Randomized Controlled Trial

. 2020 Oct 31;396(10260):1413-1421.

doi: 10.1016/S0140-6736(20)31553-1. Epub 2020 Sep 28.

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial

Christopher C Parker¹, Noel W Clarke², Adrian D Cook³, Howard G Kynaston⁴, Peter Meidahl Petersen⁵, Charles Catton⁶, William Cross⁷, John Logue⁸, Wendy Parulekar⁹, Heather Payne¹⁰, Rajendra Persad¹¹, Holly Pickering³, Fred Saad¹², Juliette Anderson¹³, Amit Bahl¹⁴, David Bottomley¹⁵, Klaus Brasso¹⁶, Rohit Chahal¹⁷, Peter W Cooke¹⁸, Ben Eddy¹⁹, Stephanie Gibbs²⁰, Chee Goh²¹, Sandeep Gujral²², Catherine Heath²³, Alastair Henderson²⁴, Ramasamy Jaganathan²⁵, Henrik Jakobsen²⁶, Nicholas D James²⁷, Subramanian Kanaga Sundaram²⁸, Kathryn Lees²⁹, Jason Lester³⁰, Henriette Lindberg³¹, Julian Money-Kyrle²¹, Stephen Morris³², Joe O'Sullivan³³, Peter Ostler³⁴, Lisa Owen³⁵, Prashant Patel²⁵, Alvan Pope³⁶, Richard Popert³⁷, Rakesh Raman³⁸, Martin Andreas Røder¹⁶, Ian Sayers³⁹, Matthew Simms⁴⁰, Jim Wilson⁴¹, Anjali Zarkar⁴², Mahesh K B Parmar³, Matthew R Sydes⁴³

Affiliations

¹ Department of Oncology, Royal Marsden NHS Foundation Trust, Sutton, UK; Institute of Cancer Research, Sutton, UK.
² Department of Oncology, Genito-Urinary Cancer Research Group, The Christie Hospital, Manchester, UK; Department of Surgery, The Christie Hospital, Manchester, UK; Department of Urology, Salford Royal Hospitals, Manchester, UK.
³ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK.
⁴ Department of Urology, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
⁵ Department of Oncology, Copenhagen Prostate Cancer Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁶ Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
⁷ Department Of Urology, St James's University Hospital, Leeds, UK.
⁸ Department of Oncology, The Christie Hospital, Manchester, UK.
⁹ Department of Oncology, Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada.
¹⁰ Department of Oncology, University College London Hospitals, London, UK.
¹¹ Department of Urology, Bristol Urological Institute, North Bristol Hospitals, Bristol, UK.
¹² Department of Urology, Centre Hospitalier de l'Université de Montreal, Montreal, QC, Canada.
¹³ Department of Oncology, Mid Yorkshire Hospitals NHS Trust, Wakefield, UK.
¹⁴ Department of Oncology, Bristol Cancer Institute, University Hospitals Bristol, Bristol, UK.
¹⁵ St James's Institute of Oncology, Leeds, UK.
¹⁶ Department of Urology, Copenhagen Prostate Cancer Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁷ Department of Urology, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
¹⁸ Department of Urology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK.
¹⁹ Department of Urology, East Kent Hospitals University Foundation Trust, Canterbury, UK.
²⁰ Department of Oncology, Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, UK.
²¹ Department of Oncology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK.
²² Department of Urology, Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, UK.
²³ Department of Clinical Oncology, University Hospital Southampton, Southampton, UK.
²⁴ Department of Urology, Maidstone and Tunbridge Wells NHS Trust, Maidstone, UK.
²⁵ Department of Urology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
²⁶ Department of Urology, Herlev University Hospital, Herlev, Denmark.
²⁷ Institute of Cancer Research, London, UK; Department of Oncology, Royal Marsden NHS Foundation Trust, London, UK.
²⁸ Department of Urology, Mid Yorkshire Hospitals NHS Trust, Wakefield, UK.
²⁹ Kent Oncology Centre, Maidstone Hospital, Kent, UK.
³⁰ Department of Oncology, South West Wales Cancer Centre, Swansea, UK.
³¹ Department of Oncology, Herlev University Hospital, Herlev, Denmark.
³² Department of Clinical Oncology, Guys Hospital, London, UK.
³³ Department of Clinical Oncology, Belfast Health and Social Care Trust, Belfast, UK.
³⁴ Mount Vernon Cancer Centre, Northwood, UK.
³⁵ Department of Oncology, Leeds Cancer Centre, St James's University Hospital, Leeds, UK.
³⁶ Department of Urology, Hillingdon Hospital, Middlesex, UK; Mount Vernon Hospital, Northwood, UK; Mount Vernon Cancer Centre, Northwood, UK.
³⁷ Department of Urology, Guys Hospital, London, UK.
³⁸ Department of Clinical Oncology, Kent Oncology Centre, Canterbury, UK.
³⁹ Department of Oncology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK.
⁴⁰ Department of Urology, Hull University Hospitals NHS Trust, Hull, UK.
⁴¹ Department of Urology, Anuerin Bevan University Health Board, Newport, UK.
⁴² Department of Oncology, University Hospital Birmingham, Birmingham, UK.
⁴³ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK. Electronic address: m.sydes@ucl.ac.uk.

PMID: 33002429
PMCID: PMC7616947
DOI: 10.1016/S0140-6736(20)31553-1

Randomized Controlled Trial

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial

Christopher C Parker et al. Lancet. 2020.

. 2020 Oct 31;396(10260):1413-1421.

doi: 10.1016/S0140-6736(20)31553-1. Epub 2020 Sep 28.

Authors

Affiliations

¹ Department of Oncology, Royal Marsden NHS Foundation Trust, Sutton, UK; Institute of Cancer Research, Sutton, UK.
² Department of Oncology, Genito-Urinary Cancer Research Group, The Christie Hospital, Manchester, UK; Department of Surgery, The Christie Hospital, Manchester, UK; Department of Urology, Salford Royal Hospitals, Manchester, UK.
³ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK.
⁴ Department of Urology, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
⁵ Department of Oncology, Copenhagen Prostate Cancer Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁶ Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
⁷ Department Of Urology, St James's University Hospital, Leeds, UK.
⁸ Department of Oncology, The Christie Hospital, Manchester, UK.
⁹ Department of Oncology, Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada.
¹⁰ Department of Oncology, University College London Hospitals, London, UK.
¹¹ Department of Urology, Bristol Urological Institute, North Bristol Hospitals, Bristol, UK.
¹² Department of Urology, Centre Hospitalier de l'Université de Montreal, Montreal, QC, Canada.
¹³ Department of Oncology, Mid Yorkshire Hospitals NHS Trust, Wakefield, UK.
¹⁴ Department of Oncology, Bristol Cancer Institute, University Hospitals Bristol, Bristol, UK.
¹⁵ St James's Institute of Oncology, Leeds, UK.
¹⁶ Department of Urology, Copenhagen Prostate Cancer Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁷ Department of Urology, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
¹⁸ Department of Urology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK.
¹⁹ Department of Urology, East Kent Hospitals University Foundation Trust, Canterbury, UK.
²⁰ Department of Oncology, Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, UK.
²¹ Department of Oncology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK.
²² Department of Urology, Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, UK.
²³ Department of Clinical Oncology, University Hospital Southampton, Southampton, UK.
²⁴ Department of Urology, Maidstone and Tunbridge Wells NHS Trust, Maidstone, UK.
²⁵ Department of Urology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
²⁶ Department of Urology, Herlev University Hospital, Herlev, Denmark.
²⁷ Institute of Cancer Research, London, UK; Department of Oncology, Royal Marsden NHS Foundation Trust, London, UK.
²⁸ Department of Urology, Mid Yorkshire Hospitals NHS Trust, Wakefield, UK.
²⁹ Kent Oncology Centre, Maidstone Hospital, Kent, UK.
³⁰ Department of Oncology, South West Wales Cancer Centre, Swansea, UK.
³¹ Department of Oncology, Herlev University Hospital, Herlev, Denmark.
³² Department of Clinical Oncology, Guys Hospital, London, UK.
³³ Department of Clinical Oncology, Belfast Health and Social Care Trust, Belfast, UK.
³⁴ Mount Vernon Cancer Centre, Northwood, UK.
³⁵ Department of Oncology, Leeds Cancer Centre, St James's University Hospital, Leeds, UK.
³⁶ Department of Urology, Hillingdon Hospital, Middlesex, UK; Mount Vernon Hospital, Northwood, UK; Mount Vernon Cancer Centre, Northwood, UK.
³⁷ Department of Urology, Guys Hospital, London, UK.
³⁸ Department of Clinical Oncology, Kent Oncology Centre, Canterbury, UK.
³⁹ Department of Oncology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK.
⁴⁰ Department of Urology, Hull University Hospitals NHS Trust, Hull, UK.
⁴¹ Department of Urology, Anuerin Bevan University Health Board, Newport, UK.
⁴² Department of Oncology, University Hospital Birmingham, Birmingham, UK.
⁴³ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK. Electronic address: m.sydes@ucl.ac.uk.

PMID: 33002429
PMCID: PMC7616947
DOI: 10.1016/S0140-6736(20)31553-1

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.

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Conflict of interest statement

Competing Interests

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf Please see the end of the manuscript for full list of author disclosures.

Declaration Of Interests

Prof. Parker reports grants, personal fees and other from Bayer, other from AAA and personal fees from Janssen, outside the submitted work.
Prof. Clarke reports personal fees from Janssen, during the conduct of the study; personal fees from Janssen, outside the submitted work.
Dr. Catton reports grants from Canadian Cancer Trials Group, during the conduct of the study; personal fees from Bayer Corp, grants from Astra-Zeneca, personal fees from Abbvie Corp, personal fees from Janssen Corp, personal fees from Astellas Corp, outside the submitted work.
Dr. Payne reports personal fees from Janssen, personal fees from Astellas, personal fees from Astra Zeneca, personal fees from Ferring, personal fees from Ipsen, outside the submitted work.
Dr. Saad reports grants, personal fees and non-financial support from Astellas, grants, personal fees and non-financial support from Amgen, grants, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from Sanofi, grants, personal fees and non-financial support from Pfizer, grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Myovant, outside the submitted work.
Dr. Lindberg reports personal fees and non-financial support from Astellas Phama, personal fees and non-financial support from Bayer, personal fees and non-financial support from Janssen, personal fees and non-financial support from Sanofi Aventis, personal fees from Roche, outside the submitted work.
Dr. Zarkar reports other fees from Bayer, personal fees from Pfizer, personal fees from Janssen, personal fees from Astellas, grants from Sanofi, personal fees from EUSA Pharma, outside the submitted work.
Prof. Parmar reports grants and non-financial support from Astellas, grants and non-financial support from Clovis Oncology, grants and non-financial support from Novartis, grants and non-financial support from Pfizer, grants and non-financial support from Sanofi, outside the submitted work.
Prof. Sydes reports grants and non-financial support from Astellas, grants and non-financial support from Clovis Oncology, grants and non-financial support from Novartis, grants and non-financial support from Pfizer, personal fees from Eli Lilly, grants, personal fees and non-financial support from Janssen, grants and non-financial support from Sanofi, outside the submitted work.

All remaining authors declare none.

Figures

**Figure 2**
a. Biochemical PFS b. Non-protocol HT

See this image and copyright information in PMC

Comment in

Timing of radiotherapy after radical prostatectomy.
Tilki D, D'Amico AV. Tilki D, et al. Lancet. 2020 Oct 31;396(10260):1374-1375. doi: 10.1016/S0140-6736(20)31957-7. Epub 2020 Sep 28. Lancet. 2020. PMID: 33002430 No abstract available.
Salvage radiotherapy: a new standard of care.
Sidaway P. Sidaway P. Nat Rev Clin Oncol. 2021 Jan;18(1):5. doi: 10.1038/s41571-020-00443-3. Nat Rev Clin Oncol. 2021. PMID: 33067593 No abstract available.
Salvage radiotherapy: a new standard of care.
Sidaway P. Sidaway P. Nat Rev Urol. 2020 Dec;17(12):657. doi: 10.1038/s41585-020-00392-7. Nat Rev Urol. 2020. PMID: 33077912 No abstract available.
Adjuvant Versus Early Salvage Radiation Therapy After Radical Prostatectomy for Men With Adverse Pathologic Features-The Debate Continues.
Chen RC, Choudhury A. Chen RC, et al. Int J Radiat Oncol Biol Phys. 2021 Mar 15;109(4):839-843. doi: 10.1016/j.ijrobp.2020.12.022. Int J Radiat Oncol Biol Phys. 2021. PMID: 33610298 No abstract available.
Re: Timing of Radiotherapy After Radical Prostatectomy (RadicalS-RT): A Randomised, Controlled Phase 3 Trial.
Ghadjar P, Wiegel T. Ghadjar P, et al. Eur Urol. 2021 Jul;80(1):117. doi: 10.1016/j.eururo.2021.02.016. Epub 2021 Feb 19. Eur Urol. 2021. PMID: 33612373 No abstract available.
Postoperative radiotherapy in prostate cancer.
Ghadjar P, Höcht S, Wiegel T. Ghadjar P, et al. Lancet. 2021 May 1;397(10285):1623. doi: 10.1016/S0140-6736(21)00273-7. Lancet. 2021. PMID: 33933203 No abstract available.
Radikale Prostatektomie: Adjuvante versus Salvage-Radiatio.
[No authors listed] [No authors listed] Aktuelle Urol. 2022 Feb;53(1):12-13. doi: 10.1055/a-1559-4803. Epub 2022 Jan 25. Aktuelle Urol. 2022. PMID: 35078254 German. No abstract available.
Immediate or salvage radiotherapy after radical prostatectomy: Do we finally know?
Srinivasan S, Kunder S, Maitre P, Murthy V. Srinivasan S, et al. Natl Med J India. 2021 Sep-Oct;34(5):282-284. doi: 10.25259/NMJI_127_21. Natl Med J India. 2021. PMID: 35593236 No abstract available.

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Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial

Affiliations

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

Research Materials

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