Association of Treatment With 5α-Reductase Inhibitors and Prostate Cancer Mortality Among Older Adults | Clinical Pharmacy and Pharmacology | JAMA Network Open | JAMA Network
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Table 1.  Baseline Patient Characteristics at Prostate Cancer Diagnosis
Baseline Patient Characteristics at Prostate Cancer Diagnosis
Table 2.  Prostate Cancer–Specific, Noncancer, and All-Cause Mortality
Prostate Cancer–Specific, Noncancer, and All-Cause Mortality
1.
Berry  SJ, Coffey  DS, Walsh  PC, Ewing  LL.  The development of human benign prostatic hyperplasia with age.  J Urol. 1984;132(3):474-479. doi:10.1016/S0022-5347(17)49698-4PubMedGoogle ScholarCrossref
2.
Andriole  GL, Guess  HA, Epstein  JI,  et al; PLESS Study Group.  Treatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial.  Urology. 1998;52(2):195-201. doi:10.1016/S0090-4295(98)00184-8PubMedGoogle ScholarCrossref
3.
Sarkar  RR, Parsons  JK, Bryant  AK,  et al.  Association of treatment with 5α-reductase inhibitors with time to diagnosis and mortality in prostate cancer.  JAMA Intern Med. 2019;179(6):812-819. doi:10.1001/jamainternmed.2019.0280PubMedGoogle ScholarCrossref
4.
Azoulay  L, Eberg  M, Benayoun  S, Pollak  M.  5α-Reductase inhibitors and the risk of cancer-related mortality in men with prostate cancer.  JAMA Oncol. 2015;1(3):314-320. doi:10.1001/jamaoncol.2015.0387PubMedGoogle ScholarCrossref
5.
Hall  SE, Holman  CDJ, Wisniewski  ZS, Semmens  J.  Prostate cancer: socio-economic, geographical and private-health insurance effects on care and survival.  BJU Int. 2005;95(1):51-58. doi:10.1111/j.1464-410X.2005.05248.xPubMedGoogle ScholarCrossref
6.
Hanson  HA, Martin  C, O’Neil  B,  et al.  The relative importance of race compared to health care and social factors in predicting prostate cancer mortality: a random forest approach [published online June 27, 2019].  J Urol. doi:10.1097/JU.0000000000000416PubMedGoogle Scholar
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    Research Letter
    Oncology
    October 18, 2019

    Association of Treatment With 5α-Reductase Inhibitors and Prostate Cancer Mortality Among Older Adults

    Author Affiliations
    • 1Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla
    • 2Department of Urology, University of California, San Diego, La Jolla
    JAMA Netw Open. 2019;2(10):e1913612. doi:10.1001/jamanetworkopen.2019.13612
    Introduction

    5α-reductase inhibitors (5-ARIs) are used to treat benign prostatic enlargement, a common condition causing urinary outflow obstruction.1 They also reduce prostate-specific antigen (PSA) by approximately 50%.2 Our group has recently published that among US military veterans, 5-ARIs are associated with delays in prostate cancer (PC) diagnoses, higher grade and stage at presentation, and worse PC-specific mortality (PCSM), presumably because of misinterpreted PSA values.3 We hypothesized that these results are generalizable to the broader US population.

    Methods

    This cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The study was considered exempt from review by the University of California, San Diego institutional review board because it used deidentified data. Data analysis was performed from February 1, 2019, through April 30, 2019.

    We used the Surveillance, Epidemiology, and End Results Program–Medicare linked database and identified patients with stage I to IV PC and known PSA level at diagnosis between January 1, 2008, and December 31, 2013; no missing covariate information; and Medicare Part D coverage. Patients were required to have at least 1 year of prediagnosis Medicare enrollment for comorbidity assessment. All patients were followed up until death or December 31, 2015.

    We extracted demographic and comorbidity variables, prescription drug information, and tumor-level variables. We defined 5-ARI use as any prescription of finasteride or dutasteride at least 6 months before a PC diagnosis. We doubled the PSA level for 5-ARI users per the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.4 We did not include in our models staging or treatment information as covariates because they are on the causal pathway between exposure and outcome.4

    We tested for differences in covariates between exposure groups using χ2 and Wilcoxon rank sum tests. We used multivariable Fine-Gray competing risk regression models to obtain estimates of PCSM and noncancer mortality accounting for competing risk of death. We used multivariable Cox proportional hazards regression models to obtain hazard ratio (HR) estimates of all-cause mortality (ACM). Statistical tests were 2-sided, with P < .05 considered statistically significant, and were conducted with SAS statistical software version 9.4 (SAS Institute Inc) and R statistical software version 3.5.1 (R Project for Statistical Computing).

    Results

    The final cohort included 30 313 patients, with median (interquartile range) follow-up of 3.75 (2.33-5.25) years. A total of 2373 patients (7.83%) were prescribed 5-ARIs at least 6 months before PC diagnosis, with a median (interquartile range) treatment duration of 2.46 (1.45-3.74) years. The 4-year cumulative incidence of death from PC was 5.3% in 5-ARI users and 2.8% in nonusers.

    Compared with participants who did not receive 5-ARI, those who did were more likely to present with disease that was high grade (Gleason score 8-10) (18% vs 29%, respectively; difference, 12%; 95% CI, 9%-13%; P < .001), high risk (28% vs 38%; difference, 9%; 95% CI, 8%-11%; P < .001), clinically node positive (2% vs 3%; difference, 1%; 95% CI, 0.6%-2%; P < .001), and clinically metastatic (2% vs 3%; difference, 1%; 95% CI, 0.5%-2%; P < .001). Furthermore, median (interquartile range) adjusted PSA level at diagnosis was significantly higher in 5-ARI users compared with nonusers (14.2 [9.0-24.0] ng/mL vs 6.6 [4.8-10.2] ng/mL; difference, 7.6 ng/mL; 95% CI, 7.0-8.2 ng/mL; P < .001 [to convert to micromoles per liter, multiply by 1.0]) (Table 1).

    Use of 5-ARIs was associated with an increased risk of PCSM (subdistribution HR, 1.38; 95% CI, 1.10-1.73; P = .005) and ACM (HR, 1.15; 95% CI, 1.01-1.30; P = .04). There were no differences in noncancer mortality (subdistribution HR, 1.06; 95% CI, 0.91-1.23; P = .47) (Table 2).

    Discussion

    This cohort study found that 5-ARI users presented with higher adjusted PSA levels and PC disease burden. They also had worse PCSM and ACM, but not worse noncancer mortality. These results are consistent with our recently published findings3 that observed that among US veterans, 5-ARI use was associated with worse PCSM (subdistribution HR, 1.39; 95% CI, 1.27-1.52; P < .001) and ACM (HR, 1.10; 95% CI, 1.05-1.15; P < .001). Like other studies,3-6 we found that comorbidities, unmarried status, old age, low income, and black race were risk factors for PCSM, which adds validity to our findings. One study limitation included the possibility of misclassification bias, in which 5-ARIs were not used as prescribed.

    Our results suggest a need for increased awareness of 5-ARI–induced PSA suppression, clearer guidelines for early PC detection, and systems-based mechanisms to help improve care for men using 5-ARIs.

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    Article Information

    Accepted for Publication: September 3, 2019.

    Published: October 18, 2019. doi:10.1001/jamanetworkopen.2019.13612

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Kumar A et al. JAMA Network Open.

    Corresponding Author: Brent S. Rose, MD, Department of Radiation Medicine and Applied Sciences, University of California, Altman Clinical and Translational Research Institute Bldg, 9452 Medical Center Dr, La Jolla, CA 92037 (bsrose@ucsd.edu).

    Author Contributions: Messrs Kumar and Nalawade had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Kumar, Riviere, Parsons, Murphy, Rose.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Kumar, Murphy, Rose.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Kumar, Nalawade, Riviere, Murphy, Rose.

    Administrative, technical, or material support: Murphy, Rose.

    Supervision: Sarkar, Parsons, Rose.

    Conflict of Interest Disclosures: Mr Kumar reported receiving personal fees from Sympto Health outside the submitted work. Mr Riviere reported receiving personal fees from Peptide Logic LLC outside the submitted work. Dr Sarkar reported receiving personal fees from Boston Consulting Group outside the submitted work. Dr Murphy reported receiving consulting fees from Boston Consulting Group outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was supported by the National Institutes of Health (grant TL1TR001443 to Messrs Kumar and Riviere and Dr Sarkar).

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    References
    1.
    Berry  SJ, Coffey  DS, Walsh  PC, Ewing  LL.  The development of human benign prostatic hyperplasia with age.  J Urol. 1984;132(3):474-479. doi:10.1016/S0022-5347(17)49698-4PubMedGoogle ScholarCrossref
    2.
    Andriole  GL, Guess  HA, Epstein  JI,  et al; PLESS Study Group.  Treatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial.  Urology. 1998;52(2):195-201. doi:10.1016/S0090-4295(98)00184-8PubMedGoogle ScholarCrossref
    3.
    Sarkar  RR, Parsons  JK, Bryant  AK,  et al.  Association of treatment with 5α-reductase inhibitors with time to diagnosis and mortality in prostate cancer.  JAMA Intern Med. 2019;179(6):812-819. doi:10.1001/jamainternmed.2019.0280PubMedGoogle ScholarCrossref
    4.
    Azoulay  L, Eberg  M, Benayoun  S, Pollak  M.  5α-Reductase inhibitors and the risk of cancer-related mortality in men with prostate cancer.  JAMA Oncol. 2015;1(3):314-320. doi:10.1001/jamaoncol.2015.0387PubMedGoogle ScholarCrossref
    5.
    Hall  SE, Holman  CDJ, Wisniewski  ZS, Semmens  J.  Prostate cancer: socio-economic, geographical and private-health insurance effects on care and survival.  BJU Int. 2005;95(1):51-58. doi:10.1111/j.1464-410X.2005.05248.xPubMedGoogle ScholarCrossref
    6.
    Hanson  HA, Martin  C, O’Neil  B,  et al.  The relative importance of race compared to health care and social factors in predicting prostate cancer mortality: a random forest approach [published online June 27, 2019].  J Urol. doi:10.1097/JU.0000000000000416PubMedGoogle Scholar
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