Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes: A Systematic Review and Patient-Level Meta-analysis | Oncology | JAMA Oncology | JAMA Network
[Skip to Navigation]
Figure.  Forest Plots of Androgen Deprivation Therapy (ADT) and Gleason Grade Group (GG) Associated With All-Cause Mortality
Forest Plots of Androgen Deprivation Therapy (ADT) and Gleason Grade Group (GG) Associated With All-Cause Mortality

Forest plot derived from network meta-analysis of ADT effect on all-cause mortality, stratified by (A) GG 4 vs (B) GG 5. Note that the reference value (HR 1.00) for each forest plot is radiation therapy (RT) alone. The hazard ratios (HRs) and 95% confidence intervals (95% CI) are presented in ascending order, with their associated P-score (a frequentist analog to the surface under the cumulative ranking curve). C, Forest plot derived from meta-analysis of association of GG 4 vs GG 5 with all-cause mortality, stratified by ADT duration. HRs and 95% CI for each ADT duration stratum are presented, along with corresponding treatment effect (TE; log[HR]) and the standard error of the TE (seTE).

Table 1.  Summary of Trials Included in Meta-analysis With Breakdown by Gleason Score
Summary of Trials Included in Meta-analysis With Breakdown by Gleason Score
Table 2.  Crude Event Incidence for Metastases, Prostate Cancer-Specific Mortality, and All-Cause Mortality
Crude Event Incidence for Metastases, Prostate Cancer-Specific Mortality, and All-Cause Mortality
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.

Introduction

Multiple randomized clinical trials have demonstrated a survival benefit to combining long-duration androgen deprivation therapy (ADT) with radiotherapy (RT) for high-risk prostate cancer (PCa).1 Androgen deprivation therapy has multiple adverse effects2 and several trials have investigated shortening ADT duration. Although most trials conflate the outcomes for patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease, GG 5 PCa has been consistently shown to follow a more aggressive natural history, and the effect of ADT duration might differ between the two.3 To identify differences in the association of ADT duration with clinical outcomes of patients with GG 4 and GG 5 PCa, we performed an individual patient-level meta-analysis of 6 randomized clinical trials (Table 1).4-9 Our working hypothesis was that longer durations of ADT would offer significant survival benefits in both groups.

Methods

Details of trial selection and specific trial information are provided in eFigure 1 and eTable 1 in the Supplement. Long-term ADT (LTADT) was defined as 28 to 36 months, whereas short-term ADT (STADT) was defined as 4 to 6 months. The primary endpoints were distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS). For DMFS and OS, patient-level data were used to obtain trial-specific hazard ratio (HR) estimates of pairwise treatment effects after fitting multivariable Cox proportional hazards models adjusting for age, specific Gleason score (eg, 9 vs 10), interaction of treatments and GG, and T-stage. For CSS, HRs were obtained by fitting cause-specific competing risk models with competing events, such as noncancer-related deaths treated as censored observations. For studies with small sample size, Firth’s bias correction method10 was applied in the estimation of individual models to obtain stable estimates. A network meta-analysis (NMA)10,11 approach was adopted for direct/indirect pairwise meta-analysis of treatments. Based on novel graph-theory methodology and electrical networks, this frequentist method derives an NMA framework that enables incorporation of indirect comparisons constructed from 2 studies that have 1 treatment in common, while accounting for the correlated treatment effects in multiarm trials (eFigure 2 in the Supplement).11 Fixed-effect and random-effects models were adopted after evaluating the heterogeneity and inconsistency of the included studies by between-studies variance, percentage of the total variability in a set of effect sizes owing to true heterogeneity, and Q test for heterogeneity/inconsistency, and treatments were ranked by P score, a frequentist analogue to the surface under the cumulative ranking curve. Traditional random-effects meta-analyses were performed to compare outcomes between GG 5 and GG 4 disease as a function of ADT duration. All statistical analyses were conducted using SAS statistical software (version 9.4, SAS Institute Inc) and Packages “netmeta” (Network Meta-Analysis using Frequentist Methods) and “meta” in the R statistical software environment (version 3.3.1, R Foundation).11

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, with a median follow-up of 6.4 years. Baseline characteristics and clinical outcome are provided in Table 2 and eTable 2 in the Supplement. Individual trial Cox proportional hazard models for DMFS, CSS, and OS suggested variable effects between GG 4 and GG 5 patients (eTable 3 in the Supplement). The NMA found that among patients with GG 4 disease, both LTADT and STADT offered improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.72 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .02 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44) (Figure)4-9 (eFigure 3 and eTable 4 in the Supplement). Among patients with GG 5 disease, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .01), 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).

Forest plot analyses of outcomes from traditional random-effects meta-analyses comparing GG 4 and GG 5 patients are shown in the Figure and in eFigure 4 in the Supplement. Both among patients receiving STADT and among all patients overall (regardless of ADT duration), those with GG 5 disease had inferior OS compared with those with GG 4 disease (HR, 1.40; 95% CI, 1.05-1.88; P = .05 for STADT and HR, 1.25; 95% CI, 1.07-1.47; P = .04 all patients). Among patients receiving LTADT or lifelong ADT, there was no significant difference in OS between GG 5 and GG 4 disease (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).

Discussion

In this individual patient-level meta-analysis, longer durations of ADT were found to improve clinical outcomes for patients with GG 4 and GG 5 disease in distinct ways. Among patients with GG 4 disease, both LTADT and STADT offered improved OS over RT alone, whereas lifelong ADT did not. Among patients with GG 5 disease, lifelong ADT improved OS over RT alone, whereas neither LTADT nor STADT did. Overall, and among patients receiving STADT, GG 5 disease was associated with worse OS; LTADT and lifelong ADT appear to mitigate this difference. Similar patterns were seen for DMFS and CSS endpoints, though these endpoints contained more uncertainty than the OS endpoint owing to potential misclassification. These results also provide prospectively obtained evidence that patients with GG 5 disease receiving RT have inferior outcomes compared with those with GG 4 disease.

Androgen deprivation therapy may improve outcomes in RT-treated patients with high-risk PCa through a combination of systemic effects on micrometastatic disease and direct radiosensitizing effects in the prostate,12 and adjuvant ADT has been shown to suppress the induction of androgen receptor activity by RT.13 If GG 5 PCa has greater RT induction of androgen receptor activity than GG 4 disease, a longer period of adjuvant ADT would be required for a similar therapeutic effect, explaining the clear benefit of lifelong ADT in treating GG 5 disease. The lack of any significant survival benefit for lifelong ADT in treating GG 4 disease may reflect a lack of statistical power; for CSS and DMFS, it may also reflect the relative uncertainty of these endpoints. Alternatively, the known sequelae of lifelong ADT may counteract any potential oncologic benefit, potentially explaining the lack of an OS benefit.

The lack of benefit for any outcome with LTADT in GG 5 disease might suggest that the magnitude of the benefit may have been too small to detect even with a meta-analysis. A multi-institutional analysis of GG 5 patients identified a significant CSS benefit to extreme dose escalation with a brachytherapy boost over standard dose-escalated RT, despite a significantly longer ADT duration with standard dose-escalated RT.14 Although this might suggest that less radiosensitizing ADT is required with higher RT doses, the median duration of ADT with extreme dose escalation was still 12 months, and the study was retrospective. Finally, a recent randomized trial comparing 18 months of ADT with 36 months of ADT for high-risk PCa did not identify a difference in survival outcomes with longer duration ADT.9 However, were data from this trial to be incorporated into the present meta-analysis, patients receiving 18 months of ADT would likely be considered as having received an intermediate duration between LTADT and STADT, rather than receiving STADT.

Limitations

There are several limitations to this study. Foremost, this constitutes an unplanned subset analysis of multiple randomized clinical trials, and thus the findings must be interpreted with the knowledge that none of the trials were specifically powered or designed to evaluate differences in outcome based on GG.15 Limitations include a lack of centralized pathology review, the use of radiation doses that would be considered substandard today, and the high enrichment of patients with locally advanced lesions compared with modern cohorts (66% with cT3 disease). Regarding pathology review, this is a limitation with regard to concordance between studies but also, owing to changes in the Gleason grading system over time, may affect the applicability of these findings to GG 4 and GG 5 PCas diagnosed in the present day. However, all of these limitations apply to the general applicability of these trials to the modern era, yet they still define the present standard of care. In addition, the most robust effect noted is that of lifelong ADT in the GG 5 group and was observed in a trial initiated 31 years ago in which staging studies were relatively insensitive. It is possible that the benefit of lifelong ADT might come primarily from controlling occult metastases, rather than reflecting the biology of the primary disease. However, this would be expected to be true for patients with GG 4 disease as well, and lifelong ADT did not offer a statistically significant benefit in those patients. Finally, the studies varied in the use of concurrent nonsteroidal anti-androgens in conjunction with luteinizing hormone releasing hormone agonists, as well as the timing of initiation of ADT.

Conclusions

Prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit in different ways. Use of STADT and LTADT offer OS improvements in GG 4 disease, but not GG 5 disease; the opposite is true for lifelong ADT. Strategies to maintain the efficacy of ADT while minimizing its duration (eg, enhanced potency agents) should be investigated.

Back to top
Article Information

Corresponding Author: Amar U. Kishan, MD, Department of Radiation Oncology, University of California, Los Angeles, 200 Medical Plaza, Ste B265, Los Angeles, CA 90095 (aukishan@mednet.ucla.edu).

Accepted for Publication: June 14, 2018.

Published Online: September 20, 2018. doi:10.1001/jamaoncol.2018.3732

Author Contributions: Dr Kishan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kishan, Hanks, Nickols, Reiter, Kupelian, Steinberg, King.

Acquisition, analysis, or interpretation of data: Kishan, Wang, Seiferheld, Collette, K. Sandler, H. Sandler, Bolla, Maingon, De Reijke, Hanks, Nickols, Rettig, Drakaki, Spratt, Kupelian, Steinberg, King.

Drafting of the manuscript: Kishan, Wang, Collette, Hanks, Steinberg, King.

Critical revision of the manuscript for important intellectual content: Kishan, Wang, Seiferheld, Collette, K. Sandler, H. Sandler, Bolla, Maingon, De Reijke, Nickols, Rettig, Drakaki, Reiter, Spratt, Kupelian, Steinberg, King.

Statistical analysis: Kishan, Wang, Collette.

Obtained funding: Kishan.

Administrative, technical, or material support: Kishan, K. Sandler, H. Sandler, De Reijke, Hanks, Rettig, Spratt, Steinberg, King.

Study supervision: Kishan, H. Sandler, Bolla, Maingon, Nickols, Rettig, Drakaki, Kupelian, Steinberg, King.

Conflict of Interest Disclosures: Dr Kupelian reports serving on the scientific advisory board for ViewRay Inc. Dr Nickols reports receiving a grant from Varian Systems and support for a trial from Janssen, and serving as a consultant to Nanobiotix for activities outside the submitted work. Dr Sandler reports personal fees from Sanofi, Janssen, Ferring, NantHealth, and Dendreon. No other disclosures are reported.

Disclaimer: The statements in this article are solely the responsibility of the authors.

References
1.
Nguyen  PL.  Optimization of the radiation management of high-risk prostate cancer.  Semin Radiat Oncol. 2017;27(1):43-49. doi:10.1016/j.semradonc.2016.08.009PubMedGoogle ScholarCrossref
2.
Nguyen  PL, Alibhai  SM, Basaria  S,  et al.  Adverse effects of androgen deprivation therapy and strategies to mitigate them.  Eur Urol. 2015;67(5):825-836. doi:10.1016/j.eururo.2014.07.010PubMedGoogle ScholarCrossref
3.
D’Amico  AV.  Is Gleason grade 5 prostate cancer resistant to conventional androgen deprivation therapy?  Eur Urol. 2016;69(5):761-763. doi:10.1016/j.eururo.2015.08.057PubMedGoogle ScholarCrossref
4.
Pilepich  MV, Winter  K, Lawton  CA,  et al.  Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—long-term results of phase III RTOG 85-31.  Int J Radiat Oncol Biol Phys. 2005;61(5):1285-1290. doi:10.1016/j.ijrobp.2004.08.047PubMedGoogle ScholarCrossref
5.
Pilepich  MV, Winter  K, John  MJ,  et al.  Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate.  Int J Radiat Oncol Biol Phys. 2001;50(5):1243-1252. doi:10.1016/S0360-3016(01)01579-6PubMedGoogle ScholarCrossref
6.
Horwitz  EM, Bae  K, Hanks  GE,  et al.  Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer.  J Clin Oncol. 2008;26(15):2497-2504. doi:10.1200/JCO.2007.14.9021PubMedGoogle ScholarCrossref
7.
Bolla  M, Gonzalez  D, Warde  P,  et al.  Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin.  N Engl J Med. 1997;337(5):295-300. doi:10.1056/NEJM199707313370502PubMedGoogle ScholarCrossref
8.
Bolla  M, de Reijke  TM, Van Tienhoven  G,  et al; EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group.  Duration of androgen suppression in the treatment of prostate cancer.  N Engl J Med. 2009;360(24):2516-2527. doi:10.1056/NEJMoa0810095PubMedGoogle ScholarCrossref
9.
Bolla  M, Maingon  P, Carrie  C,  et al.  Short androgen suppression and radiation dose escalation for intermediate- and high-risk localized prostate cancer: results of EORTC trial 22991.  J Clin Oncol. 2016;34(15):1748-1756. doi:10.1200/JCO.2015.64.8055PubMedGoogle ScholarCrossref
10.
Rücker  G.  Network meta-analysis, electrical networks and graph theory.  Res Synth Methods. 2012;3(4):312-324. doi:10.1002/jrsm.1058PubMedGoogle ScholarCrossref
11.
Team  RDCR. a language and environment for statistical computing. 2016; https://www.gbif.org/tool/81287/r-a-language-and-environment-for-statistical-computing. Accessed November 15, 2017.
12.
Polkinghorn  WR, Parker  JS, Lee  MX,  et al.  Androgen receptor signaling regulates DNA repair in prostate cancers.  Cancer Discov. 2013;3(11):1245-1253. doi:10.1158/2159-8290.CD-13-0172PubMedGoogle ScholarCrossref
13.
Spratt  DE, Evans  MJ, Davis  BJ,  et al.  Androgen receptor upregulation mediates radioresistance after ionizing radiation.  Cancer Res. 2015;75(22):4688-4696. doi:10.1158/0008-5472.CAN-15-0892PubMedGoogle ScholarCrossref
14.
Kishan  AU, Cook  RR, Ciezki  JP,  et al.  Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 prostate cancer.  JAMA. 2018;319(9):896-905. doi:10.1001/jama.2018.0587PubMedGoogle ScholarCrossref
15.
Brookes  ST, Whitley  E, Peters  TJ, Mulheran  PA, Egger  M, Davey Smith  G.  Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.  Health Technol Assess. 2001;5(33):1-56. doi:10.3310/hta5330PubMedGoogle ScholarCrossref
×