Abstract

Background

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.

Objectives

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.

Search methods

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.

Selection criteria

We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants.

Data collection and analysis

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.

Main results

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.

Authors' conclusions

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.

Author(s)

Marco Vinceti, Tommaso Filippini, Cinzia Del Giovane, Gabriele Dennert, Marcel Zwahlen, Maree Brinkman, Maurice PA Zeegers, Markus Horneber, Roberto D'Amico, Catherine M Crespi

Abstract

Plain language summary

Selenium for preventing cancer

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.

Author(s)

Marco Vinceti, Tommaso Filippini, Cinzia Del Giovane, Gabriele Dennert, Marcel Zwahlen, Maree Brinkman, Maurice PA Zeegers, Markus Horneber, Roberto D'Amico, Catherine M Crespi

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

A large body of evidence is now available from high‐quality randomised controlled trials on effects of selenium supplementation on cancer risk, with two new studies published since the last version of this review (Vinceti 2014). None of the new relevant studies have provided information to change the conclusions of the previous version of this review. Overall, results of these studies have consistently shown no effect of selenium in preventing the type of cancer most consistently and strongly associated with antecedent selenium exposure ‐ prostate cancer ‐ or in preventing cancer overall, even when assessment focused on participants with the lowest selenium status at baseline. These intervention studies have suggested that selenium administration on the order of 200 µg/d increased risk of non‐melanoma skin cancer, advanced prostate cancer (in individuals with highest baseline exposure), dermatological abnormalities, and type 2 diabetes. No trial involving administration of low doses of selenium, on the order of 50 to 100 µg/d, has been performed so far.

An update of the meta‐analysis of observational cohort studies continues to show lower risk of cancer and of some specific cancers (colorectal, prostate, and breast) in participants with highest exposure levels at baseline, but these studies are at substantial risk of bias from exposure misclassification and unmeasured confounding. In addition, results of these observational studies are inconsistent and sometimes are strongly conflicting, and no evidence of any dose‐response relation emerged from our analysis when we considered background selenium status or differences in baseline selenium exposure.

Overall, findings of our review do not provide evidence supporting a cancer–preventive effect of selenium in humans.

Implications for research 

Some questions regarding selenium, such as whether selenium might influence cancer risk in individuals with very low or very high baseline exposure to this element, or in individuals with different genotypes, have not been fully resolved, although currently available evidence from randomised trials offers little support for such hypotheses. For ethical reasons, in the light of potential toxicity of selenium supplementation and failure of the most recent and well‐conducted experimental cohort studies to find beneficial effects, new randomised trials on the selenium and cancer relation are unlikely to be undertaken in the future. Therefore expanding results of the SELECT trial and of other high‐quality trials to examine additional outcomes such as liver cancer and non‐melanoma skin cancer, as recently happened for other outcomes (Kryscio 2017; Lance 2017), and to analyse subgroups with specific characteristics (baseline selenium exposure and genetic factors), continues to appear to be the best available option for clarifying these issues. Unfortunately, most of these randomised controlled trials (RCTs), including the Selenium and Vitamin E Cancer Prevention Trial (SELECT), could not address possible sex differences because they enrolled only men.

Finally, when interpreting the results of both intervention and observational studies, it must be taken into account that various chemical forms of selenium have very different nutritional and toxicological properties, and that almost all observational studies have assessed only total selenium exposure. Future observational studies would contribute to a better understanding of the selenium and cancer relation by including selenium speciation among their exposure assessment methods when evaluating cancer risk.

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