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There are at least 35 observational epidemiological studies, including prospective cohort and case-controlled studies, involving smoking and non-smoking men and women from diverse regions of the world, which have consistently found a positive association between dietary or serum beta-carotene levels and reduced risk of cancer © 2007 Elsevier Australia

(Cooper et al 1999). This association, however, does not necessarily imply a causal link, because it may be an association between beta-carotene ingestion and other dietary or lifestyle factors (Peto et al 1981). Beta-carotene intake is linked to a variety of healthy dietary and lifestyle factors, as well as being highly correlated with the intake of many other protective dietary phytochemicals and nutrients (Cooper et al 1999).

The link between beta-carotene levels and cancer prevention in epidemiological studies is contrasted with the findings of two large intervention trials that reported increased lung cancer risk with synthetic beta-carotene supplementation (Heinonen et al 1994, Omenn et al 1996b).

The Alpha-Tocopherol Beta-Carotene (ATBC) Cancer Prevention Study, also known as the 'Finnish study', was the first large intervention trial to test the hypothesis that beta-carotene reduces the risk of lung cancer. This double-blind, placebo-controlled primary-prevention trial involved 29,133 male smokers, 50-69 years of age, who were randomised to receive daily supplementation with alpha-tocopherol (50 mg/day) alone, synthetic (all-trans) beta-carotene (20 mg/day) alone, or both. After a follow-up period of 5-8 years the results suggested that there was an unexpected 18% increase in the incidence of lung cancer with an associated 8% higher mortality among those who received beta-carotene (Heinonen et al 1994). Subgroup analysis revealed that the increased risk with beta-carotene supplementation was only greater for those who smoked at least 20 cigarettes per day, with the risk of those who smoked 5-19 cigarettes/day being no greater than the placebo group. An increased risk was also observed for those who consumed more than 11 g/day alcohol compared with those with a lower intake (Albanes et al 1996). Further analysis found no effect of beta-carotene supplementation on the risk of pancreatic cancer (Rautalahti et al 1999), colorectal cancer (Albanes et al 2000), urothelial or renal cell cancer (Virtamo et al 2000), or gastric cancer (Malila et al 2002).

The Carotene and Retinol Efficacy Trial (CARET) tested the effect of synthetic, alltrans beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the incidence of lung cancer, other cancers, and death in 18,314 participants who were at high risk for lung cancer because of a history of heavy smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were unexpectedly found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group (Omenn et al 1996a). Further analysis revealed results similar to the

ATBC study, with the increased risk of lung cancer being greatest for heavy smokers and those with the highest alcohol intake, while former smokers were found to have a similar risk to those taking placebo (Omenn et al 1996a).

The finding of an increased risk of lung cancer in smokers taking beta-carotene in the ATBC and CARET studies is consistent with a number of other studies. A prospective cohort study of 59,910 French women found that self-reported supplemental use of beta-carotene was directly associated with double the risk of cancers among smokers, yet dietary beta-carotene intake was associated with less than half the risk of tobacco-related cancers among non-smokers in a statistically significant dose-dependent relationship (Touvier et al 2005). Similarly, the results of a case-control study of 362 adenoma cases and 427 polyp-free controls suggest a protective effect for colon cancer with beta-carotene in non-smokers and an adverse effect in smokers (Senesse et al 2005). Alcohol intake and cigarette smoking were also observed to modify the effect of beta-carotene supplementation on the risk of colorectal adenoma recurrence in another double-blind, placebo-controlled clinical trial involving 864 patients randomised to receive either beta-carotene (25 mg), vitamin C (1000 mg) or vitamin E (400 mg), beta-carotene with vitamins C and E, or placebo, which after 4 years found no evidence that supplementation reduced the incidence of adenomas (Greenberg et al 1994). Subgroup analysis from this study, however, found that beta-carotene supplementation was associated with a marked decrease in the risk of one or more recurrent adenomas among subjects who neither smoked cigarettes nor drank alcohol, but conferred a modest increase in the risk of recurrence among those who either smoked or drank alcohol and double the risk for those who both smoked and drank (Baron et al 2003).

The results of these studies are contrasted with those from the Physicians' Health Study, which found no effect of beta-carotene supplementation on cancer risk in smokers or non-smokers. This RCT of 50 mg of synthetic beta-carotene given on alternate days involved 22,071 US male physicians, 11 % of whom were smokers. After more than 12 years of follow-up, no overall effect on cancer incidence was evident with beta-carotene supplementation (Hennekens et al 1996) and no benefit or harm was observed for lung, prostate or colon cancer (Cook et al 2000) or for squamous cell carcinoma (Frieling et al 2000). Subgroup analysis of this study population revealed that total cancer was modestly reduced with supplementation among those aged more than 70 years, and total cancers and colon cancer was reduced in those who drank alcohol daily (Cook et al 2000). Total cancers and prostate cancer were also reduced in those in the highest BMI quartile (Cook et al 2000) and those with low baseline beta-carotene levels (Cook et al 1999), while those

with high baseline levels had a non-significant increased risk of prostate cancer with beta-carotene supplementation (Cook et al 1999).

Similar to the results of the Physicians' Health Study the results of the Women's Health Study, which involved 39,876 women supplemented with 50 mg of beta-carotene on alternate days for 2 years, found no benefit or harm from beta-carotene supplementation on the incidence of cancer or cardiovascular disease in apparently healthy women, with no benefit or harm also being observed for the 13% of women who were smokers at baseline (Lee et al 1999).

In contrast to these results, a RCT performed on a poorly nourished population found a lower cancer incidence with beta-carotene supplementation. This study involved 29,584 adults aged between 40 and 69 years from Linxian County, China, which has one of the world's highest rates of oesophageal/gastric cardia cancer and a persistently low intake of several micronutrients. In this study people were randomised to receive retinol and zinc, riboflavin and niacin, vitamin C and molybdenum, or beta-carotene, vitamin E, and selenium at doses that ranged from 1 - to 2-fold the US RDI for a period of 6 years. Results revealed a significantly lower total mortality among those receiving supplementation with beta-carotene, vitamin E, and selenium, mainly attributable to lower cancer rates, especially stomach cancer (Blot et al 1993). Possible reasons for the mixed results The mixed results from the beta-carotene intervention studies have created significant debate. The results of a review of carotenoid research by the International Agency for Research on Cancer suggest there is a lack of cancer-preventive activity for beta-carotene when it is used as a supplement at high doses (Vainio & Rautalahti 1998). This is supported by a more recent study that examined the relationship between dietary beta-carotene and lung cancer using pooled data from seven cohort studies that involved 399,765 participants and 3155 lung cancer cases. This study found that dietary beta-carotene intake was not associated with increased or decreased lung cancer risk in never, past, or current smokers (Mannisto et al 2004).

The mixed results from beta-carotene intervention studies may also be a reflection of a difference between natural and synthetic beta-carotene, as the negative intervention studies have all used synthetic rather than natural beta-carotene. These studies, however, do provide consistent evidence for a link between dietary and serum beta-carotene levels and reduced cancer risk. Even in the studies that found an adverse effect of beta-carotene supplementation, study participants with the highest intake and serum concentrations of beta-carotene at baseline developed fewer subsequent lung cancers, regardless of their intervention assignment (Albanes 1999, Beta-carotene 92

Holick et al 2002). therefore, although monotherapy with synthetic beta-carotene is

no longer generally recommended, there continues to be a consistent call for an Increased consumption of beta-carotene-contalning foods to assist In prevention of cancer (Mayne 1996, Pryor et al 2000).

Oral leucoplakia Beta-carotene consumption has been found to be Inversely associated with precancerous lesions of the oral cavity in tobacco users (Gupta et al 1999) and it is suggested that there is a significant role for antioxidant nutrients in preventing oral cancer (Garewal & Schantz 1995). This is supported by the findings of multiple clinical trials in which beta-carotene and vitamin E have been shown to produce regression of oral leucoplakia, a premalignant lesion for oral cancer (Garewal 1994).

In a more recent, double-blind, randomised controlled trial involving 160 people, 360 mg/week of beta-carotene for 12 months was found to induce regression in oral precancerous lesions with half of the responders relapsing after ceasing supplementation. Similarly, another multicentre, double-blind, placebo-controlled trial found improvement in dysplasia with 60 mg/day of beta-carotene for 6 months (Garewal et al 1999).

These studies are contrasted with a subgroup analysis involving 409 white male cigarette smokers from the ATBC Study that suggested that beta-carotene supplementation does not play an essential role in preventing oral mucosal changes in smokers (Liedeetal 1998).

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