Alpha-blockers are commonly prescribed for the medical treatment of benign prostatic hyperplasia (BPH). Because BPH affects older men who are also at risk for prostate cancer, a relationship between these medications and prostate cancer risk would have considerable public health implications. Indeed, a study of 1864 men aged at least 40 years from the National Health and Nutrition Examination Survey (NHANES) with at least one prostate-specific antigen test reported that alpha-blockers were among the 10 most commonly used medication classes, with 4.4% of men taking them . The purpose of this article is to review the evidence about prostate cancer risk among men using alpha-blocker therapy.
Many different types of alpha-blockers are used in the management of BPH. These include doxazosin, terazosin, tamsulosin, alfuzosin, and silodosin. Because of their frequent use in adult men at risk for prostate cancer, a relationship between alpha-blockers and this malignancy would have important public health ramifications. Interestingly, there is some experimental evidence providing rationale for a possible link between alpha-blockers and prostate cancer risk.
Basic science studies have demonstrated antiangiogenesis and proapoptotic properties of alpha-blockers on prostate tumor cells. For example, Kyprianou and Benning [2▪▪] examined cell viability, DNA synthesis, and apoptosis in human PC-3 and DU-145 prostate cancer cell lines exposed to doxazosin, terazosin, and tamsulosin. Doxazosin was associated with decreased cell viability in both cell lines, a reduction in DNA synthesis, and increased apoptosis. Terazosin was also associated with decreased cell viability in the PC-3 but not the DU-145 prostate cells, and tamsulosin had no effect on cell viability in either cell line. Similarly, when administered to nude mice containing PC-3 prostate cancer xenografts, tamsulosin had no effect, whereas doxazosin was associated with a significant decrease in tumor size. It is noteworthy that these alpha-blockers have a different chemical composition: doxazosin is a quinazoline derivative, whereas tamsulosin is a sulfonamide derivative . Quinazoline compounds have been shown to exert strong antiangiogenic effects , which may impair prostate cancer growth by targeting the neovascularization process . Overall, these experimental findings suggest that all alpha-blockers may not be equal in their relation to prostate tumor inhibition [2▪▪].
Only a few clinical studies have reported on the relationship between alpha-blockers and prostate cancer in human populations. In a large Veterans Affairs population, Harris et al.  reported a significantly lower cumulative incidence of prostate cancer (1.65 versus 2.41%) in alpha-blocker users versus nonusers, equating to approximately 7.6 fewer prostate cancer cases per 1000 exposed. However, among men with prostate cancer, there was no significant relationship between alpha-blocker exposure and overall survival. Details on pathologic tumor features were not reported in this study.
More recently, Murtola et al.  reported on alpha-blocker use and prostate cancer risk within the Finnish Prostate Cancer Screening Trial. In this study, there was no significant association between alpha-blocker use and overall prostate cancer incidence. However, there was a significant reduction in Gleason 7–10 tumors in the alpha-blocker exposed (versus unexposed) participants [odds ratio 0.55, 95% confidence interval (CI) 0.31–0.96]. Moreover, the significant protective association between alpha-blockers and high-grade disease increased with a longer duration of alpha-blocker use (P = 0.04).
By contrast, Orsted et al. [8▪▪] reported conflicting results in a large population-based study from Denmark. This study was designed to look at the relationship between clinical BPH with prostate cancer incidence and mortality, using four different ways to assess for BPH: hospitalization, surgery, alpha-blocker use, and 5ARI use. Using each of the four criteria, they found an increased incidence and mortality from prostate cancer among men with BPH. For men prescribed alpha-blockers from 1995 to 2006, the hazard ratio was 2.58 (95% CI 2.44–2.73) for prostate cancer death. However, as with the other studies, the retrospective nature of this analysis precludes the ability to assess a causal relationship. As discussed in an accompanying editorial comment, differential screening practices among men with BPH may have influenced the results .
Overall, there are many possible explanations for the disparity between studies, including disparate patient populations and confounding from other factors. Additionally, as basic science studies showed a different tumor inhibition profile between doxazosin and tamsulosin, this suggests that clinical studies which group together all alpha-blockers may dampen any possible relationship. As such, multicenter prospective trials would be useful to specifically examine the long-term effect of exposure to quinazoline-based alpha-blockers and prostate cancer prevention.
It is noteworthy that a different type of BPH treatment, 5-alpha reductase inhibitors (5ARIs), has been extensively studied in randomized clinical trials for prostate cancer prevention [10,11]. However, concerns were raised regarding 5ARIs and an increased risk of high-grade disease, leading the US Food and Drug Administration to reject their use in prostate cancer prevention . However, 5ARIs are still approved for the treatment of symptomatic BPH in men with an enlarged prostate.
Of note, other agents have also been explored for prostate cancer chemoprevention including selenium and vitamin E. Several epidemiologic studies suggested that these supplements may decrease prostate cancer risk [13,14], leading to the initiation of the Selenium and Vitamin E Cancer Prevention Trial. Unfortunately, the study was stopped prematurely, as the follow-up results demonstrated a statistically significant increased risk of prostate cancer in the vitamin E group compared to placebo (hazard ratio 1.17, 99% CI 1.004–1.36, P = 0.008) . The disparity between the findings in this trial compared to the preclinical studies highlights the importance of prospective clinical trials in the assessment of possible chemopreventive strategies.
Similarly, because the existing clinical studies on alpha-blockers and prostate cancer are observational, it is possible that the confounding may have played a role in the results, rather than a true influence of alpha-blocker therapy on prostate cancer risk or aggressiveness. For example, there is conflicting evidence on whether BPH itself is related to prostate cancer risk [8▪▪,16,17▪]. Meanwhile, Freedland et al.  reported that larger prostate size was associated with less high-grade prostate cancer. If the BPH itself is associated with prostate cancer incidence or aggressiveness, confounding by indication may affect the results as men with BPH were over-represented in the alpha-blocker group.
Several observational studies have suggested a possible association between alpha-blocker therapy for BPH and a reduced risk of high-grade prostate cancer, while another large study suggested an increased risk of prostate cancer mortality in the users of alpha-blockers. Because of the differences between the various alpha-blockers in laboratory studies and the significant potential for confounding in observational studies, prospective studies are necessary to better establish the relationship between specific types of alpha-blockers (e.g. quinazoline based) with long-term, cancer-specific outcomes.
The authors would like to thank Dr Natasha Kyprianou for the critical review of the manuscript. Funding: S.L. is supported by the Louis Feil Charitable Lead Trust.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 95).
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