PURPOSE There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa. METHODS MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS). RESULTS The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups. CONCLUSION The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

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BACKGROUND The combination of external‐beam radiotherapy and brachytherapy is used commonly to treat men with prostate cancer. In this analysis, the authors examined the rate of biochemical recurrence (BR) and late grade ≥3 genitourinary (GU) and gastrointestinal (GI) toxicity after treatment with external‐beam radiotherapy and brachytherapy in a multiinstitutional, cooperative group setting. METHODS All eligible patients received external‐beam radiotherapy (45 Gray [Gy] in 25 fractions) followed 2 to 6 weeks later by an interstitial implant using iodine‐125 to deliver an additional 108 Gy. BR was defined in 2 ways: according to the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Definition (ACD) and according to the Phoenix definition (PD) (prostate‐specific antigen nadir +2 ng/mL). The Radiation Therapy Oncology Group(RTOG)/European Organization for Research and Treatment of Cancer late radiation morbidity scoring system was used to grade all toxicity. RESULTS One hundred thirty‐eight patients were enrolled, and 130 were eligible for the current analysis. The median follow‐up for surviving patients was 49 months (range, 20–60 months). The 48‐month estimate of late grade ≥3 GU/GI toxicity was 15% (95% confidence interval [95% CI], 8–21%), and the 48‐month estimate of BR was 19% (95% CI, 12–26%) and 14% (95% CI, 8–20%) according to the ACD and PD, respectively. CONCLUSIONS The morbidity observed in this multiinstitutional, cooperative group study was slightly higher than that reported in recent RTOG studies using brachytherapy alone or high‐dose external‐beam radiotherapy. The BR rate observed in this report was similar to that observed with high‐dose external‐beam radiotherapy alone in similar patients. Cancer 2007. © 2007 American Cancer Society.