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Original Investigation
March 26, 2020

Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer

Author Affiliations
  • 1Department of Radiation Oncology, University of Michigan, Ann Arbor
  • 2Department of Biostatistics, University of Michigan, Ann Arbor
  • 3Department of Radiation Oncology, University of California, Los Angeles
  • 4Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 5Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
  • 6Department of Radiation Oncology, Cedars-Sinai Medical Center, West Hollywood, California
  • 7Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
  • 8Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee
  • 9Department of Medicine, University of Michigan, Ann Arbor
  • 10Department of Urology, University of Michigan, Ann Arbor
  • 11Department of Pathology, University of Michigan, Ann Arbor
  • 12Department of Urology, Northwestern University, Chicago, Illinois
  • 13Department of Medicine, Tulane Cancer Center, New Orleans, Louisiana
  • 14Department of Radiation Oncology, Duke Health, Durham, North Carolina
  • 15Department of Radiation Oncology, Sutter Medical Group, Sacramento, California
  • 16Department of Radiation Oncology, Washington University School of Medicine in St Louis, St Louis, Missouri
  • 17Department of Public Health Sciences, University of Chicago, Chicago, Illinois
  • 18Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
  • 19Department of Radiation Oncology, University of California, San Francisco
  • 20Department of Urology, University of California, San Francisco
  • 21Department of Medicine, University of California, San Francisco
JAMA Oncol. Published online March 26, 2020. doi:10.1001/jamaoncol.2020.0109
Visual Abstract. Secondary Analysis of Association of Presalvage Radiotherapy Prostate-Specific Antigen With Net Benefit From Long-term Antiandrogen Therapy
Secondary Analysis of Association of Presalvage Radiotherapy Prostate-Specific Antigen With Net Benefit From Long-term Antiandrogen Therapy
Key Points

Question  For men with recurrent prostate cancer after radical prostatectomy, can prostate-specific antigen (PSA) level be used to help predict outcomes of long-term antiandrogen treatment added to salvage radiotherapy (SRT)?

Findings  In this secondary analysis of the RTOG 9601 trial, pre-SRT PSA level of higher than 1.5 ng/mL was associated with an overall survival benefit with long-term antiandrogen therapy. Patients treated at a PSA of 0.6 ng/mL or less had no overall survival improvement, but had a greater than 3-fold increase in high-grade cardiac and neurologic events and a 2-fold increase in other cause mortality with 2 years of bicalutamide.

Meaning  Antiandrogen treatment has morbidity, and pre-SRT PSA can be used to personalize who derives net benefit of hormone therapy with SRT.


Importance  In men with recurrent prostate cancer, addition of long-term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment.

Objective  To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT.

Interventions  Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years.

Design, Setting, and Participants  In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019.

Main Outcomes and Measures  The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM).

Results  Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P = .01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P = .05).

Conclusions and Relevance  These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population.

Trial Registration  ClinicalTrials.gov Identifier: NCT00002874

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