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Journal of Clinical Oncology, Vol 25, No 23 (August 10), 2007: pp. 3462-3468 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.8936 Statins and the Risk of Colorectal Cancer: A Meta-Analysis of 18 Studies Involving More Than 1.5 Million Patients
From the Department of Pharmacology, School of Medicine, University of Athens; Center for Disease Control and Prevention, Athens; and the Department of Pharmacology, School of Medicine, University of Patras, Patras, Greece Address reprint requests to Stefanos Bonovas, MD, MSc, Department of Pharmacology, School of Medicine, University of Athens, 75 Mikras Asias Str, Athens 11527, Greece; e-mail: sbonovas{at}med.uoa.gr
Purpose Statins have been suggested to prevent colorectal cancer. Several epidemiologic studies have evaluated this association, whereas randomized controlled trials (RCTs) on cardiovascular outcomes provide relevant data as a secondary end point. Our aim was to examine the strength of this association through a detailed meta-analysis of the studies published on the subject in peer-reviewed literature. Methods A comprehensive search for studies published up to December 2006 was performed, reviews of each study were conducted, and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates with 95% CIs were calculated using the fixed- and random-effects models. Results Eighteen studies involving more than 1.5 million participants contributed to the analysis. They were grouped on the basis of study design, and separate meta-analyses were conducted. There was no evidence of an association between statin use and risk of colorectal cancer either among RCTs (RR = 0.95; 95% CI, 0.80 to 1.13; n = 6) or among cohort studies (RR = 0.96; 95% CI, 0.84 to 1.11; n = 3). However, statin use was associated with a modest reduction in the risk of colorectal cancer among case-control studies (RR = 0.91; 95% CI, 0.87 to 0.96; n = 9). Low evidence of publication bias or heterogeneity was found. Conclusion Our meta-analysis results do not support the hypothesis that statins strongly reduce the risk of colorectal cancer, when taken for management of hypercholesterolemia. However, we cannot rule out a modest reduction in risk or an effect associated with higher doses of statins.
Statins are some of the most widely prescribed drugs worldwide.1 They lower serum cholesterol by competitively inhibiting the activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in the mevalonate synthesis pathway.2 Multiple randomized controlled trials (RCTs) have demonstrated the beneficial effects of statins on cardiovascular morbidity and mortality in a variety of populations. A growing body of literature suggests that statins may have chemopreventive potential against colorectal cancer. They have been shown to inhibit colorectal carcinogenesis in rodent models.3-7 However, the clinical relevance of these data remains unclear. The results of animal and mechanistic studies are difficult to extrapolate to humans, but they cannot be dismissed. At a minimum, they require us to look for such effects in human populations. Several epidemiologic studies have examined the relation between statins and colorectal cancer. It was the publication by Poynter et al8 that captured the most attention in the literature, with a 47% reduction in the risk of colorectal cancer based on a case-control study in Israel, with an accompanying editorial stating that it is perhaps time for a paradigm shift in chemoprevention to "beyond the one drug, one disease model."9 In contrast to results from this particular study, other observational studies do not support an association between statin use and colorectal cancer risk.10-13 Conversely, a number of meta-analyses of RCTs of statins for cardiovascular outcomes demonstrated no association between statin use and cancer risk.14-17 It is unlikely, however, that exposure to a drug such as statins affects the incidence of all types of cancer, and increases or decreases in any specific type of cancer are likely to be masked by random variation in the effects of statins on all other cancers. The end point of all cancers, therefore, is not very sensitive, and a negative finding does not suggest a lack of an effect at a particular site. Thus, the effect of statins on the risk of colorectal cancer remains to be determined. To address this issue, we conducted a detailed meta-analysis of studies published in the peer-reviewed literature.
Search Strategy We identified studies by a systematic literature search of MEDLINE (1966 through December 2006) and Web of Science (1970 through December 2006) databases. Search terms included "HMG-CoA reductase inhibitor(s)," "statin(s)," "atorvastatin," "cerivastatin," "fluvastatin," "lovastatin," "mevastatin," "pravastatin," "rivastatin," "rosuvastatin," or "simvastatin," combined with "cancer(s)," "neoplasm(s)," or "malignancy(ies)." The title and abstract of studies identified in the search were scanned to exclude any that clearly were irrelevant. The full text of the remaining articles was read to determine whether it contained information on the topic of interest. The reference lists of articles with information on the topic were also reviewed for additional pertinent studies. Abstracts of research presented at related conferences were also searched.
Selection Criteria RCTs were considered eligible if they evaluated a statin therapy compared with placebo or no treatment, had no other intervention difference between the experimental and the control group, enrolled at least 2,000 participants, had a minimum duration of 3 years, and reported the incidence of colorectal cancer during the trial. The fourth criterion was used because the benefits of the intervention may require long-term exposure. We did not assess the methodologic quality of the primary studies, given that quality scoring in meta-analyses of observational studies is controversial, as it is for RCTs.18,19 Scores constructed in an ad hoc fashion may lack demonstrated validity, and results may not be associated with quality.20 Instead, we performed several subgroup analyses.
Data Extraction Risk ratios and 95% CIs were calculated for each RCT by reconstructing contingency tables based on the number of participants randomly assigned and the number of participants with incident colorectal cancer (intention-to-treat analysis). In observational studies, we extracted the RR estimates that reflected the greatest degree of control for potential confounders. Differences in data extraction were resolved by consensus, referring back to the original article.
Statistical Analysis Studies were grouped on the basis of study design, and two separate meta-analyses were conducted: one meta-analysis of RCTs and a second meta-analysis of observational studies. This was done to examine consistency of results across varying study designs with different potential biases. Furthermore, we compared the summary RR estimates derived from the two separate meta-analyses with a test of interaction.22 We used two techniques to calculate the pooled RR estimates: the Mantel-Haenszel method,23 which assumes a fixed-effects model, and the DerSimonian-Laird method,24 which assumes a random-effects model. In the absence of heterogeneity, the fixed- and the random-effects models provide similar results. When heterogeneity is found, the random-effects model is considered to be more appropriate, although both models may be biased.25 Publication bias was assessed using the Begg and Mazumdar adjusted rank correlation test26 and the Egger regression asymmetry test.27 To evaluate whether the results of the studies were homogeneous, we used the Cochran's Q test28 with a .10 level of significance. We also calculated the I2 statistic,29,30 which describes the percentage variation across studies that is due to heterogeneity rather than chance. Negative values of I2 were put equal to zero, so that I2 lies between 0% (ie, no observed heterogeneity) and 100%. All P values are two tailed. For all tests (except for heterogeneity), a probability level less than .05 was considered statistically significant. This work was performed according to the guidelines proposed by the Meta-Analysis of Observational Studies in Epidemiology group,31 and the Quality of Reporting of Meta-Analyses recommendations for improving the quality of meta-analyses of RCTs.32 STATA software was used for the statistical analyses (STATA Corp, College Station, TX).
Search Results Eighteen independent studies met the predefined inclusion criteria.8,10-13,33-45 Six of 18 studies were RCTs of statins for cardiovascular outcomes,33-38 nine were case-control studies,8,10,11,13,40-42,44,45 and three were cohort studies.12,39,43 These 18 studies included more than 1.5 million participants. The number of colorectal cancer cases ranged from 33 to 245 in the RCTs, from 56 to 18,440 in the case-control studies, and from 249 to 3,006 in the cohort studies. Four of the 18 studies had been published solely in abstract form.41,42,44,45 Five of six RCTs were placebo controlled,33,35-38 whereas one RCT was a nonblinded trial comparing statin treatment with a usual-care control group.34 All RCTs reported site-specific cancer outcomes (secondary end points) including colorectal cancer. Therefore, we were able to conduct a post hoc analysis of these trials and calculate risk ratios for colorectal cancer in an intention-to-treat analysis. All observational studies 8,10-13,39-45 evaluated exposure to statins and risk of colorectal cancer (except for one cohort study43 that examined use of all cholesterol-lowering drugs as a surrogate measure for statin use), and were controlled for potential confounding factors (at least for age and sex) by matching or adjustments. The publication dates of the studies included in the meta-analysis ranged between 1996 and 2007. Study designs, along with the RR estimates and 95% CIs, are listed in Table 1 for the RCTs and in Table 2 for the observational studies.
Meta-Analysis of RCTs Six large RCTs contributed to the analysis.33-38 A total of 55,113 individuals participated in these trials: 27,557 in treatment groups and 27,556 in control groups. The participants had a mean follow-up of approximately 5.9 years. A total experience of 325,000 person-years was reached. Three trials33,35,38 reported a lower risk of colorectal cancer in the treatment group, whereas the other three trials34,36,37 reported a higher risk (Table 1). None was statistically significant. Meta-analysis of all six reports showed no evidence for an association between statin treatment and risk of colorectal cancer. The overall rate of colorectal cancer was 1.08% in the statin group (297 incident cases) and 1.14% in the control group (313 incident cases). The association of statin use with colorectal cancer was not statistically significant assuming either a fixed-effects model (RR = 0.95; 95% CI, 0.81 to 1.11), or a random-effects model (RR = 0.95; 95% CI, 0.80 to 1.13; Table 3). Figure 1 graphs the RR estimates and 95% CIs from the individual trials and the pooled results. The Cochran's Q test had a P value of .36 and the corresponding I2 statistic was 9%, both indicating little variability between studies that cannot be explained by chance. The P values for the Begg's and the Egger's tests were P = .99 and P = .88, respectively, both suggesting that an assumption of no publication bias is reasonable.
When the analysis was restricted to trials that evaluated statin therapy compared with placebo,33,35-38 the results did not substantially change (fixed-effects model: RR = 0.91; 95% CI, 0.77 to 1.08; random-effects model: RR = 0.91; 95% CI, 0.77 to 1.09; Cochran's P = .40 and I2 = 1%; Begg's P = .81 and Egger's P = .74). Similarly, after stratifying the data in two subgroups (lipophilic33,35,37 v lipophobic statins34,36,38), we did not find any statistically significant association between lipophilic or lipophobic statins and risk of colorectal cancer (Table 3).
Meta-Analysis of Observational Studies When the studies published solely in abstract form41,42,44,45 were excluded from the analysis, the association between statins and colorectal cancer risk was marginally significant assuming a fixed-effects model (RR = 0.90; 95% CI, 0.81 to 0.99), but not statistically significant assuming a random-effects model (RR = 0.87; 95% CI, 0.76 to 1.01; Table 3). However, the random-effects model generally is believed to be more appropriate, because it provides a more conservative estimate of the pooled effect size.25 The P values for the Begg's and the Egger's tests for publication bias were P = .39 and P = .50, respectively. In contrast, the Cochran's Q test had a P value of .10, and the corresponding quantity I2 was 42%, indicating a moderately large degree of inconsistency across the studies. In a sensitivity analysis in which one study at a time was excluded and the rest were analyzed, we identified the study by Poynter et al8 as contributing most to the between-study variability. To examine consistency across varying study designs with different potential biases, we stratified data into subgroups on the basis of study design. The slight reduction of colorectal cancer risk was statistically significant among the case-control studies (random-effects model, RR = 0.91; 95% CI, 0.87 to 0.96; n = 9), but was not evident among the cohort studies (random-effects model, RR = 0.96; 95% CI, 0.84 to 1.11; n = 3; Table 3). Figure 1 illustrates the RR estimates and 95% CIs from the individual studies and the pooled results.
Combined Analysis Furthermore, we performed a combined analysis of RCTs and observational studies. The Cochran's Q test had a P value of .35 and the corresponding I2 statistic was 7%, indicating little between-study variability. The P values for the Begg's and the Egger's tests were P = .45 and P = .54, respectively, both suggesting a low probability of publication bias. Statin use was statistically significantly associated with a modest reduction of approximately 8% in the risk of colorectal cancer (fixed-effects model: RR = 0.92; 95% CI, 0.90 to 0.95; random-effects model: RR = 0.92; 95% CI, 0.89 to 0.96). However, this particular analysis was dominated by the observational studies (12 studies; 1.5 million participants). These studies accounted for the 96.8% and the 94.2% of the weight in the fixed- and the random-effects model, respectively.
Meta-analysis serves as a valuable tool for studying rare and unintended effects of a treatment. It extends prior randomized and nonrandomized studies by permitting synthesis of data and providing more stable estimates of effect. The results of the present study exclude the strong protective effect of statins found in the study by Poynter et al.8 Both meta-analyses of RCTs (n = 6) and prospective cohort studies (n = 3) showed no evidence for an association between statin use and risk of colorectal cancer. On the other hand, meta-analysis of retrospective case-control studies (n = 9) showed statin use to be statistically significantly associated with a reduction of approximately 8% in the risk of colorectal cancer. Thus, a modest protective effect cannot be excluded. When a meta-analysis of published literature is performed, consideration of study bias is critical. Existence of a bias in favor of publication of statistically significant results is well documented in the literature.46-48 However, the likelihood of important selection or publication bias in our results is small. During the identification and selection process, we did not exclude any article because of methodologic characteristics or any subjective quality criteria, and the Begg's as well as the Egger's test revealed no relation between the estimate of RR and study size. We are confident that important publication bias due to preferential publication of large studies with significant findings is unlikely to have occurred. Nevertheless, our meta-analysis had several limitations. We did not search for unpublished studies or for original data. However, we did not impose any exclusion criteria with regard to language, place of publication, or quality. The first meta-analysis included a group of trials of statins for cardiovascular outcomes in varying populations regarding age and subsequent cancer risk. Treatment and follow-up times only lasted for an average of 5.9 years, which could be thought as a short period—compared with the latency time between the initiation and the clinical detection of a cancer—to draw definite conclusions. Likewise, the fact that occurrence of colorectal cancer was not the primary objective of these trials might have affected the detection rate, but this factor would probably have affected both arms of the trials equally. Conversely, the second meta-analysis included observational studies that lacked the experimental random allocation of the intervention necessary to test exposure-outcome hypotheses optimally. It is possible that associations between statin use and colorectal cancer in observational studies are confounded by unknown or unmeasured social and behavioral factors associated with both exposure and outcome. Even when statistical adjustments are made for potential confounders, this may inadequately capture the full extent of the complex ways in which social and behavioral factors may confound associations between statins and cancer. Several studies have suggested that the use of statins reflects social and economic differences.49-54 In particular, individuals of higher socioeconomic classes are more likely to be prescribed a statin. A social gradient in statin use may reflect social inequalities in health, health care use, or health care quality. Conversely, a series of published studies have documented large disparities in cancer burden by socioeconomic status.55,56 Factors such as poverty, inadequate education, and lack of health insurance seem to be far more important than biologic differences, as much as to say that "poverty is a carcinogen." Socioeconomic factors influence cancer risk factors such as tobacco use, poor nutrition, physical inactivity, and obesity. Income, education, and health insurance coverage influences access to appropriate early detection, and treatment. Poor communities may have limited access to fresh foods and healthy nutrition, and are provided with fewer opportunities for recreational physical activity. Therefore, residual confounding cannot be excluded as a potential explanation for the modest reduction observed in the case-control studies. Statin use may not be actually associated with colorectal cancer risk, but rather serves as a proxy indicator of a host of factors that protect against cancer. In conclusion, our results do not support the hypothesis that statins strongly reduce the risk of colorectal cancer, when taken at low doses for managing hypercholesterolemia. However, we cannot rule out a modest reduction in risk or an effect associated with higher doses of statins. Until additional evidence is established, physicians need to be vigilant in ensuring that use of statins remains restricted to the approved indications.
The author(s) indicated no potential conflicts of interest.
Conception and design: Stefanos Bonovas, Kalitsa Filioussi, Christodoulos S. Flordellis, Nikolaos M. Sitaras Collection and assembly of data: Stefanos Bonovas, Kalitsa Filioussi Data analysis and interpretation: Stefanos Bonovas, Nikolaos M. Sitaras Manuscript writing: Stefanos Bonovas Final approval of manuscript: Stefanos Bonovas, Kalitsa Filioussi, Christodoulos S. Flordellis, Nikolaos M. Sitaras Other: Nikolaos M. Sitaras [Study supervision]
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
