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
Is there any evidence for combining surgery and XRT +/- ADT for treatment of localized high risk prostate cancer?
Presumably, this is a question inquiring about planned post-operative RT. If so, surgery followed by adjuvant, post-operative radiation therapy (PORT) has been profiled extensively in several RCTs: EORTC 22911, SWOG 8794, ARO 96-02, FinnProstataX. The two more recent trials, ARO 96-02 and FinnProsta...
What is your PSA threshold for obtaining PSMA PET for biochemical failure after RP?
I typically order a PSMA PET after ~0.20. Sometimes lower if there are multiple aggressive features or poor prognostic factors (i.e. SVI with no lymph node dissection and persistently positive PSA of 0.15 after RP). This approach seems to be a reasonable threshold to me based on two considerations: ...
Do you consider ADT intensification with enzalutamide or abiraterone in patients receiving adjuvant radiation with ADT?
I agree with Dr. @Dr. First Last.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 had N+ disease. Was largely GS7 and pT3a population and not the very high risk patients that select surgeons choose to operate on....
Given results of SAKK 09/10 in which dose escalation for salvage prostate radiotherapy to 70 Gy was not superior to 64 Gy, would you ever consider a higher dose?
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Would you treat pelvic lymph nodes in your salvage prostate patient after RP without adverse features due to a limited/no pelvic lymph node sampling?
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. 44% of the patients on RADICALS had no lymph node dissection. Strongest evidence in favor is SPPORT, with biochemical contr...
Would you consider radical prostatectomy for a young male with unfavorable intermediate risk cT3a prostate cancer and PSMA PET concerning for regional lymph nodes involvement but negative conventional imaging?
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 advanced imaging. There have recently been two trials published from the Netherlands, PEPPER (using 68¸Ga-PSMA-11) and SALT (using 1...
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Do you consider tertiary grade pattern, LVI or PNI on prostatectomy specimens as adverse features to recommend EBRT and ADT for patients with unfavorable intermediate prostate CA after prostatectomy with undetectable PSA?
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 trials which define a benefit for ADT in this setting, RTOG 9601 and GETUG AFU-16 had a lower limit of a PSA of 0.2 at treatment in...