Statins and PSA Recurrence Post-radical Prostatectomy
By William Ershler, MD
Synopsis: Statin use in patients undergoing radical prostatectomy for prostate cancer was associated with a dose-dependent reduced risk of biochemical recurrence.
Abstract & Commentary
Source: Hamilton RJ, et al. Statin medication use and the risk of biochemical recurrence after radical prostatectomy. Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Cancer 2010;116:3389-3398.
Drugs in the statin class have clearly demonstrated clinical benefit, particularly in lowering cholesterol and reducing cardiovascular mortality.1 However, statins influence a number of biological responses beyond those observed on lipid metabolism, and many of these are relevant to cancer biology, including a damping down of inflammatory pathways, as well as angiogenesis and cell proliferation, all of which are known to influence cancer development and growth.2-5 Thus, there has been considerable interest in determining a role for drugs in this class in either prevention or treatment of cancer, and much of this work has been done with regard to prostate cancer (PC). Although there have been conflicting results with regard to disease prevention,1,2,6 large prospective, cohort studies have found that statins may lower the risk of advanced prostate cancer.7,8 Furthermore, the authors of the current report had previously demonstrated that for men without prostate cancer, prostate-specific antigen (PSA) levels declined after starting statins, and this decline was independently proportional to the statin dose and the amount by which cholesterol levels lowered.9
Thus, to determine the effect of statin use on prostate-cancer risk, a large-scale investigation on as homogeneous a population as possible would be required. Accordingly, Hamilton and colleagues, using the Shared Equal Access Regional Cancer Hospital (SEARCH),10 examined the association between statin use and outcomes in men undergoing radical prostatectomy.
For this, they examined the time to PSA recurrence in 1,319 men who underwent radical prostatectomy (RP) at one of three Veterans Administration Medical Centers within the United States. The time to PSA recurrence was compared between users and nonusers of statin at surgery using Cox proportional hazards models adjusted for multiple clinical and pathological features.
In total, 236 (18%) men were taking statins at RP. Median follow-up was 24 months for statin users and 38 for nonusers. Statin users were older (p < .001) and underwent RP more recently (p < .001). Statin users were diagnosed at lower clinical stages (p = .009) and with lower PSA levels (p = .04). However, statin users tended to have higher biopsy Gleason scores (p = .002). After adjusting for multiple clinical and pathological factors, statin use was associated with a 30% lower risk of PSA recurrence (HR, 0.70; 95% CI, 0.50-0.97; p = .03), which was dose-dependent.
Commentary
Because of the described anti-inflammatory and antiproliferative effects of statins, their effect on cancer development and growth has become an active research question. With regard to prostate cancer, epidemiologic and clinical trials have been conflicting. In observational studies, such as the current report, cautions are raised because patients receiving statins are quite possibly different with regard to other risk factors, some of which are difficult to control. In this study, for example, whereas statin use was associated with a significant reduction in PSA recurrence in patients with low or intermediate BMI, for those with BMI > 35 kg/m2, statin use was associated with increased recurrence risk (HR, 17.3; 95% CI, 3.39-88.1; p = .001). Thus, the authors are to be credited for examining and controlling for as many PC risk variables as possible and for choosing a fairly specific population (those having received radical prostatectomy). In general, statin use was associated with a dose-dependent reduction in the risk of biochemical recurrence.
Put into context, it should be recalled that in healthy men, statin use has been associated with a reduction in PSA.9 Thus, whether the delay in PSA recurrence translates into a survival advantage remains to be determined. Clearly, a prospective, randomized trial would be best to answer this question; however, with the ubiquitous use of drugs in the statin class these days, such a trial will be difficult to conduct.
References
1. Baigent C, et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.
2. Demierre MF, et al. Statins and cancer prevention. Nat Rev Cancer. 2005;5:930-942.
3. Rao S, et al. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci U S A. 1999;96:7797-7802.
4. Weis M, et al. Statins have biphasic effects on angiogenesis. Circulation. 2002;105:739-745.
5. Youssef S, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420:78-84.
6. Dale KM, et al. Statins and cancer risk: a meta-analysis. JAMA. 2006;295:74-80.
7. Platz EA, et al. Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst. 2006;98:1819-1825.
8. Flick ED, et al. Statin use and risk of prostate cancer in the California Men's Health Study cohort. Cancer Epidemiol Biomarkers Prev. 2007;16:2218-2225.
9. Hamilton RJ, et al. The influence of statin medications on prostate-specific antigen levels. J Natl Cancer Inst. 2008;100:1511-1518.
10. Hamilton RJ, et al. Race, biochemical disease recurrence, and prostate-specific antigen doubling time after radical prostatectomy: results from the SEARCH database. Cancer. 2007;110:2202-2209.
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