Journal of the National Cancer Institute Advance Access originally published online on December 30, 2008
JNCI Journal of the National Cancer Institute 2009 101(1):2-4; doi:10.1093/jnci/djn453
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Published by Oxford University Press 2008.
EDITORIALS |
Vitamin Supplements and Cancer Prevention: Where Do Randomized Controlled Trials Stand?
Affiliation of author: Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
Correspondence to: Demetrius Albanes, MD, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Blvd, Room 3044, Bethesda, MD 20892 (e-mail:daa{at}nih.gov).
Cancer chemoprevention as a concept and research methodology that examines inhibition of human carcinogenesis by nutritional, phytochemical, and other pharmacological substances dates to at least the early 1980s (1,2). At that time, a flurry of chemoprevention trials was launched predicated on epidemiological observations regarding potential protective roles for a wide range of foods and nutrients, including retinoids, beta carotene, calcium, and lower dietary fat in several cancers, and on basic research that provided both corroboration of the hypotheses through tumor inhibition in experimental models and evidence relevant to the responsible biological mechanisms. However, only a few of the randomized controlled studies, or RCT’s, have demonstrated the hoped-for reductions—or even unanticipated benefits—in incidence or recurrence of neoplasia from nutrient supplementation or dietary modification. For example, the Nutritional Prevention of Cancer Study, which aimed to prevent nonmelanoma skin cancers with selenized yeast, failed to do so, but unexpected yet statistically significant reductions in prostate, lung, and colorectal cancers were observed (3). Similarly, the Nutritional Intervention Trial targeted a high esophageal cancer incidence area and found a 21% reduction in gastric (but not esophageal) cancer mortality in response to a selenium, beta carotene, and vitamin E combination (4). In the Calcium Polyp Prevention Study, daily supplementation with calcium carbonate did lead to a 15% reduction in colorectal adenomatous polyp recurrence (5). The majority of similar cancer trials demonstrated no chemopreventive efficacy for their primary neoplastic endpoints [eg, (6–9)], and in some there was evidence of unexpected harmful effects, such as an increased number of lung cancers in those receiving beta carotene in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (10,11) and Beta-Carotene and Retinol Efficacy Trial (CARET) (12,13), and an increased number of colorectal neoplasias in participants receiving folic acid in the Aspirin/Folate Polyp Prevention Study (14). Other nonsupplementation trials of dietary modification including two that assessed the effect of lower fat intake yielded statistically null results for their primary hypotheses (15,16), although the latter study showed a small breast cancer incidence reduction.
The findings of Lin et al. (17) in this issue of the Journal fall into the well-populated category of null trials. Using a factorial design, the Women's Antioxidant Cardiovascular Study, or WACS, tested supplementation for 8–10 years with beta carotene (50 mg daily), vitamin C (as ascorbic acid, 500 mg daily), and vitamin E (as RRR-alpha-tocopherol, 600 IU every other day) in more than 7600 women who at study entry were at least 40 years old and at elevated risk of cardiovascular disease. Based on 624 cancer diagnoses (41% of which were breast cancers) and 176 cancer deaths, the investigators observed relative risks (RRs) for the beta carotene, vitamin C and vitamin E trial arms of 1.00, 1.11, and 0.93, respectively, for overall cancer incidence, and 0.84, 1.28, and 0.87, respectively, for relative mortality. The investigators concluded that the vitamins had no effect, singly or in combination. Duration of active supplementation within the range studied, compliance, and "drop-in" use of extrastudy supplements did not appear to account for the findings. By contrast, the "lack of complete follow-up" alluded to by the investigators as a methodological limitation [presumably the 93% follow-up completeness through January 31, 2005 (18), and/or exclusion of approximately 40 unconfirmed cases] or the high cardiovascular disease (CVD) risk of the study population which might overshadow other health benefits may have contributed to the lack of efficacy for the cancer endpoints. Neither the antioxidants nor the fourth intervention added later—a combination of folic acid and vitamins B6 and B12 – had any statistically significant effects in terms of cardiovascular disease endpoints (18,19). Their just-reported findings for folic acid–B vitamins and cancer were that overall rates and breast cancer rates were comparable in the active and placebo arms (20). Thus, taken as a whole, WACS provides little or no evidence that such vitamin supplementation as tested offers any measurable preventive impact on cancer in women.
Despite the trial's conclusion that there were no overall benefits for primary cancer prevention, two of the specific findings reported by Lin et al. (17) deserve additional mention because they corroborate previous trial results and demonstrate the potential for site-specific efficacy. The first is the possible effect of vitamin E supplementation in preventing colorectal cancer (RR = 0.63), similar to what was observed in the ATBC Study (20) and in a pooled analysis of serum tocopherol levels in cohort studies (21). The second is the elevated lung cancer risk in the beta carotene arm, along with modest excess overall cancer risk in smokers and heavier drinkers. The suggested harmful effects from vitamin C for lung and pancreatic cancers, with the former effect achieving statistical significance, are also noteworthy and raise questions concerning the chemopreventive potential of ascorbic acid. All these observations, based on the randomized design, represent value-added data that will contribute to a better understanding of cancer etiology and prevention and the appropriate role of these micronutrient supplements.
Nutritional intervention trials inevitably test multiple biological effects that can and should be expected even with single-agent supplements such as those used in WACS. Functionally diverse putative cancer preventive mechanisms have been demonstrated for vitamins C and E, beta carotene, and many other nutrients that have been tested in tumorigenesis and cell culture experiments. These mechanisms include inhibition of, or interference with, oxidative damage and free radical formation, cell proliferation, retinoic acid receptor signaling, angiogenesis, nitrosamine formation, and inflammation, as well as enhancement of apoptosis, cellular differentiation, and immune function (22). Nutritional supplements also modulate integral cellular detoxification and other metabolic pathways, notably cytochrome p450 enzymes (e.g., CYP 1A1), that have extensive and diverse effects on metabolism [see, for example, (23)]. This could be one explanation for some of the findings of recent meta-analyses suggesting adverse effects in trials where dosages and the role of high-risk populations have been considered [eg, (24, 25)]. Conversely, because cell culture experiments can demonstrate beneficial effects for thousands of compounds on myriad molecular targets (26) they should be followed by careful examination of safety clinical and observational data before selection of interventional agents, dosages, and target populations for future trials.
WACS is but the most recently reported example of an informative, efficient, "multitasked" prevention study. Controlled trials allow for the simultaneous examination of primary and multiple secondary endpoints and thus help the research community, public health and medical practitioners, and the public gain a more comprehensive understanding of cancer preventative strategies that might be considered, including possible modifications of prevalent lifestyle behaviors such as vitamin supplement use in the United States (27). These RCTs are an integral and important component of nutritional epidemiological cancer research programs that test mature hypotheses in the appropriate populations. The conduct of these trials has depended on experimental, dietary, and serologic studies that allowed for rational selection of candidate micronutrients that could be ethically and safely tested in controlled settings. Consideration of supplementation dosages should be in line with observational data where evidence based on middle-level or higher (but physiological and not pharmacological) intakes suggests benefit. Vitamin E may be an example of this with WACS and many of the trials discussed here opting for 300–400 IU of alpha-tocopherol per day in the face of the ATBC Study's beneficial findings for prostate cancer (and possibly colorectal and lung cancers) based on a 50-IU dose. Selection of study populations should also consider the possibility that persons of low or deficient nutritional status might be most susceptible to intervention efficacy [eg, (4,29)].
The recent announcement of early termination of the Selenium and Vitamin E Cancer Prevention Trial's (SELECT) interventions because of lack of efficacy and observation of possible adverse events (ie, small and not statistically significant increases in type 2 diabetes in those receiving selenium alone and in prostate cancer incidence in the vitamin E (alone) group) should serve as a reminder that the unexpected can happen in these well-designed trials (30). Large controlled studies are perhaps more likely to reveal unanticipated outcomes owing to at least two factors. One is the intense balancing that randomization imposes such that "confounding" and case–control differences in highly correlated lifestyle characteristics and risk factors play no role in an intervention outcome in a large RCT (although effect modification of efficacy can and has occurred). The other is the highly specific "exposure" represented by the intervention(s)—not a questionnaire estimation of a self-reported nutrient intake or a one-time blood sampling. Careful, comprehensive surveillance for a wide range of potential clinical outcomes and unknown adverse effects required for efficacy and safety monitoring in trials also contributes to multifaceted and unanticipated outcomes.
Progress in the field of cancer prevention, as in most scientific pursuits, can vary from slow, incremental accumulation and synthesis of new findings relevant to a range of hypotheses, to quantum advances from much anticipated corroboration or refutation of hypotheses and pure surprises. It is easy to view unexpected RCT outcomes as failures or proof of an overly simplified or overly sold concept, and obviously, the most satisfying trials are those that deliver the goods; that is, they show their anticipated cancer prevention effects. Null trials or those with unexpected outcomes should not, however, be viewed as failures; they have and will continue to shed light on the causes of cancer and help us discover the means for its prevention.
REFERENCES
1. Sporn MB. Combination chemoprevention of cancer. Nature (1980) 287(5778):107–108.[CrossRef][Web of Science][Medline]
2. Peto R, Doll R, Buckley JD, Sporn MB. Can dietary beta-carotene materially reduce human cancer rates? Nature (1981) 290(5803):201–208.[CrossRef][Medline]
3. Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA (1996) 276(24):1957–1963.
4. Blot WJ, Li JY, Taylor PR, et al. Nutrition Intervention Trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst (1993) 85(18):1483–1492.
5. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. N Engl J Med (1999) 340(2):101–107.
6. Wactawski-Wende J, Kotchen J, Anderson G, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med (2006) 354(7):684–696.
7. Lee I, Cook N, Gaziano J, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer. JAMA (2005) 294(1):56–65.
8. Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med (2004) 164(22):2335–2342.
9. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med (1996) 334(18):1145–1149.
10. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med (1994) 330(15):1029–1035.
11. Albanes D, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst (1996) 88(21):1560–1570.
12. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med (1996) 334(18):1150–1155.
13. Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst (1996) 88(21):1550–1559.
14. Cole B, Baron J, Sandler R, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA (2007) 297(21):2351–2359.
15. Schatzkin A, Lanza E, Corle D, et al. Lack of effect of a low-fat, high fiber diet on the recurrence of colorectal adenomas. N Engl J Med (2000) 342(16):1149–1155.
16. Prentice R, Thomas C, Caan B, et al. Low-fat dietary pattern and cancer incidence in the woman's health initiative dietary modification randomized controlled trial. J Natl Cancer Inst (2007) 99(20):1534–1543.
17. Lin J, Cook NR, Albert C, et al. Vitamin C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst (2008) 101(1):14–23.[CrossRef][Web of Science][Medline]
18. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med (2007) 167(15):1610–1618.
19. Albert C, Cook N, Gaziano J, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among woman at high risk for cardiovascular disease. JAMA (2008) 299(17):2027–2036.
20. Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA (2008) 300(17):2012–2021.
21. Albanes D, Malila N, Taylor PR, et al. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland). Cancer Causes Control (2000) 11(3):197–205.[CrossRef][Web of Science][Medline]
22. Longnecker MP, Martin-Moreno JM, Knekt P, et al. Serum alpha-tocopherol concentration in relation to subsequent colorectal cancer: pooled data from five cohorts. J Natl Cancer Inst (1992) 84(6):430–435.
23. Sporn MB, Liby KT. Cancer chemoprevention: scientific promise, clinical uncertainty. Nat Clin Pract Oncol (2005) 2(10):518–525.[CrossRef][Web of Science][Medline]
24. Naithani R, Huma LC, Moriarty RM, et al. Comprehensive review of cancer chemopreventive agents evaluated in experimental carcinogenesis models and clinical trials. Curr Med Chem (2008) 15(11):1044–1071.[CrossRef][Web of Science][Medline]
25. Liu C, Russell RM, Wang XD. Exposing ferrets to cigarette smoke and a pharmacological dose of beta-carotene supplementation enhance in vitro retinoic acid catabolism in lungs via induction of cytochrome P450 enzymes. J Nutr (2003) 133(1):173–179.
26. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA (2007) 297(7):842–857.
27. Albanes D. Antioxidant supplements and mortality. JAMA (2007) 298(4):400.
28. Ervin RB, Wright JD, Reed-Gillette D. Prevalence of leading types of dietary supplements used in the Third National Health and Nutrition Examination Survey, 1988–94. Adv Data (2004) 349:1–7.[Medline]
29. Duffield-Lillico AJ, Dalkin BL, Reid ME, et al. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int (2003) 91(7):608–612.[CrossRef][Web of Science][Medline]
30. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). [published online ahead of print December 9, 2008]JAMA. doi:10.1001/jama.2008.864.
Related Articles in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2009 101: 1.
J Natl Cancer Inst 2009 101: 1.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||