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Brief Report
January 2019

Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes: A Systematic Review and Patient-Level Meta-analysis

Author Affiliations
  • 1Department of Radiation Oncology, University of California, Los Angeles, Los Angeles
  • 2Department of Urology, University of California, Los Angeles, Los Angeles
  • 3Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, Los Angeles
  • 4NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
  • 5European Organization for Research and Treatment of Cancer Headquarters, Brussels, Belgium
  • 6Department of Radiation Oncology, Cedars Sinai, Los Angeles, California
  • 7Department of Radiation Oncology, Centre Hospitalier Universitaire de Grenoble, Grenoble, France
  • 8Centre Georges-François Leclerc, Dijon, Sorbonne Université Paris, Paris, France
  • 9Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, the Netherlands
  • 10Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 11Department of Radiation Oncology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, California
  • 12Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles
  • 13Division of Hematology and Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, Los Angeles, California
  • 14Department of Radiation Oncology, University of Michigan, Ann Arbor
JAMA Oncol. 2019;5(1):91-96. doi:10.1001/jamaoncol.2018.3732
Key Points

Question  Do Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) prostate cancers respond differently to increasing durations of androgen deprivation therapy (ADT) with radiotherapy?

Findings  In this systematic review and meta-analysis of 992 patients with GG 4 to 5 disease, short-term ADT and long-term ADT only improved overall survival among patients with GG 4 disease, and lifelong ADT only improved overall survival in patients with GG 5 disease.

Meaning  Longer durations of ADT improved outcomes in GG 4 and GG 5 disease, with different optimal durations; strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.

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.

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