Lancet 2020 Sep 28
Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.
ABSTRACT
BACKGROUND
The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression.
METHODS
We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. 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. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047.
FINDINGS
Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020).
INTERPRETATION
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.
FUNDING
Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.
Related Questions
NRG GU-006 included the following as part of its eligibility criteria: “Persistent elevation of PSA after prostatectomy measured within 90 days ...
New comment by Radiation Oncologist at Delaware Valley Urology Cancer Treatment Center ( January 21, 2021)
In the adjuvant and salvage settings, when would you refrain from using ADT?
Are there other adverse features aside from seminal vesicle invasion, positive margins, or extraprostatic extension that you consider?
New answer by Radiation Oncologist at National Institutes of Health Clinical Center (May 23, 2021)
No, I don’t think there is any current available evidence to define a benefit for ADT in the post-operative setting for patients with an undetectable PSA. The two major ...
Gleason 4+3=7 and PSA 4
New answer by Radiation Oncologist at National Institutes of Health Clinical Center (June 7, 2021)
I would approach this scenario by considering two main issues. The first issue is what the probability of the patient truly having pN+ disease based on cN+ findings on advance...
For the purpose of this question, please assume an initially undetectable post-prostatectomy PSA, no presence of positive margins, extracapsular exten...
New answer by Radiation Oncologist at UC San Diego (August 28, 2021)
No, not based on lack of extended PLND, alone.RADICALS left lymph node coverage to physician discretion, and only 3% of salvage patients received pelvic lymph node irradiation...
For higher risk patients, eg PSA >0.5 or high risk gleason score, etc, would you consider dose escalation still? Prior data had suggested benefit t...
Are there clinical features (post-op PSA, Decipher score, pN+, pT3, etc) that would inform your decision?
New answer by Radiation Oncologist at Case Western Reserve University/ University Hospitals Seidman Cancer Center (February 11, 2022)
I agree with Dr. @Andrew J. Armstrong.One thing to note is ~3% of RADICALS, for example, included pT3b and high grade disease, and almost no patients in the ART vs SRT trials ...
New comment by Radiation Oncologist at National Institutes of Health Clinical Center ( August 20, 2022)
I have also seen it in my practice, and this circumstance has been reported in the literature. This scenario is best studied in the metastatic setting. For example, an imaging...