Prostatectomy (RP) is a treatment (tx) option even for high-risk prostate cancer (PC) per the NCCN guidelines. We report the long-term follow-up of a pilot clinical trial using an aggressive multimodal approach integrating chemo-hormone tx, prostatectomy (RP) and adjuvant radiation (RT) in men with high/very high-risk PC.Preoperative tx entailed 6 months (mo) of chemo-hormones consisting of LHRH agonist (6 mo) integrated with adriamycin (A) and docetaxel (T). Two dose levels of A and T were incorporated with LHRH agonist tx: a higher dose (HD) of A (50mg/m2) and T (70mg/m2), and a lower dose (LD) of A (15mg/m2) and T (30mg/m2). HD chemo was given on 2 separate occasions (3 days post LHRH injection) in an effort to take advantage of the expected testosterone surge that occurs 3-5 days post LHRH agonist tx, while LD chemotherapy was given at other time points during the 6-month neoadjuvant period. This was followed by RP. The median post-op RT dose was 70.2 Gy (whole pelvis, with cone downs; range: 64.8-70.2) via 3D-CRT/IMRT. Three patients did not undergo RP after neoadjuvant chemo-hormone tx and went on to receive definitive RT (75.6 Gy). The overall survival (OS), disease-free survival (DFS), freedom from PSA failure (bNED, PSA > 0.2), and late GI/GU toxicity rates were calculated using the Kaplan-Meier method.A total of 22 men were enrolled from 2002-2006. Median pre-tx age, PSA and Gleason score were 61 years (range, 43-70), 24.1 ng/ml (range, 1.6-168.3) and 7 (range, 6-10), respectively. A total of 77% of patients received all therapy as planned. Median follow-up for the entire cohort and those alive were 10.9 years (range, 3.4-18.4) and 16.8 years (range, 15-18.4), respectively. The 15-year OS, DFS and bNED rates were 31.2%, 22.7% and 46.2%, respectively. Six patients (27%) never achieved PSA < 0.2. Worst acute grade 3 and 4 toxicity rates were 68% and 32%, respectively. The 15-year actuarial grade 3 or worse late GU toxicity rate was 13%. There was no grade 3 or worse late GI toxicities and no grade 5 acute or late toxicity.Despite an aggressive multimodal regimen that incorporated chemo-hormones, RP and adjuvant RT for high/very high-risk prostate cancer, the 15-year bNED rate was only 46.5%. Therefore, the role of RP and neoadjuvant chemo-hormone therapy remains questionable among high-risk patients in light of superior long-term outcomes demonstrated in trials like ASCENDE-RT that incorporated brachytherapy boost with RT and androgen deprivation.