Prostate cancer: No need for radiotherapy after surgery

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Men with prostate cancer can be spared radiotherapy after surgery, according to late breaking results of the RADICALS-RT trial presented at the ESMO Congress 2019 in Barcelona, Spain. The study answers a longstanding question about whether the benefits of radiotherapy after surgery outweigh the side-effects.

RADICALS-RT is the largest ever trial of postoperative radiotherapy in prostate cancer. It found no difference in disease recurrence at five years between men who routinely had radiotherapy shortly after surgery and men who had radiotherapy later, if the cancer came back.

Study first author Professor Chris Parker, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK said: “The results suggest that radiotherapy is equally effective whether it is given to all men shortly after surgery or given later to those men with recurrent disease. There is a strong case now that observation should be the standard approach after surgery and radiotherapy should only be used if the cancer comes back.”

“The good news is that in future, many men will avoid the side-effects of radiotherapy,” added Parker. “These include urinary leakage and narrowing of the urethra, which can make urination difficult. Both are potential complications after surgery alone, but the risk is increased if radiotherapy is used as well.”

The findings were confirmed in a collaborative meta-analysis, also presented at the ESMO Congress 2019, combining results of RADICALS with two similar trials, RAVES and GETUG-AFU17. Author of the analysis, Dr Claire Vale, MRC Clinical Trials Unit, University College London, UK, said: “Results of the ARTISTIC meta-analysis confirm those of RADICALS, and provide greater evidence to support the routine use of observation and early salvage radiotherapy.”

“The meta-analysis provides the best opportunity to assess whether adjuvant radiotherapy may still have a role in some groups of men, and to investigate longer term outcomes,” added Vale.

Commenting on the data, Dr Xavier Maldonado, Hospital Universitari Vall d’Hebron, Barcelona, said: “These are the first results to suggest that postoperative radiotherapy for prostate cancer could be omitted or delayed in some patients. This will shorten the duration of treatment for these patients and allow better use of resources since today’s radiotherapy is technically sophisticated and therefore expensive. However, strict follow-up will be needed to identify patients requiring salvage radiotherapy.”

Maldonado noted that longer follow-up is needed for the main endpoint of RADICALS-RT, which is freedom from distant metastases at ten years, and to comprehensively report on toxicities.

Regarding the need for future research, Maldonado said the focus should be pinpointing which patients still require adjuvant radiotherapy to avoid a very early local relapse and potential subsequent metastases. “We need to develop genomic classifiers to help decide the best management strategy for each patient – whether it should include surgery and/or radiotherapy, and at which time points,” he said.

RADICALS-RT (NCT00541047) enrolled 1,396 patients after surgery for prostate cancer from the UK, Denmark, Canada, and Ireland. Men were randomly allocated to postoperative radiotherapy or the standard approach of observation only, with radiotherapy kept as an option if the disease recurred.

At a median follow-up of five years, progression free survival was 85% in the radiotherapy group and 88% in the standard care group (hazard ratio [HR] 1.10; 95% confidence interval [CI] 0.81-1.49; p=0.56).

Self-reported urinary incontinence was worse at one year in 5.3% of patients receiving radiotherapy compared to 2.7% who had standard care (p=0.008). Radiation Therapy Oncology Group (RTOG) grade 3/4 urethral stricture was reported at any time in 8% versus 5% of the radiotherapy and standard care groups, respectively (p=0.03). Longer follow-up is needed to report on survival and on the primary outcome of freedom from distant metastases.

The ARTISTIC collaboration meta-analysis included three randomised trials comparing adjuvant radiotherapy with early salvage radiotherapy following prostatectomy for men with localised prostate cancer: RADICALS (ISRCTN40814031), GETUG-AFU 17 (NCT00667069), and RAVES (NCT00860652). The analysis was planned before the results of the trials were known.

The results are based on all 2,151 men included in the three trials, of whom 1,074 were randomised to adjuvant radiotherapy and 1,077 men were randomised to early salvage radiotherapy – o those, 395 men (37%) have commenced salvage treatment to date. The analysis found no evidence that adjuvant radiotherapy improves event free survival compared to early salvage radiotherapy (HR 1.12; 95% CI 0.88-1.42; p=0.37). (4) Based on these results, the difference in five-year event free survival is likely only to be around 1%.

Abstract 1
Background: The optimal timing of RT after RP for prostate cancer (PCa) is uncertain. RADICALS-RT compared the efficacy and safety of adjuvant RT (aRT) versus an observation policy with salvage RT for PSA failure (Obs+sRT).
Methods: Patients with post-op PSA≤0.2ng/ml and ≥1 risk factor (pT3/4, Gleason 7-10, positive margins or pre-op PSA≥10ng/ml) were randomised ≤22wk after surgery to aRT or Obs+sRT for PSA failure (PSA≥0.1ng/ml or 3 consecutive rises). Stratification factors were Gleason score, margin status, RT schedule (52.5Gy/20f, 66Gy/33f) and centre. The primary outcome measure (OM) was freedom-from-distant metastases (FFDM) with >1200 pts needed for 80% power to detect an improvement from 90% to 95% at 10yr with aRT. It is too early to present results on the primary OM, but we present secondary OMs: bPFS (any of PSA≥0.4ng/ml post-RT, PSA≥2.0ng/ml at any time, local/distant progression, deferred HT, PCa death), freedom-from-non-protocol hormone therapy (HT), safety (RTOG scale), and patient reported OMs (ICSmaleSF). Standard survival analysis methods were used.

Results: 1396 pts were randomised (697 aRT, 699 Obs+sRT) from Oct-2007 to Dec-2016 (82% UK, 13% Denmark, 4% Canada, 1% Ireland). Median follow-up is 5yr. 93% (649/697) aRT started RT within 5mo; 33% (228/699) Obs+sRT started RT by 8yr after randomisation; 26% (166/649) aRT and 31% (71/228) Obs+sRT reported HT with their RT. With 169 events, bPFS at 5yr was 85% v 88% for aRT and Obs+sRT, respectively: HR=1.10 (95%CI 0.81-1.49, p=0.56). Freedom-from-non-protocol HT at 5yr was 92% v 94% (HR=1.24, 95%CI 0.76-2.01, p=0.39). Self-reported urinary incontinence was worse at 1yr in 5.3% vs 2.7% (p=0.008), and RTOG Grade 3/4 urethral stricture was reported at any time in 8% vs 5% (p=0.03), for aRT & Obs+sRT, respectively.
Conclusions: First results from RADICALS-RT do not show a benefit for aRT after RP in this patient group. Further follow-up is needed to report on long-term OMs, including FFDM. Adjuvant RT after RP increases risk of urinary morbidity. An observation policy with sRT for PSA failure should be the current standard after RP.

Authors
C Parker, NW Clarke, A Cook, HG Kynaston, P Meidahl Petersen, W Cross, R Persad, C Catton, J Logue, H Payne, F Saad, K Brasso, H Lindberg, A Zarkar, R Raman, MA Roder, C Heath, WR Parulekar, MKB Parmar, M Sydes

Abstract 2
Background: Three randomised trials, RADICALS (ISRCTN40814031), GETUG-AFU 17 (NCT00667069) and RAVES (NCT00860652), have compared adjuvant radiotherapy (ART) with a policy of salvage radiotherapy for PSA failure (SRT) after radical prostatectomy for men with localised prostate cancer, but have limited power for long-term outcomes. Therefore, the ARTISTIC collaboration prospectively planned a series of meta-analyses for each outcome.

Methods: Using a framework for adaptive meta-analysis (FAME), we prospectively defined our methods, including a consistent definition of PSA-driven event-free survival (EFS), prior to knowledge of trial results (CRD42019132669). We anticipated 240 events across all trials by Autumn 2019, giving 90% power to detect a 5% absolute difference in 5-year EFS. This provided a firm basis for a meta-analysis at this time.
Results: Across the 3 trials, 1074 men were randomised to ART and 1077 to SRT. To date, 395 men (37%) had commenced SRT. Patient characteristics were balanced within trials and overall. Men had median age of 65 years and most (77%) had a Gleason sum score of 7. Median follow-up ranged from 47 to 61 months. In August 2019, RADICALS and GETUG-AFU 17 provided EFS results for the meta-analysis (interim for GETUG-AFU 17). RAVES currently could only supply freedom from biochemical failure results. However, as the vast majority of first events across all trials are biochemical failures, these results have been pooled in a preliminary meta-analysis of EFS. Based on 245 events, the meta-analysis shows no evidence that EFS is improved with ART compared to SRT (HR=1.09, 95% CI=0.86-1.39, p=0.47). This translates to a potential absolute difference of 1% at 5 years in favour of SRT (95% CI: 2% in favour ART to 4% in favour of SRT).
Conclusions: This collaborative, prospective and early meta-analysis of all men from 3 randomised trials, suggests that SRT and ART offer similar outcomes for EFS. However, SRT spares many men from receiving RT, and associated side-effects. Final data from GETUG-AFU 17 and RAVES may help establish whether some subgroups of men might benefit from either treatment. Longer follow-up is needed for a meta-analysis of metastasis-free survival.

Authors
CL Vale, M Brihoum, S Chabaud, A Cook, D Fisher, S Forcat, C Fraser-Browne, A Herschtal, A Kneebone, S Nénan, C Parker, MKB Parmar, M Pearse, P Richaud, E Rogozińska, P Sargos, MR Syde, JF Tierney

European Society for Medical Oncology (ESMO) material and abstracts

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