ESMO 2019: Timing of Radiotherapy after Radical Prostatectomy: First Results from the RADICALS Radiation Therapy Randomised Controlled Trial

Barcelona, Spain (UroToday.com) Men who undergo surgery as definitive therapy for their localized prostate cancer generally only receive subsequent radiation therapy if their surgical pathology shows certain adverse pathologic features (adjuvant radiotherapy or aRT) or if they experience biochemical recurrence (early salvage radiotherapy or eSRT). Two prior trials randomizing men with high-risk prostatectomy features to adjuvant versus salvage therapy reached differing conclusions regarding overall survival benefit, with SWOG 8794 showing a benefit in pathologic stage T3 disease, but the larger EORTC 22911 trial showed no survival benefit.  In addition to their opposing conclusions, these trials utilized less stringent PSA criteria for the initiation of salvage therapy; for example, in SWOG 8794, relapse was defined as PSA > 0.4 ng/mL. Thus, whether aRT is superior to eSRT after prostatectomy with regards to patient survival remains an open question. Three ongoing trials aim to address this question, with one trial and an interim meta-analysis presented at ESMO 2019. 

The RADICALS-RT trial (NCT00541047) has randomized 1396 men with intermediate to high risk localized prostate cancer to adjuvant radiotherapy versus early salvage radiotherapy. Inclusion criteria were men who have undergone radical prostatectomy within 22 weeks of enrollment, a post-operative PSA of ≤ 0.2 ng/mL,  and one or more of the following: (1) pT3/T4 disease, (2) Gleason 7-10 disease, (3) Pre-operative PSA ≥ 10 ng/mL, and (4) Positive surgical margins. Eligible patients were randomized 1:1 to adjuvant radiotherapy versus early salvage radiotherapy (eSRT). Criteria for eSRT were either (1) 2 consecutive PSA rises and PSA > 0.1 ng/mL or (2) 3 consecutive PSA rises regardless of whether the final reading was greater than 0.1 ng/mL. If receiving radiotherapy, patients could either receive 66 Gy in 33 fractions or 52.5 Gy in 20 fractions. Concurrent hormonal therapy was not mandated by the trial protocol. The primary outcome of this trial is freedom from distant metastases, and secondary outcomes are biochemical progression-free survival, freedom from non-protocol hormonal therapy, clinical progression, safety, and overall survival. To facilitate a planned meta-analysis across three trials, the biochemical progression-free survival and safety data were presented by Dr. Parker at this conference. Biochemical progression-free survival was defined as the first of: (1) PSA ≥ 0.4 ng/mL after RT, (2) PSA > 2.0 ng/mL at any time, (3) Clinical progression, (4) Initiation of non-protocol hormonal therapy, or (5) Death from prostate cancer.

Patient characteristics were well-balanced between the adjuvant and eSRT cohorts, with almost 700 men in each group. Approximately half the patients in each cohort had Gleason 3+4 = 7 disease, with ~16% of each cohort having Gleason > 7 disease. One quarter of patients in each cohort had pT2 disease, the rest had pT3/T4 disease. Positive margins were presents in 63% of patients, and seminal vesicle involvement was present in ~20% of each cohort. 93% of patients randomized to adjuvant radiotherapy actually received therapy within five months of prostatectomy, and 33% of men in the eSRT cohort received radiotherapy. 65% of men who received radiotherapy received 66 Gy in total. 26% of men in the adjuvant cohort, and 31% of men in the eSRT cohort received concurrent hormonal therapy with radiation. 

At a median follow-up of 5 years, the hazard ratio for adjuvant radiotherapy was 1.10 (0.81 – 1.49, p = 0.56) for biochemical progression-free survival. The hazard ratio for adjuvant radiotherapy with regards to initiation of non-protocol hormonal therapy was 0.88 (0.58 -1.33, p = 0.53). In the eSRT arm, 22 distant metastases events had occurred, with 8 deaths from prostate cancer. Using RTOG scales for urinary and GI safety, more grade 3 or greater toxicity events were noted with adjuvant radiotherapy as might be expected given more patients received therapy in that arm, though rates were less than 5% for urinary toxicity and less than 1% for GI toxicity. More patients in the adjuvant radiotherapy group reported urinary and fecal symptoms both at year 1 (statistically significant) and year 5 (not statistically significant).

In conclusion, this study showed no statistically significant difference with regards to biochemical progression-free survival and freedom from subsequent hormonal therapy between adjuvant radiotherapy and early salvage radiotherapy. Adjuvant radiotherapy was associated with an increased number of urinary and bowel adverse effects as might be expected given the much higher numbers of patients receiving therapy in this group. 

Presented by: Professor Christopher Parker, Consultant Clinical Oncologist BA BM BChir MD FRCR MRCP, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, Sutton, United Kingdom 

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain
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