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Does benign prostatic hyperplasia treatment with alpha-blockers affect prostate cancer risk?

Loeb, Stacya; Gupta, Angelab; Losonczy, Liab; Tosoian, Jeffreyb; Walsh, Patrick C.b

doi: 10.1097/MOU.0b013e32835abcf2
BENIGN PROSTATIC HYPERPLASIA: Edited by Bob Djavan

Purpose of review To determine whether alpha-blockers, commonly used for the treatment of benign prostatic hyperplasia, are associated with prostate cancer risk.

Recent findings Alpha-blockers have been associated with a reduced risk of prostate cancer aggressiveness in some observational studies and an increased risk in other studies. However, this relationship is complex as different alpha-blockers have divergent effects in laboratory studies and there are many confounders in daily practice such as differential screening practices.

Summary Both benign prostatic hyperplasia and prostate cancer are common conditions in the aging male population, such that an interaction between alpha-blockers and prostate cancer risk is clinically relevant. Prospective evidence is necessary to establish a definitive link.

aDepartment of Urology, New York University, New York, New York

bBrady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Correspondence to Stacy Loeb, MD, 550 1st Avenue, VZ30 6th Floor, 612, New York, NY 10016, USA. Tel: +1 646 501 2559; fax: +1 212 263 4549; e-mail: stacyloeb@gmail.com

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INTRODUCTION

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 [1]. The purpose of this article is to review the evidence about prostate cancer risk among men using alpha-blocker therapy.

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REVIEW

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.

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Basic research

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 [3]. Quinazoline compounds have been shown to exert strong antiangiogenic effects [4], which may impair prostate cancer growth by targeting the neovascularization process [5]. Overall, these experimental findings suggest that all alpha-blockers may not be equal in their relation to prostate tumor inhibition [2▪▪].

Box 1

Box 1

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Clinical studies

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. [6] 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. [7] 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 [9].

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Discussion

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 [12]. 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) [15]. 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. [18] 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.

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CONCLUSION

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.

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Acknowledgements

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.

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Conflicts of interest

There are no conflicts of interest.

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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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REFERENCES

1. Chang SL, Harshman LC, Presti JC Jr. Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. J Clin Oncol 2010; 28:3951.
2▪▪. Kyprianou N, Benning CM. Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis. Cancer Res 2000; 60:4550.

A basic science study on alpha-blockers and prostate cancer cell lines.

3. Partin JV, Anglin IE, Kyprianou N. Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction. Br J Cancer 2003; 88:1615.
4. Keledjian K, Garrison JB, Kyprianou N. Doxazosin inhibits human vascular endothelial cell adhesion, migration, and invasion. J Cell Biochem 2005; 94:374.
5. Garrison JB, Kyprianou N. Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediated pathway. Cancer Res 2006; 66:464.
6. Harris AM, Warner BW, Wilson JM, et al. Effect of alpha1-adrenoceptor antagonist exposure on prostate cancer incidence: an observational cohort study. J Urol 2007; 178:2176.
7. Murtola TJ, Tammela TL, Maattanen L, et al. Prostate cancer incidence among finasteride and alpha-blocker users in the Finnish Prostate Cancer Screening Trial. Br J Cancer 2009; 101:843.
8▪▪. Orsted DD, Bojesen SE, Nielsen SF, et al. Association of clinical benign prostate hyperplasia with prostate cancer incidence and mortality revisited: a nationwide cohort study of 3,009,258 men. Eur Urol 2011; 60:691.

A population-based epidemiologic study on BPH medications and prostate cancer mortality.

9. Kopp RP, Freedland SJ, Parsons JK. Associations of benign prostatic hyperplasia with prostate cancer: the debate continues. Eur Urol 2011; 60:699.
10. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010; 362:1192.
11. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349:215.
12. Theoret MR, Ning YM, Zhang JJ, et al. The risks and benefits of 5alpha-reductase inhibitors for prostate-cancer prevention. N Engl J Med 2011; 365:97.
13. Duffield-Lillico AJ, Dalkin BL, Reid ME, et al. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int 2003; 91:608.
14. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330:1029.
15. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011; 306:1549.
16. Buckley BS, Lapitan MC, Simpson CR, et al. Risk of prostate cancer associated with benign prostate disease: a primary care case-control study. Br J Gen Pract 2011; 61:e684.
17▪. Schenk JM, Kristal AR, Arnold KB, et al. Association of symptomatic benign prostatic hyperplasia and prostate cancer: results from the prostate cancer prevention trial. Am J Epidemiol 2011; 173:1419.

A clinical study of the association between BPH and prostate cancer in men from PCPT.

18. Freedland SJ, Isaacs WB, Platz EA, et al. Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: a search database study. J Clin Oncol 2005; 23:7546.
Keywords:

alpha-blockers; BPH; prognosis; prostate cancer; risk

© 2013 Lippincott Williams & Wilkins, Inc.