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.
Bibliographical noteFunding Information:
CCP reports grants, personal fees, and other from Bayer, other from AAA, and personal fees from Janssen, outside the submitted work. NWC reports personal fees from Janssen, during the conduct of the study; and personal fees from Janssen, outside the submitted work. CC reports grants from Canadian Cancer Trials Group, during the conduct of the study; personal fees from Bayer, grants from AstraZeneca, and personal fees from AbbVie, Janssen, and Astellas, outside the submitted work. HPa reports personal fees from Janssen, Astellas, AstraZeneca, Ferring, and Ipsen, outside the submitted work. FS reports grants, personal fees, and non-financial support from Astellas, Amgen, Janssen, Bayer, Sanofi, Pfizer, AstraZeneca, and Myovant, outside the submitted work. HL reports personal fees and non-financial support from Astellas Phama, Bayer, Janssen, and Sanofi Aventis, and personal fees from Roche, outside the submitted work. AZ reports other fees from Bayer, personal fees from Pfizer, Janssen, Astellas, and EUSA Pharma, and grants from Sanofi, outside the submitted work. MKBP reports grants and non-financial support from Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, outside the submitted work. MRS reports grants and non-financial support from Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, personal fees from Eli Lilly, and grants, personal fees, and non-financial support from Janssen, outside the submitted work. All other authors declare no competing interests.
We recognise the efforts of all trial team members at the trials units and hospitals who have supported and engaged with RADICALS. A list of investigators and oversight committee members is given in the appendix (pp 9–15 ). We thank Tim Morris for putting the time-to-event graphs into KMunicate format. Grant funding in the UK was provided by the Clinical Trials Advisory Award Committee on behalf of Cancer Research UK (UK/C7829/A6381). Funding in Canada was provided by the Canadian Cancer Society (704970). The trial was further supported at the MRC Clinical Trials Unit at UCL by a core grant from the MRC, now part of the UK Research and Innovation (MC_UU_12023/28). UK sites were part of the Health Research Clinical Research Network. This paper represents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research. The views expressed are those of the authors and not necessarily those of the NHS or the NIHR. Matthew R Sydes and Mahesh K B Parmar are funded by the MRC. We thank all of the research staff who worked with the investigators and each site. Finally, and most importantly, we recognise and thank all of the participants of the trial and the families and friends who supported them. Clinical trials only happen because people choose to join them.
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