Amar U Kishan1,2, Xiaoyan Wang3, Wendy Seiferheld4, Laurence Collette5, Kiri A Sandler1, Howard M Sandler6, Michel Bolla7, Philippe Maingon8, Theo De Reijke9, Gerald E Hanks10, Nicholas G Nickols1,11, Matthew Rettig12,13, Alexandra Drakaki12, Robert E Reiter2, Daniel E Spratt14, Patrick A Kupelian1, Michael L Steinberg1, Christopher R King1. 1. Department of Radiation Oncology, University of California, Los Angeles, Los Angeles. 2. Department of Urology, University of California, Los Angeles, Los Angeles. 3. Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, Los Angeles. 4. NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania. 5. European Organization for Research and Treatment of Cancer Headquarters, Brussels, Belgium. 6. Department of Radiation Oncology, Cedars Sinai, Los Angeles, California. 7. Department of Radiation Oncology, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. 8. Centre Georges-François Leclerc, Dijon, Sorbonne Université Paris, Paris, France. 9. Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, the Netherlands. 10. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 11. Department of Radiation Oncology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, California. 12. Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles. 13. Division of Hematology and Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, Los Angeles, California. 14. Department of Radiation Oncology, University of Michigan, Ann Arbor.
Abstract
Importance: Androgen deprivation therapy (ADT) improves survival outcomes in patients with high-risk prostate cancer (PCa) treated with radiotherapy (RT). Whether this benefit differs between patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease remains unknown. Objective: To determine whether the effectiveness of ADT duration varies between patients with GG 4 vs GG 5 PCa. Design, Setting, and Participants: Traditional and network individual patient data meta-analyses of 992 patients (593 GG 4 and 399 GG 5) who were enrolled in 6 randomized clinical trials were carried out. Main Outcomes and Measures: Multivariable Cox proportional hazard models were used to obtain hazard ratio (HR) estimates of ADT duration effects on overall survival (OS) and distant metastasis-free survival (DMFS). Cause-specific competing risk models were used to estimate HRs for cancer-specific survival (CSS). The interaction of ADT with GS was incorporated into the multivariable models. Traditional and network meta-analysis frameworks were used to compare outcomes of patients treated with RT alone, short-term ADT (STADT), long-term ADT (LTADT), and lifelong ADT. Results: Five hundred ninety-three male patients (mean age, 70 years; range, 43-88 years) with GG 4 and 399 with GG 5 were identified. Median follow-up was 6.4 years. Among GG 4 patients, LTADT and STADT improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.70 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .03 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44). Among GG 5 patients, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .04), whereas neither LTADT nor STADT did (HR, 0.80; 95% CI, 0.45-1.44 and HR, 1.13; 95% CI, 0.69-1.87; P = .45 and P = .64, respectively). Among all patients, and among those receiving STADT, GG 5 patients had inferior OS compared with GG 4 patients (HR, 1.25; 95% CI, 1.07-1.47 and HR, 1.40; 95% CI, 1.05-1.88, respectively; P = .02). There was no significant OS difference between GG 5 and GG 4 patients receiving LTADT or lifelong ADT (HR, 1.21; 95% CI, 0.89-1.65 and HR, 0.85; 95% CI, 0.53-1.37; P = .23 and P = .52, respectively). Conclusions and Relevance: These data suggest that prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit with different optimal durations. Strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.
Importance: Androgen deprivation therapy (ADT) improves survival outcomes in patients with high-risk prostate cancer (PCa) treated with radiotherapy (RT). Whether this benefit differs between patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease remains unknown. Objective: To determine whether the effectiveness of ADT duration varies between patients with GG 4 vs GG 5 PCa. Design, Setting, and Participants: Traditional and network individual patient data meta-analyses of 992 patients (593 GG 4 and 399 GG 5) who were enrolled in 6 randomized clinical trials were carried out. Main Outcomes and Measures: Multivariable Cox proportional hazard models were used to obtain hazard ratio (HR) estimates of ADT duration effects on overall survival (OS) and distant metastasis-free survival (DMFS). Cause-specific competing risk models were used to estimate HRs for cancer-specific survival (CSS). The interaction of ADT with GS was incorporated into the multivariable models. Traditional and network meta-analysis frameworks were used to compare outcomes of patients treated with RT alone, short-term ADT (STADT), long-term ADT (LTADT), and lifelong ADT. Results: Five hundred ninety-three male patients (mean age, 70 years; range, 43-88 years) with GG 4 and 399 with GG 5 were identified. Median follow-up was 6.4 years. Among GG 4 patients, LTADT and STADT improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.70 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .03 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44). Among GG 5 patients, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .04), whereas neither LTADT nor STADT did (HR, 0.80; 95% CI, 0.45-1.44 and HR, 1.13; 95% CI, 0.69-1.87; P = .45 and P = .64, respectively). Among all patients, and among those receiving STADT, GG 5 patients had inferior OS compared with GG 4 patients (HR, 1.25; 95% CI, 1.07-1.47 and HR, 1.40; 95% CI, 1.05-1.88, respectively; P = .02). There was no significant OS difference between GG 5 and GG 4 patients receiving LTADT or lifelong ADT (HR, 1.21; 95% CI, 0.89-1.65 and HR, 0.85; 95% CI, 0.53-1.37; P = .23 and P = .52, respectively). Conclusions and Relevance: These data suggest that prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit with different optimal durations. Strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.
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