According to GLOBOCAN 2008 published by the International Agency for Research on Cancer, esophageal cancer is the eighth most common cancer, with 3.8% of all cancer cases, and the sixth leading cause of death from cancer, with 5.4% of all cancer deaths worldwide estimated in 2008.¹ Along with genetic causes, lifestyle and environmental factors are considered to be important in the development of esophageal cancer.² Among lifestyle factors, fruits and vegetables are rich in vitamins or antioxidants, which may have anticarcinogenic activities by various mechanisms removing free radicals and inhibiting the formation of N-nitroso compounds.²?⁴

Previous epidemiological studies have investigated the association between the risk of esophageal cancer and the intake of fruits and vegetables rich in vitamins and antioxidants, and those findings are mixed. In 2006, a meta-analysis of 10 epidemiological studies (1 cohort and 9 case-control studies) suggested that higher consumption of vitamin C and beta-carotene was significantly associated with a decreased risk of esophageal adenocarcinoma with odds ratios of 0.49 and 0.46, respectively.⁵

In the meantime, several randomized controlled trials (RCTs)⁶?¹⁵ have reported the association between vitamin or antioxidant supplements and the risk of esophageal cancer. However, no RCTs have suggested that there was any preventive efficacy of vitamin or antioxidant supplements on esophageal cancer. Further, there has been no quantitative meta-analysis of RCTs on this issue reported so far.

The purpose of this study was to examine the quantitative preventive efficacy of vitamin and antioxidant supplements on esophageal cancer by using a meta-analysis of RCTs by type of vitamin or antioxidant supplements, methodological quality, and high risk or non-high risk groups for esophageal cancer.

1. Selection of trials

A total of 171 articles were retrieved after searching three databases and relevant bibliographies (Fig. 1). After excluding duplicated articles and reviewing articles based on those title and abstracts, we reviewed 24 articles with those full texts and then included 10 trials in the final analysis. We excluded 14 articles because of identical populations (n=7), insufficient data (n=4), and studies not relevant to our subject (n=3).

2. General characteristics of trials

A total of 126,828 subjects with the 70,959 vitamin and antioxidant supplement and 55,869 placebo groups from 10 RCTs. As shown in Table 1, the selected trials were published from 1985 through 2007, spanning 22 years. The countries in which the studies were performed were as follows: US (n=3), China (n=3), Finland (n=1), Canada (n=1), UK (n=1), and France (n=1). The periods of treatment and follow-up ranges between 2 and 10.1 years. All trials used placebos as a control group. The types of vitamin and antioxidant supplements were vitamin A, vitamin B2, Vitamin C, vitamin E, beta-carotene, and selenium.

3. Efficacy of vitamin or antioxidant supplements in all 10 trials

In a fixed-effects model meta-analysis of all 22 trials, there was no efficacy of vitamin and antioxidant supplements in the prevention of esophageal cancer (RR, 1.04; 95% CI, 0.86?1.25; I²=0.0%) (Fig. 2). There was no evidence of publication bias in the selected studies (Egger’s test, P for bias=0.913; The Begg’s funnel plot was symmetrical) (Fig. 3).

4.  Methodological quality of trials

Table 2 shows the methodological quality of trials based on the Jadad scale. Eight trials received 4 or higher points and were classified as having a high quality, whereas two trials received 3 points and were classified as having a low quality.

5. Subgroup meta-analyses by type of supplements

In the subgroup meta-analyses by type of supplements based on the fixed-effect model, none of the antioxidant supplements had any significant preventive efficacy in the prevention of esophageal cancer: vitamin A (RR, 1.06; 95% CI, 0.86?1.30; n=3), vitamin B2 (RR, 1.33; 95% CI, 0.30?5.91; n=1), vitamin C (RR, 1.00; RR, 0.81?1.24: n=3), vitamin E (RR, 1.00; 95% CI, 0.81?1.22; n=6), folate (RR, 0.41; 95% CI, 0.02?9.76), beta-carotene (RR, 1.05; 95% CI, 0.87?1.27; n=7), and selenium (RR, 0.94; 95% CI, 0.74?1.18; n=3) (Table 3).

6. Subgroup meta-analyses by type of quality and risk group

The subgroup meta-analyses by type of quality showed no preventive efficacy of vitamin and antioxidant supplements on esophageal cancer for both high quality (RR, 1.06; 95% CI, 0.87?1.28; n=8) and low quality (RR, 0.70; 95% CI, 0.31?1.61; n=2) trials. Similarly, no preventive efficacy was found in both high risk (RR, 1.04; 95% CI, 0.85?1.28; n=4) and non-high risk (RR, 1.01; 95% CI, 0.65?1.568; n=6) groups for esophageal cancer.

The current meta-analysis of RCTs found that there was no efficacy of vitamin and antioxidant supplements in the prevention of esophageal cancer. Further, subgroup analyses by type of supplements, methodological quality, and risk group for esophageal cancer revealed no preventive efficacy of those supplements.

Our findings were inconsistent with those of previously published epidemiological studies and a meta-analysis of epidemiological studies, which had reported that people with the highest levels of antioxidant intake such as vitamin C or beta-carotene had an about 50% lower risk compared to those with lower levels of intake.⁵

There are several possible explanations for the inconsistent findings between observational epidemiological studies and RCTs. First, retrospective case-control studies are susceptible to recall and selection biases.¹⁸ Esophageal cancer patients might recall wrongly their consumption of fruit and vegetables rich in vitamin and antioxidants. Even though they had have adequate intakes of fruit and vegetables long before their diagnosis of esophageal cancer, they might think incorrectly that they had consumed less foods because they had dyspepsia and loss of appetite due to cancer right before that diagnosis. Also, selection bias might affect the results because cases or controls are not representative of the population. Second, there are differences in functions and components between natural vitamin or antioxidants and synthetic ones. For example, synthetic alpha-tocopherol (all-rac-alpha-tocopherol), which is composed of equal amounts of the 8 different stereoisomers of alpha-tocopherol, is different from its natural form (RRR-alpha-tocopherol).¹⁹ Also, the human body absorbs and excretes natural and synthetic vitamin E differently, and those biological activities are different.^19,20 As for beta-carotene, experimental studies reported that beta-carotene might play a potential protective role against cancer initiation.²¹ However, it may act as a prooxidant in the presence of chronic oxidative stress such as smoking; this may induce the oxidation of beta-carotene and DNA oxidative damage and finally lead to lung cancer.^18,22

Third, eliminating reactive oxygen species by antioxidant supplementation might interfere with several essential defensive mechanisms like apoptosis and detoxification and unexpectedly increase mortality.²³ Last, antioxidant supplements might have interdependency and show those efficacy only when given in combination.²⁴

There are several limitations in our study. First, we were unable to include several recent RCTs^25,26 because data for esophageal cancer were not reported. Second, the statistical power of the current meta-analysis is very low because the incidence of esophageal cancer is very low, compared with other types of common cancers. Further lager RCTs are needed to confirm our findings. Last, we were unable to apply our findings to healthy populations. Of 10 trials, only two trials involved general healthy populations, while the remaining trials involved a history of certain diseases or high risk populations for esophageal cancer.

In summary, unlike observational epidemiological studies, the current meta-analysis of RCTs found that there is no clinical evidence to support the efficacy of vitamin and antioxidant supplements in the prevention of esophageal cancer.