Many of the randomized controlled trials (RCTs) investigating a protective role for antioxidant nutrients in cancer prevention (Table 3) have focused on ^-carotene. A study in Linxian, China, of a rural population with poor nutritional status found that supplementation with a combination of ^-carotene, selenium, and vitamin E for 5 years provided a 21% reduction in stomach cancer mortality and a 13% reduction in all cancer deaths. Although interesting, the population studied was likely to have very low intakes of a number of micronutrients and this study does not contribute to knowledge about the effects of individual antioxidants or offer any insight into their effects on populations with good nutritional status.

The findings of a number of large double-blind RCTs in well-fed subjects using high-dose ^-carotene supplements (either alone or in combination with other agents) have generally been unsupportive of any protective effect, although most have only focused on high-risk groups (e.g., smokers, asbestos workers, and older age groups). In the ATBC Cancer Prevention Trial, in which 29 000 male smokers were randomly assigned to receive ^-carotene and/ or a-tocopherol or placebo each day, ^-carotene showed no protective effect on the incidence of any type of cancer after approximately 6 years. In fact, concern was raised following the publication of the findings of this trial because those randomized to receive this vitamin had an 18% higher risk of lung cancer (RR, 1.18; 95% CI, 3-36) as well as an 8% higher total mortality than nonreci-pients. Subgroup analyses suggested that the adverse effect of ^-carotene on lung cancer risk was restricted to heavy smokers and that the risk appeared to be transient, being lost at follow-up

4-6 years after cessation of supplementation.

The CARET was also terminated early because of similar findings; subjects receiving a combination of supplements (30 mg ^-carotene and vitamin A daily) experienced a 28% increased risk of lung cancer incidence compared with the placebo group (RR, 1.28; 95% CI, 1.04-1.57). Subgroup analyses also suggested that the effect was found in current, but not former, smokers. In contrast, in the Physicians Health Study, supplementation of male physicians with 50 mg ^-carotene on alternate days had no effect on cancer incidence (men who were smokers did not experience any benefit or harm). The Heart Protection Study also demonstrated no effect on

5-year cancer incidence or mortality from supplementation with 20 mg ^-carotene in combination with vitamins E and C in individuals at high risk of CVD, despite increases in blood concentrations of these nutrients (plasma ^-carotene concentrations increased 4-fold). They did not, however, find any harmful effects from these vitamins.

A number of trials have attempted to investigate the effect of ^-carotene supplementation on nonme-lanoma skin cancer, the most common forms of which are basal cell and squamous cell carcinomas (these types of cells are both found in the top layer of the skin). However, none have shown any significant effect on skin cancer prevention. For example, the Physicians Health Study found no effect after 12 years of ^-carotene supplementation on the development of a first nonmelanoma skin cancer. The Nambour Skin Cancer Prevention Trial of 1621

Table 3 Summary of large intervention trials (>1000 subjects) investigating the role of antioxidants and cancer in primary prevention


Characteristics of subjects



Effect of antioxidant supplementation


29133 smokers, Finland



50 mg a-tocopherol and/ or 20 mg p-carotene

18% increase in lung cancer in p-carotene group (no effect in vitamin E group) 34% reduction in incidence of prostate cancer in vitamin E group

No effect of either vitamin on colorectal, pancreatic, or urinary tract cancer


14 254 smokers, 4060 asbestos workers, United States

Male and Female


30 mg p-carotene and 25 000IU retinol

Lung cancer increased by 28%


20536 at high CVD risk, United Kingdom

Male and Female


20 mg p-carotene, 600 mg a-tocopherol, and 250 mg vitamin C

No effect on cancer incidence or mortality


29 584 poorly nourished, China

Male and Female


15 mg p-carotene, 30 mg a-tocopherol, and 50 mg selenium

Cancer deaths declined by 13%

Stomach cancer declined by 21%


1621 (73% without

Male and Female

41 42

30 mg p-carotene with or

No effect on basal cell or

skin cancer at

without sunscreen

squamous cell carcinoma

baseline), Australia



22 071 physicians, United States



50 mg p-carotene and/or aspirin (alternate days)

No effect on incidence of malignant neoplasms or nonmelanoma skin cancer


1204 former asbestos workers, Australia

Male and Female


30 mg p-carotene or 25000 IU retinol (no placebo group)

No effect of p-carotene on cancer mortality


39876, United States



50 mg p-carotene (alternate days)

No effect on cancer incidence

ATBC, Alpha Tocopherol Beta Carotene Prevention Study; CARET, Beta Carotene and Retinol Efficacy Trial; HPS, Heart Protection Study; LCPS, Linxian Cancer Prevention Study; NSCPT, Nambour Skin Cancer Prevention Trial; PHS, Physicians Health Study; VACP, Vitamin A and Cancer Prevention; WHS, Women's Health Study; CVD, Cardio Vascular disease.

men and women followed for nearly 5 years (most of whom had no history of skin cancer at baseline) showed that those supplemented with 30 mg p-carotene did not experience any reduction in risk of basal cell or squamous cell carcinoma or the occurrence of solar keratoses (precancerous skin growths that are a strong determinant of squamous cell carcinoma). A 5-year trial of 1805 men and women with recent nonmelanoma skin cancer (the Skin Cancer Prevention Study) also found that supplementation with 50 mg of p-carotene gave no protection against either type of skin cancer, although this may have been because these cancers have a long latency period of approximately 12 years (Table 4).

Together, these trials suggest that p-carotene supplements offer no protection against cancer at any site and, among smokers, may actually increase the risk of lung cancer. Investigators have sought to explain these findings by proposing that components of cigarette smoke may promote oxidation of p-carotene in the lungs, causing it to exert a proox-idant (rather than antioxidant) effect and act as a tumor promoter.

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