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

Evaluation of proteomic profiles of normal mucosa, Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC) obtained from humans and the Levrat’s rat model of BE/EAC.

e14689 Background: EAC from BE is increasing, and prognosis is poor. Representative models are critical to understanding BE/EAC and developing therapies. We refined the Levrat’s model of BE/EAC and showed that a SMO inhibitor prevented BE/EAC (Proc ASCO 2012). To validate the rat model as representative of human and explore differentially expressed proteins/pathways, we evaluated the proteomic profiles of nl/BE/EAC from humans and rats. Methods: GE reflux was induced in 6-8 wk old male Sprague–Dawley rats by the Levrat’s procedure--approved by the IACUC. Incidence of BE/EAC at 28 wks was 90%/70%. Human nl/BE/EAC samples were obtained from the PENG database--IRB approved. Histology confirmed by a single pathologist (JD). Following LCM from paraffin, digests were analyzed in triplicate by nanoflow LC-MS/MS with a hybrid linear ion trap-Orbitrap Velos mass spectrometer followed by online nanoflow LC. Mass spectral data representing ~ 20-30,000 CID spectra were searched, and a quantitative estimate of relative abundance was obtained. Kruskal-Wallis non-parametric ANOVA was employed, and clusters were compared within and between humans and rats. Results: Data is available for rat tissues, 10 samples each for nl/BE/EAC. Heirarchical clustering of 410 features yielded 3 statistically significantly distinct groups corresponding to normal, BE and EAC (ANOVA p &lt; 0.001). Pair-wise comparison between groups yielded statistically significant (p &lt; 0.05) differential protein expression as follows: nl vs BE~550; nl vs EAC~450; BE vs EAC~150. For EAC, proteins were differentially expressed in pathways including: protein degradation/synthesis, cell death, growth and proliferation (NF-kB, EIF4A, Akt, b-tubulin). Analysis of human tissues and comparison to rat will be presented at the meeting. Conclusions: Proteomic evaluation of normal/BE/EAC tissues from the Levrat’s model of BE/EAC yielded distinct protein patterns for nl/BE/EAC. Proteins differentially expressed in EAC vs normal/EAC are involved in cancer related pathways. Differentially expressed proteins may provide targets for therapy, which could be tested in the Levrat’s model. </jats:p