Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies

Highlights

• 39 cohort and 2 case-control studies involving 990,649 participants are reached.

• We evaluate study quality using the Newcastle–Ottawa Scale.

• Statin use before or after cancer diagnosis improves survival of cancer patients.

• The dose–response effects of postdiagnosis statin use on mortality is assessed.

Abstract

Background

Previous studies have examined the effect of statin use on the mortality in cancer patients, but the results are inconsistent. A meta-analysis was performed to assess the association with all available studies.

Methods

Relevant studies were identified by searching PubMed and EMBASE to April 2015. We calculated the summary hazard ratios (HRs) and 95% confidence intervals (CIs) using random-effects models. We estimated combined HRs associated with defined increments of statin use, using random-effects meta-analysis and dose–response meta-regression models.

Results

Thirty-nine cohort studies and two case-control studies involving 990,649 participants were included. The results showed that patients who used statins after diagnosis had a HR of 0.81 (95% CI: 0.72–0.91) for all-cause mortality compared to non-users. Those who used statin after diagnosis (vs. non-users) had a HR of 0.77 (95% CI: 0.66–0.88) for cancer-specific mortality. Prediagnostic exposure to statin was associated with both all-cause mortality (HR = 0.79, 95% CI: 0.74–0.85) and cancer-specific mortality (HR = 0.69, 95% CI: 0.60–0.79). Stratifying by cancer type, the three largest cancer-type subgroups were colorectal, prostate and breast cancer and all showed a benefit from statin use. HRs per 365 defined daily doses increment were 0.80 (95% CI: 0.69–0.92) for all-cause mortality and 0.77 (95% CI: 0.67–0.89) for cancer-specific mortality. A 1 year increment in duration only conferred a borderline decreased risk of death.

Conclusions

In conclusion, the average effect of statin use, both postdiagnosis and prediagnosis, is beneficial for overall survival and cancer-specific survival.

Introduction

Cancer is a very serious health problem worldwide, and is the leading cause of death in economically developed countries and the second leading cause of death in developing countries [1]. Considering the different causes, the different tissues affected, and the different symptoms, cancer is a very complex and still incurable disease. Although much effort has been directed at comprehending carcinogenesis and a lot of progress has been achieved, there is still no effective treatment for most cancers.

Recently, the potential anticancer properties of statins have attracted more interest. Statins, among the most frequently prescribed drugs worldwide, reduce serum cholesterol and prevent cardiovascular diseases [2]. They block 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which inhibits the conversion of HMG-CoA to the cholesterol precursor mevalonate, the rate limiting step in cholesterol synthesis [3]. Statins may exert their anticancer effect via lowering protein prenylation [4], reducing tumor cell proliferation and migration [5], [6], inhibiting of rat sarcoma (Ras) signaling [7], inducing apoptosis through phosphorylation of Akt and down-regulation of mammalian target of rapamycin (mTOR) [8], and other pleiotropic effects on the cellular level.

In the last decade, a number of observational studies have tried to examine the effect of statin use on outcome in patients with several cancer types including breast [5], [9], [10], [11], [12], prostate [13], [14], [15], [16], [17], [18], ovarian[19], [20], [21], lymphoma [22], [23], renal cell carcinoma [8], [24], [25] and colorectal cancer [4], [26], [27], [28], [29], [30], [31], [32] et al.; some have suggested that statin use was associated with longer survival, while others report no benefit. To date, no meta-analysis has been conducted concerning the therapeutic value of statins on the survival of cancer patients. Therefore, we performed a meta-analysis with all available studies to explore the association between pre- and post-diagnosis statin use and the survival of cancer patients, for both cancer-specific mortality and all-cause mortality. Besides, we also performed a dose–response analysis to further evaluate the potential dose–response relation.