Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Prostate high dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer: Efficacy results from a randomized phase II clinical trial of one fraction of 19 Gy or two fractions of 13.5 Gy: A 9-year update.

BACKGROUND AND PURPOSE: High dose-rate (HDR) brachytherapy as a monotherapy is an accepted treatment for localized prostate cancer, but the optimal dose and fractionation schedule remain unknown. We report on the efficacy of a randomized Phase II trial comparing HDR monotherapy delivered as 27 Gy in 2 fractions vs. 19 Gy in 1 fraction with a median follow-up of 9 years. MATERIALS AND METHODS: Enrolled patients had low or intermediate-risk disease, <60 cc prostate volume and no androgen deprivation use. Patients were randomized to 27 Gy in 2 fractions delivered one week apart vs a single fraction of 19 Gy. RESULTS: 170 patients were randomized: median age 65 years, median follow-up 107 months and median baseline PSA 6.35 ng/ml. NCCN risk categories comprised low (19 %), favourable (51 %), and unfavourable intermediate risk (30 %). The median PSA at 8 years was 0.08 ng/ml in the 2-fraction arm vs. 0.89 ng/ml in the single-fraction arm. The cumulative incidence of local failure at 8 years was 11.2 % in the 2-fraction arm vs. 35.9 % in the single-fraction arm (p < 0.001). The incidence of distant failure at 8 years was 3.8 % in the 2-fraction arm and 2.5 % in the single-fraction arm (p = 0.6). CONCLUSIONS: HDR monotherapy delivered in two fractions of 13.5 Gy demonstrated a persistent cancer control rate at 8 years and was well-tolerated. Single-fraction monotherapy yielded poor oncologic control and is not recommended. These findings contribute to the ongoing discourse on optimal HDR monotherapy strategies for low and intermediate-risk prostate cancer.