Review question
We reviewed the evidence investigating the relation between selenium intake and cancer prevention. This review updates the most recent Cochrane review on this topic (Vinceti 2014), which was an update of Dennert 2011.
Background
Selenium is a naturally occurring element that individuals are exposed to mainly through food consumption, although exposure can also occur through air, drinking water, and dietary supplements. Small amounts of selenium are essential for certain biological functions in humans, but slightly higher amounts can pose a toxicity risk, making selenium an element with a narrow, but as yet not well-defined, safe range of exposure. Selenium occurs in many different chemical forms with different biological activity. From the late 1960s, a few observational studies reported that people with high levels of selenium in their diet or in their body tissues had lower risk of cancer, and some laboratory studies showed that selenium could inhibit the growth of cancer cells. This led to widespread interest in selenium supplements and claims that taking such supplements could prevent cancer. Since that time, many more observational studies have been conducted to compare cancer rates among individuals with high and low selenium exposure. More recently, several randomised controlled trials designed to assess whether selenium supplementation can prevent cancer have been carried out. These trials played a major role in enhancing our understanding of the relation between selenium and cancer risk as a result of their stronger study design as compared with observational studies. The most recent trials in particular have shown high methodological quality and statistical power. Several trials focused on whether selenium could prevent prostate cancer.
Study characteristics
This review includes 10 trials in which adults were randomly assigned to receive selenium supplements or placebo, and 70 observational studies in which adults were followed over time to determine whether their baseline selenium status was associated with their risk of cancer. The evidence is current to January 2017.
Key results
All of the high-quality randomised trials reported no effect of selenium on reducing overall risk of cancer or risk of particular cancers, including the most investigated outcome - prostate cancer. Some trials unexpectedly suggested that selenium may increase risks of high-grade prostate cancer, type 2 diabetes, and dermatological abnormalities.
Observational studies have yielded inconsistent evidence of a possible effect of selenium exposure on cancer risk, with no evidence of a dose-response relation. When we pooled results of these studies, overall they suggested an inverse relation between cancer exposure and subsequent incidence of any cancer or some specific cancers, such as colon and prostate cancer. However, observational studies have major weaknesses. The selenium exposure status of participants could have been misclassified owing to limitations of the indicators of selenium exposure used, as well as to uncertainty regarding the particular selenium species contributing to overall exposure. In addition, unmeasured confounding from lifestyle or nutritional factors - a major and well-known source of bias in nutritional epidemiology studies of observational design - could have been present. Therefore, the internal validity of these studies is limited.
Currently, the hypothesis that increasing selenium intake may reduce cancer risk is not supported by epidemiological evidence. Additional research is needed to assess whether selenium may affect the risk of cancer in individuals with specific genetic backgrounds or nutritional status, and to determine how the various chemical forms of selenium compounds may have different effects on cancer risk.
Well-designed and well-conducted RCTs have shown no beneficial effect of selenium supplements in reducing cancer risk (high certainty of evidence). Some RCTs have raised concerns by reporting a higher incidence of high-grade prostate cancer and type 2 diabetes in participants with selenium supplementation. No clear evidence of an influence of baseline participant selenium status on outcomes has emerged in these studies.
Observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types, but null and direct relations have also been reported, and no systematic pattern suggesting dose-response relations has emerged. These studies suffer from limitations inherent to the observational design, including exposure misclassification and unmeasured confounding.
Overall, there is no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans. However, more research is needed to assess whether selenium may modify the risk of cancer in individuals with a specific genetic background or nutritional status, and to investigate possible differential effects of various forms of selenium.
This review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer.
To gather and present evidence needed to address two research questions:
1. What is the aetiological relationship between selenium exposure and cancer risk in humans?
2. Describe the efficacy of selenium supplementation for cancer prevention in humans.
We updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries.
We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants.
We performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach.
We included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,448 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk.
Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed.
In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individuals with low blood selenium levels could reduce their risk of cancer (particularly prostate cancer) by increasing selenium intake - has not been confirmed. As RCT participants have been overwhelmingly male (88%), we could not assess the potential influence of sex or gender.
We included 15 additional observational cohort studies (70 in total; over 2,360,000 participants). We found that lower cancer incidence (summary odds ratio (OR) 0.72, 95% CI 0.55 to 0.93; 7 studies, 76,239 participants) and lower cancer mortality (OR 0.76, 95% CI 0.59 to 0.97; 7 studies, 183,863 participants) were associated with the highest category of selenium exposure compared with the lowest. Cancer incidence was lower in men (OR 0.72, 95% CI 0.46 to 1.14, 4 studies, 29,365 men) than in women (OR 0.90, 95% CI 0.45 to 1.77, 2 studies, 18,244 women). Data show a decrease in risk of site-specific cancers for stomach, colorectal, lung, breast, bladder, and prostate cancers. However, these studies have major weaknesses due to study design, exposure misclassification, and potential unmeasured confounding due to lifestyle or nutritional factors covarying with selenium exposure beyond those taken into account in multi-variable analyses. In addition, no evidence of a dose-response relation between selenium status and cancer risk emerged. Certainty of evidence was very low for each outcome. Some studies suggested that genetic factors might modify the relation between selenium and cancer risk - an issue that merits further investigation.