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Randomized Controlled Trial
. 2024 Jul;35(7):656-666.
doi: 10.1016/j.annonc.2024.03.010. Epub 2024 Apr 5.

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047)

C C Parker  1 , P M Petersen  2 , A D Cook  3 , N W Clarke  4 , C Catton  5 , W R Cross  6 , H Kynaston  7 , W R Parulekar  8 , R A Persad  9 , F Saad  10 , L Bower  11 , G C Durkan  12 , J Logue  13 , C Maniatis  3 , D Noor  3 , H Payne  14 , J Anderson  15 , A K Bahl  16 , F Bashir  17 , D M Bottomley  15 , K Brasso  18 , L Capaldi  19 , C Chung  3 , P W Cooke  20 , J F Donohue  21 , B Eddy  22 , C M Heath  23 , A Henderson  21 , A Henry  24 , R Jaganathan  25 , H Jakobsen  26 , N D James  27 , J Joseph  28 , K Lees  29 , J Lester  30 , H Lindberg  31 , A Makar  32 , S L Morris  33 , N Oommen  34 , P Ostler  35 , L Owen  36 , P Patel  37 , A Pope  35 , R Popert  33 , R Raman  38 , V Ramani  39 , A Røder  40 , I Sayers  41 , M Simms  42 , V Srinivasan  43 , S Sundaram  44 , K L Tarver  45 , A Tran  13 , P Wells  46 , J Wilson  47 , A M Zarkar  48 , M K B Parmar  3 , M R Sydes  49 ; RADICALS investigators
Affiliations
Randomized Controlled Trial

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047)

C C Parker et al. Ann Oncol. 2024 Jul.

Abstract

Background: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure.

Patients and methods: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT.

Results: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017).

Conclusion: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy.

Trial identification: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Keywords: clinical trial; long-term follow-up; observational; prostate cancer; radiotherapy; randomised controlled trial.

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Conflict of interest statement

Disclosure

CCP reports advisory board for AAA and Blue Earth Therapeutics and ITM Oncologics. PMP reports personal fees for participation on advisory board for AAA Nordic, MSD, Pfizer Denmark and Bayer A/S Denmark. CC reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer Corp, Knight Therapeutics, and AbbVie. NDJ reports personal fees for participation on advisory board for AstraZeneca, Bayer, Janssen, Merck, Novartis and Sanofi; institutional fees for Expert Testimony for Janssen and Sanofi; personal fees for being an Invited Speaker for Merck Sharp & Dohme (UK) Limited. FS reports advisory board for Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck, Myovant, Novartis and Pfizer; local PI for Amgen, Astellas, Bayer, BMS, Janssen, Merck, Novartis, Pfizer and Sanofi; coordinating PI for AstraZeneca. LB reports a previous role, unrelated to the present manuscript, part funded by NIHR BRC. AMZ reports personal fees from Pfizer, Janssen, Astellas, MSD and EUSA Pharma; and support for attendance of a conference from Bayer. MKBP reports, as CTU director, research funding to MRC Clinical Trials Unit from: Abcodia Pvt Ltd, Akagera, Amgen, Aspirin Foundation, Astellas, AstraZeneca, Baxter, Bayer, BMS US, Bri-BioCepheid, Cipla, Clovis Inc, CSL Behring, Eli-Lilly, Emergent Biosolutions, Gilead Sciences, GlaxoSmithKline, Grifols, Janssen Products LP, Janssen-Cilag, Johnson & Johnson, Micronoma, Modus Theraputics, Mylan, Pfizer, Sanofi, Serum Institute of India, shionogi, SyntenyBiotechnology, Takeda, Tibotec, Transgene, ViiVHealthcare, Virco and Xenothera. MRS reports personal speaker fees from Janssen, Eli Lilly and Eisai; and research grants to the institution from Astellas, Clovis Oncology, Janssen, Novartis, Pfizer and Sanofi. All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1. Accrual to RADICALS-RT and patient progress through trial.
PSA, prostate-specific antigen; RT, radiotherapy.
Figure 2
Figure 2. Proportion starting radiotherapy over time.
Blue, Salvage-RT Policy Group; Red, Adjuvant-RT Group; RT, radiotherapy.
Figure 3
Figure 3. Freedom-from-distant-metastasis.
Blue, Salvage-RT Policy Group; Red, Adjuvant-RT Group; RT, radiotherapy.
Figure 4
Figure 4. Overall survival.
Blue, Salvage-RT Policy Group; Red, Adjuvant-RT Group; RT, radiotherapy.
Figure 5
Figure 5. Biochemical progression-free survival.
Blue, Salvage-RT Policy Group; Red, Adjuvant-RT Group; RT, radiotherapy.
Figure 6
Figure 6. Initiation of non-protocol hormone therapy.
Blue, Salvage-RT Policy Group; Red, Adjuvant-RT Group; RT, radiotherapy.
Figure 7
Figure 7. Incontinence ratings.
Blue, Salvage-RT Policy Group; Red, Adjuvant-RT Group.
See this image and copyright information in PMC

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