Adding Short-Term Androgen Deprivation Therapy to Radiation Therapy in Men With Localized Prostate Cancer: Long-Term Update of the NRG/RTOG 9408 Randomized Clinical Trial

• Authors: Deborah Bruner, Emory University; Christoper U Jones, Sutter Med Ctr Sacramento; Stephanie L Pugh, NRG Oncol Stat & Data Management Ctr; Howard M Sandler, Cedars-Sinai Medical Center; Michael P Chetner, University of Alberta; Mahul B Amin, University of Tennessee Health Science Center; Anthony L Zietman, Massachusetts General Hospital; Robert B Den, Thomas Jefferson University Hospital; Mark H Leibenhaut, Sutter Medical Center Sacramento; John M Longo, Froedtert; Jean-Paul Bahary, Centre Hospitalier De L’Université De Montréal-Notre Dame; Seth A Rosenthal, Sutter Med Ctr Sacramento; Luis Souhami, McGill University; Jeff M Michalski, Washington University; Alan C Hartford, Dartmouth Hitchcock Medical Center; Pradip P Amin, University of Maryland/Greenebaum Cancer Center; Mack Roach, UCSF Medical Center-Mount Zion; Don Yee, Cross Cancer Institute; Jason A Efstathiou, Massachusetts General Hospital; Joseph P Rodgers, NRG Oncol Stat & Data Management Ctr; Felix Y Feng, UCSF Medical Center-Mount Zion; William U Shipley, Massachusetts General Hospital
• Journal Title: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
• Volume: Volume 112, Number 2
• Publisher: ELSEVIER SCIENCE INC | 2022-01-06, Pages 294-303
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.ijrobp.2021.08.031
• Subjects: Health Sciences, Oncology; Statistics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Radiology, Nuclear Medicine & Medical Imaging; DOSE-ESCALATION TRIAL; RADIOTHERAPY; ONCOLOGY; SUPPRESSION; RTOG; REGRESSION; SURVIVAL; DURATION; DISEASE

Abstract

Purpose: For men with localized prostate cancer, NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 demonstrated that adding short-term androgen deprivation therapy (ADT) to radiation therapy (RT) improved the primary endpoint of overall survival (OS) and improved disease-specific mortality (DSM), biochemical failure (BF), local progression, and freedom from distant metastases (DM). This study was performed to determine whether the short-term ADT continued to improve OS, DSM, BF, and freedom from DM with longer follow-up. Methods and Materials: From 1994 to 2001, NRG/RTOG 9408 randomized 2028 men from 212 North American institutions with T1b-T2b, N0 prostate adenocarcinoma and prostate-specific antigen (PSA) ≤20ng/mL to RT alone or RT plus short-term ADT. Patients were stratified by PSA, tumor grade, and surgical versus clinical nodal staging. ADT was flutamide with either goserelin or leuprolide for 4 months. Prostate RT (66.6 Gy) was started after 2 months. OS was calculated at the date of death from any cause or at last follow-up. Secondary endpoints were DSM, BF, local progression, and DM. Acute and late toxic effects were assessed using RTOG toxicity scales. Results: Median follow-up in surviving patients was 14.8 years (range, 0.16-21.98). The 10-year and 18-year OS was 56% and 23%, respectively, with RT alone versus 63% and 23% with combined therapy (HR 0.94; 95% confidence interval [CI], 0.85-1.05; P = .94). The hazards were not proportional (P = .003). Estimated restricted mean survival time at 18 years was 11.8 years (95% CI, 11.4-12.1) with combined therapy versus 11.3 years with RT alone (95% CI, 10.9-11.6; P = .05). The 10-year and 18-year DSM was 7% and 14%, respectively, with RT alone versus 3% and 8% with combined therapy (HR 0.56; 95% CI, 0.41-0.75; P < .01). DM and BF favored combined therapy at 18 years. Rates of late grade ≥3 hepatic, gastrointestinal, and genitourinary toxicity were ≤1%, 3%, and 8%, respectively, with combined therapy versus ≤1%, 2%, and 5% with RT alone. Conclusions: Further follow-up demonstrates that OS converges at approximately 15 years, by which point the administration of 4 months of ADT had conferred an estimated additional 6 months of life.