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Statins and colorectal cancer risk: A new panacea?
Volume 130, Issue 1, Pages 278-280 (January 2006)
Lynne B. Ahn, MD, Paul C. Schroy III, MD, MPH
Poynter JN, Gruber SB, Higgins PDR, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G (Departments of Epidemiology, Internal Medicine, Human Genetics, and Pathology, University of Michigan, Ann Arbor, Michigan; Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit Health Services National Cancer Control Center, Haifa, Israel). Statins and the risk of colorectal cancer. N Engl J Med 2005;352:2184-2192.
Colorectal cancer is the third most commonly diagnosed cancer in the United States and has major health implications with approximately 145,000 new cases projected for 2005 and 56,300 deaths (Cancer J Clin 2005;55:10-30). Given these sobering statistics, it would be of societal interest to find a safe, well-tolerated chemopreventive agent that could reduce colorectal cancer risk. There are numerous placebo-controlled trials showing efficacy of a variety of agents against colorectal cancer including aspirin, celecoxib, selenium, hormone-replacement therapy, and calcium carbonate (J Clin Oncol 2005;23:378-391). To date, however, none have been advocated for routine use.
Statins are a class of cholesterol-lowering agents with putative chemopreventive activity. Interest in their role as chemopreventive agents for colorectal cancer was stimulated by in vitro data demonstrating potent effects on cell proliferation, differentiation, and apoptosis. Despite these data, clinical evidence supporting their use is mostly indirect and conflicting. Most are derived from randomized clinical trials designed to assess the effectiveness and safety of statins with respect to cardiovascular outcomes and hence underpowered to detect differences in cancer incidence (Drugs of Today 2005;41:329-334). Data from case-control studies have also been conflicting with at least two studies finding a reduced incidence of colorectal cancer and a third finding an increased incidence among statin users (Arch Intern Med 2000;160:2363-2368, J Clin Oncol 2004;22:2388-2394, Br J Cancer 2004;9:635-637).
To further elucidate whether or not statins decrease the risk of colorectal cancer, Poynter et al studied a population of 1953 patients diagnosed with colorectal cancer in northern Israel and 2015 age- and sex-matched controls over a 6-year period (1998-2004). Controls were individually matched to patients according to the year of birth, sex, primary clinic location, and ethnic group (Jewish vs non-Jewish). All study participants had similar health insurance and access to health services. Potential controls were excluded if they had a history of colorectal cancer.
All subjects were interviewed to obtain information about their personal and family history of cancer, reproductive history, medical history, medication use, physical activity level, and diet history. They were asked to recall medications used for at least 5 years. Statin use was determined based on self-report and validated by review of prescription records. Aspirin and other nonsteroidal anti-inflammatory drug (NSAID) exposure were also determined. Exposure was defined as 5 or more years of total use; no exposure was defined as less than 5 years or no use.
There were 3181 potentially eligible subjects with colorectal cancer during the study period. However, only 2146 participants were eligible, agreed to participate, and completed the in-person interview, which corresponds to a response rate of 67.5% of all eligible patients. The cohort had a mean age of 70.3; 51.2% were male. Ashkenazi Jews were overrepresented among the patients with colorectal cancer. Hypercholesterolemia was reported in more controls than reported by patients (20.9% of patients vs 26.2% of the controls; P < .001). The two groups were otherwise similar with respect to age, sex, clinic, and ethnicity.
The use of statins for at least 5 years was reported more often by controls than by patients (11.6% vs 6.1%) and was associated with a risk reduction of CRC (odds ratio, 0.50; 95% confidence interval [CI], 0.40-0.63). The inverse association between statin use and the risk of colorectal cancer remained significant even after adjusting for possible confounders, including exposure to NSAIDs, ethnic group, physical activity, hypercholesterolemia, a history of colorectal cancer in a first-degree relative, and level of vegetable consumption (odds ratio, 0.53; 95% CI, 0.38-0.74).
The type of statin used did not affect the outcome between use and relationship to colorectal cancer. Simvastatin (odds ratio, 0.49; 95% CI, 0.36-0.67) and pravastatin (odds ratio, 0.44; 95% CI, 0.31-0.63) were used most commonly and showed a similar risk reduction for colorectal cancer in the unadjusted analysis. Lipid lowering with the use of fibric acid derivatives was not associated with a similar reduction in risk (odds ratio, 1.08; 95% CI, 0.59-2.01).
Based on these results, the investigators conclude that statin use is associated with a 47% relative reduction in the risk of colorectal cancer after adjustment for other known risk factors and is specific for this class of lipid-lowering agents. Nevertheless, they acknowledge that their findings warrant further investigation in chemoprevention and therapeutic clinical trials.
The goal of chemoprevention is to use safe, well-tolerated, and affordable pharmacological agents and/or natural-occurring compounds to inhibit, reverse, or delay colorectal carcinogenesis. Among the many classes of agents evaluated to date (Gastroenterology 2004;126:1423-1447), NSAIDs have received the most attention. These agents are believed to exert their activity primarily through inhibition of the enzyme cyclooxygenase (COX), of which there are two isoforms: COX-1 and COX-2. Randomized, placebo-controlled trials have demonstrated that both nonselective COX inhibitors (primarily sulindac) and selective COX-2 inhibitors (celecoxib and rofecoxib) can reduce the size and number of adenomas in familial adenomatous polyposis (FAP) patients. Randomized, placebo-controlled trials have also demonstrated that aspirin can reduce recurrence of sporadic adenomas following polypectomy but is ineffective in reducing colorectal cancer incidence among healthy individuals, possibly due to an insufficient duration of therapy. In addition to NSAIDs, calcium, selenium, folate, and ursodeoxycholic acid have demonstrated effectiveness in mostly high-risk groups and are currently being evaluated alone or in combination with other agents in prospective randomized trials. None, however, are currently recommended for chemoprevention among average-risk patients.
Statins are a class of drugs that lower serum cholesterol by competitively inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the liver, resulting in reduced hepatic synthesis of mevalonate, the precursor of cholesterol. Interest in their use as potential chemopreventive agents is derived primarily from in vitro studies suggesting that statins possess a number of potent anti-tumor effects, including inhibition of tumor cell growth through induction of cell cycle arrest and/or apoptosis, inhibition of angiogenesis, attenuation of metastatic potential, and stimulation of cellular immunity. These effects are believed to be caused by the downstream effects of decreased synthesis of mevalonate on the mitochondrial respiratory chain, glycoprotein synthesis and isoprenylation of GTP-binding proteins, which in turn, leads to altered gene transcription of genes involved in proliferation, differentiation, and apoptosis (Eur J Cancer 2005;41:516-522). Despite these data, these agents have also been shown to induce cancers in several rodent models (JAMA 1996;275:55-60), possibly because of inability of hydrophilic statins to mitigate the increase in mevalonate synthesis in extrahepatic tissues induced by decreased levels of circulating cholesterol (Cancer Epidemiol Biomarkers Prev 2005;14:1897-1898).
Clinical studies assessing the association between statin use and cancer incidence have also produced conflicting results. The Cholesterol and Recurrent Events (CARE) trial reported a statistically significant increase in the number of breast cancer cases observed in the pravastatin treatment group (n = 12) compared to the placebo group (n = 1; P < .002), thus suggesting that statins might actually increase cancer risk (N Eng J Med 1996;335:1001-1009). The Prospective Study of Pravastatin in the Elderly at Risk, or PROSPER trial, also observed a higher incidence of newly diagnosed cancers among elderly subjects using pravastatin than in controls (hazard ratio, 1.25; 95% CI, 1.04-1.51). The investigators speculated that the relative increase in cancer deaths may have been the result of reduced cardiovascular mortality in the treatment group rather than a direct carcinogenic effect (The Lancet 2002;360:1623-1630). Despite these data, meta-analyses of data from large, randomized, controlled trials and case-control studies specifically designed to examine the association between statin use and cancer incidence have consistently found either no association (JAMA 1997;278:313-321, Am J Med 2001;110;716-723, Epidemiology 2002;13:262-267, Br J Cancer 2002;86:1436-1439, Circulation 2002;105:2341-2346) or a decrease in cancer incidence among statin users (Cancer 2004;100:2308-2316, J Clin Oncol 2004;22:2388-2394, Arch Intern Med 2000;160:2363-2368).
Several of the aforementioned studies have examined the association between statin use and colorectal cancer incidence. None, however, were specifically designed to address this issue. In the CARE trial (N Eng J Med 1996;335:1001-1009), fewer cases of colorectal cancer were observed among statin users (n = 12) compared to the placebo group (n = 21). Two subsequent case-control studies also found reduced rates of colorectal cancer among statin users. A Canadian study (Arch Intern Med 2000;160:2363-2368) observed a nonsignificant protective effect of prolonged statin use among the 56 patients with colorectal cancer compared to users of bile acid binding resins (odds ratio, 0.83; 95% CI, 0.37-1.89). A more recent and larger Danish study (J Clin Oncol 2004;22:2388-2394) also found a nonsignificant reduction in risk among 292 patients with colon cancer (odds ratio, 0.87; 95% CI, 0.48-1.57) and 148 patients with rectal cancer (odds ratio, 0.48; 95% CI, 0.16-1.48) compared to controls. Conversely, both the Air Force Coronary Atherosclerosis Prevention Study (JAMA 1998;279:1615-1622) and a case-control study involving subjects from the General Practice Research Database (Br J Cancer 2004;9:635-637) observed a higher incidence of colorectal cancer among statin users compared to controls.
The study by Poynter et al provides the strongest evidence to date suggesting that statins may reduce the risk of colorectal cancer. Unlike its predecessors, this study was designed to specifically examine the association between statin use and colorectal cancer incidence. The use of a well-defined study population with nearly 2000 colorectal cancer cases, the ability to match or adjust for potential confounders (eg, use of aspirin and other NSAIDs), and the availability of prescription records to verify statin use for both cases and controls lend credence to the results. The authors acknowledge that participation rates were lower among controls than patients and that assessment of confounders was self-reported, thus raising concerns about potential selection bias and confounding. They also acknowledge that they had limited information on dose and duration, thus compromising their ability to analyze for a dose response. Lastly, the study design does not shed light on the mechanism by which statins reduced cancer incidence. Regardless, the data are sufficiently compelling to warrant further study, as recommended by the authors.
The widespread use of statins for primary and secondary prevention of coronary heart disease and a favorable long-term safety profile strengthen the argument for their use as chemopreventive agents if deemed effective in future clinical trials. The ability of statins to reduce colorectal cancer incidence may also have therapeutic implications for patients with established colorectal cancer. Phase I and II clinical studies have shown that although oral statins can be safely administered at sufficiently high doses to achieve serum concentrations known to inhibit tumor cell growth in vitro, it is unlikely that such high doses can be sustained for sufficiently long periods of time to exert a cytotoxic effect (Eur J Cancer 2005;41:516-522). Hence, recent interest has focused primarily on exploiting their cytostatic activity by exploring the efficacy of prolonged administration in combination with other cytotoxic agents. To date, however, no such studies have been completed.
In conclusion, the study by Pointer et al provides the most compelling evidence to date, suggesting that statins may be effective chemopreventive agents against colorectal cancer. Confirmation of these results within the framework of a placebo-controlled, randomized clinical trial is mandatory before widespread use can be advocated. Like prior colorectal cancer chemoprevention trials, such a trial is likely to use adenoma recurrence rates as a surrogate biologic end-point rather than cancer incidence because of feasibility issues. The trial should be of sufficient size and design to better define the appropriate target population, optimal agent, optimal dose, and duration of therapy. Ideally, the trial might also be designed to answer the question of whether the combination of a statin plus aspirin is more effective than either agent alone, as well as shed further light on the long-term safety of statin use with respect to extracolonic cancer risk. In the event that these issues are addressed and effectiveness is confirmed, statins alone or in combination with aspirin may represent an ideal panacea capable of reducing the risk of both cardiovascular death, the nation's #1 killer, and colorectal cancer, the nation's #2 cancer killer.
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