"This report brings to light an often-suspected but previously undocumented clinical issue in great and alarming detail," says Badar M. Mian, MD.
“Journal Article of the Month” is a new Urology Times section in which Badar M. Mian, MD (left), offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, Albany, NY.
The use of 5-alpha-reductase inhibitors (5-ARIs) for voiding symptoms from enlarged prostate and PSA screening for early detection of prostate cancer are among the most frequent urologic interventions in men. When using 5-ARIs (finasteride, dutasteride), the observed PSA level should be adjusted (by a factor of 2) to obtain the representative PSA level.
While 5-ARIs have been used as a preventive measure (based on the PCPT and REDUCE trials) to reduce the risk of prostate cancer, a new report by Sarkar et al suggests that the clinical use of 5-ARIs resulted in delayed biopsy, worse pathology, and increased mortality from prostate cancer (JAMA Intern Med [published online May 6, 2019]).
The authors used the Veterans Affairs (VA) electronic platform that provides access to patient-level electronic health and administrative data for all veterans within the VA health care system, including tumor registry data. There were 80,875 men with prostate cancer and PSA level known at diagnosis between Jan. 1, 2001 and Dec. 31, 2015 who met the inclusion criteria. Prostate biopsy date and prebiopsy PSA level were available for 62,165 patients.
Also by Dr. Mian: PCa study evaluates ‘clinically meaningful’ margins, recurrence
PSA elevation was defined as PSA >4.0 ng/mL for men without 5-ARIs and 2.0 ng/mL for those men who had been prescribed 5-ARIs (then adjusted by multiplying it by 2). There were 19,065 all-cause deaths and 4,513 were due to prostate cancer. A total of 8,587 men (10.6%) were prescribed 5-ARIs at least 1 year before prostate cancer diagnosis.
The authors reported that 5-ARI users had longer delays from first “adjusted” elevated PSA to prostate biopsy (3.60 years) than patients taking alpha-blockers alone (2.11 years) or patients who did not use either medication (1.17 years). While the “unadjusted” PSA at the time of biopsy was similar among the groups (6.8 ng/mL, 6.4 ng/mL, 6.4 ng/mL), the “adjusted” PSA level for 5-ARI users (13.5 ng/mL) was significantly higher compared to other groups (p<.001) at biopsy. At diagnosis with prostate cancer, 5-ARI users were noted to have significantly worse disease characteristics compared to those not using 5-ARIs, including Gleason score ≥8 (25.2 % vs. 17%), stage T3-4 (4.7% vs. 2.9%), lymph node-positive disease (3.0% vs. 1.7%), and distant metastatic disease (6.7% vs. 2.9%).
Prostate cancer-specific mortality for 5-ARI users (13%; p<.001) was significantly higher than those using an alpha-blocker alone (8%) or who used neither (8%). Similarly, all-cause mortality was worse in 5-ARI users than other groups (45% vs. 42% vs. 36%; p<.001). Using different multivariable analyses, the use of 5-ARIs was associated with 10% to 39% increased risk of prostate cancer-specific mortality.
Next:"Clearly, these findings are concerning"Clearly, these findings are concerning. Are patients’ cancer diagnoses being delayed due to 5-ARIs? Since patients who were prescribed a 5-ARI were older and with additional comorbidities, one might speculate that they were not considered ideal candidates for PSA-based early detection and/or treatment. But the longer interval from PSA elevation to biopsy and the higher adjusted PSA level were noted even in patients who were less than 60 years of age.
In our personal communication about these unintended consequences of 5-ARI use, Patrick C. Walsh, MD, professor emeritus at Johns Hopkins, stated that he has seen some tragic outcomes from delayed diagnosis in young men receiving finasteride for voiding symptoms (or for hair loss). Dr. Walsh emphasized the fact that any rise in the PSA level in men being treated with 5-ARIs increases their risk of being diagnosed with high-grade prostate cancer by several folds, as evidenced by the published data from the PCPT. Thus, it is essential for patients and health care providers to understand that regular PSA measurements should continue in these men for as long as 5-ARIs are being used.
On its surface there may appear to be conflict between this report and the previously published reports from the PCPT (see, “5-ARI use reduces prostate Ca risk for up to 16 years"), but those two must not be conflated. This report is based on clinical use of 5-ARIs (likely for BPH and voiding symptoms) without any set protocol for PSA test or follow-up intervals, while the PCPT participants were monitored under a well-controlled protocol that included PSA, digital rectal exam, and/or biopsies. It appears that the very well-described association between 5-ARI use and PSA level (requiring multiplication of the lab-reported value of PSA by a factor of 2) may have been overlooked, and that omission may have resulted in increased mortality from prostate cancer.
This report brings to light an often-suspected but previously undocumented clinical issue in great and alarming detail. There is a clear and urgent opportunity to re-educate prescribers (both primary care physicians and urologists) about appropriate adjustments to the PSA level when using 5-ARIs in order to avoid unnecessary morbidity and mortality from prostate cancer.