (0-–2) in 8%, intermediate (3–5) in 55%, and high (6+) in 37%.

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 randomization. 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 a CAPRA-S score of 3 to 5, the hazard ration 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 ration 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 (48%) of 87 in the adjuvant radiotherapy group and 49 (60%) of 82 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 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 randomization. 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 was reported in 6% vs 4% of patients at < 2 years (P = .020) and in 4% vs 2.5% at ≥ 2 years.

A total of 33 vs 13 serious adverse events were reported. The most common in the adjuvant radiotherapy group were urinary retention in five patients, urethral stricture in three, hematuria in two, and chest pain in two; the most common in the salvage radiotherapy group were hematuria, dehydration, and myocardial infarction in two patients each. A total of three serious adverse events were considered treatment related.

Patient-reported outcome measures showed a small but significant worsening of urinary incontinence (P = .0023) and bowel incontinence (P < .0001) in the adjuvant radiotherapy group vs the salvage radiotherapy group at 1 year but no significant differences (P = .073 and P = .084, respectively) at 5 years.

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.” 

DISCLOSURE: The study was funded by Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society. Dr. Parker reported grants, personal fees, and other from Bayer, other from AAA, and personal fees from Janssen, outside the submitted work.

REFERENCE

1. Parker CC, Clarke NW, Cook AD, et al: Timing of radiotherapy after radical prostatectomy (RADICALS-RT): A randomised, controlled phase III trial. Lancet. September 28, 2020 (early release online).