ESMO 2019: Radiotherapy after Surgery Could be Omitted or Delayed in Some Prostate Cancer Patients

General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.
General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

Late-breaking results from the RADICALS-RT trial (NCT00541047 / ISRCTN40814031), presented at the ESMO Congress in Barcelona, Spain, being held September 27 – October 1, 2019, suggest that men with prostate cancer can be spared radiotherapy after surgery. [1]

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.

Trial design
The RADICALS-RT trial 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).

The study results showed that 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).

Prof Chris Parker, MD, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK

Equally effective
“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,” explained the study’s first author Prof Chris Parker, MD, a prostate cancer specialist at the Academic Urology Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom.

“The good news is that in future, many men will avoid the side-effects of radiotherapy,”  Parker added.

“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,” he observed.

Confirming the findings
The findings were confirmed in a collaborative meta-analysis called ARTISTIC, which combined the results of the RADICALS trial with two similar, randomized trials, RAVES (NCT00860652) and GETUG-AFU17 (NCT00667069), comparing adjuvant radiotherapy with early salvage radiotherapy following prostatectomy for men with localized prostate cancer.

The results of ARTISTIC were based on all 2,151 men included in the three trials, of whom 1,074 were randomized to adjuvant radiotherapy and 1,077 men were randomized to early salvage radiotherapy – of 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 1.09; 95% CI 0.86–1.39; p=0.47). Based on these results, the difference in five-year event free survival is likely only to be around 1%.

Claire Vale, Ph.D, at the MRC Clinical Trials Unit, University College London, UK.

The results of these studies were also presented at the ESMO Congress 2019. [2]

“Results of the ARTISTIC meta-analysis confirm those of the RADICALS trial and provides greater evidence to support the routine use of observation and early salvage radiotherapy,” said the author of the analysis, Claire Vale, Ph.D, at the MRC Clinical Trials Unit, University College London, UK.

“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,”  Vale, added.

Shortening treatment duration
“These are the first results to suggest that postoperative radiotherapy for prostate cancer could be omitted or delayed in some patients,” observed Xavier Maldonado, MD, Hospital Universitari Vall d’Hebron, Barcelona, Spain, commenting on the presented data.

“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 added.

Maldonado further 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.

Maldonado also noted that the focus should clearly pinpoint 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 concluded.

Clinical trials
Radiation Therapy and Androgen Deprivation Therapy in Treating Patients Who Have Undergone Surgery for Prostate Cancer (RADICALS) – NCT00541047
Radiotherapy – Adjuvant Versus Early Salvage (RAVES) – NCT00860652
Triptorelin and Radiation Therapy in Treating Patients Who Have Undergone Surgery for Intermediate-Risk Stage III or Stage IV Prostate Cancer – NCT00667069

References
[1] LBA49_PR ‘Timing of radiotherapy (RT) after radical prostatectomy (RP): first results from the RADICALS RT randomised controlled trial (RCT) [NCT00541047]‘ will be presented by Chris Parker during the Proffered Paper session on Friday, 27 September, 14:00 to 15:30 (CEST) in Sevilla Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019
[2] LBA48_PR ‘Adjuvant or salvage radiotherapy for the treatment of localised prostate cancer? A prospectively planned aggregate data meta-analysis’ will be presented by Claire L. Vale during the Proffered Paper session on Friday, 27 September, 14:00 to 15:30 (CEST) in Sevilla Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019