[Read on to see ANH comment following abstract]

Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis

Goran Bjelakovic, Dimitrinka Nikolova, Rosa G Simonetti, Christian Gluud

Lancet 2004; 364: 1219-28

The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, H:S Rigshospitalet, Copenhagen, Denmark (G Bjelakovic MD, D Nikolova MA, R G Simonetti MD, C Gluud MD); Department of Internal Medicine--Gastroenterology and Hepatology, Medical Faculty, University of Nis, Nis, Serbia and Montenegro (G Bjelakovic MD); and Divisione di Medicina, Ospedale V Cervello, Palermo, Italy (R G Simonetti MD)

Correspondence to: Dr Goran Bjelakovic, Department of Internal Medicine--Gastroenterology and Hepatology, Medical Faculty, University of Nis, 18000 Nis, Serbia and Montenegro [email protected]

Summary

Background Oxidative stress can cause cancer. Our aim was to establish whether antioxidant supplements reduce the incidence of gastrointestinal cancer and mortality.

Methods With the Cochrane Collaboration methodology, we reviewed all randomised trials comparing antioxidant supplements with placebo for prevention of gastrointestinal cancers. We searched electronic databases and reference lists (February, 2003). Outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were analysed with fixed-effect and random-effects model meta-analyses and were reported as relative risk with 95% CIs.

Findings We identified 14 randomised trials (n=170 525). Trial quality was generally high. Heterogeneity of results was low to moderate. Neither the fixed-effect (relative risk 0·96, 95% CI 0·88-1·04) nor random-effects meta-analyses (0·90, 0·77-1·05) showed significant effects of supplementation with ß-carotene, vitamins A, C, E, and selenium (alone or in combination) versus placebo on oesophageal, gastric, colorectal, pancreatic, and liver cancer incidences. In seven high-quality trials (n=131727), the fixed-effect model showed that antioxidant significantly increased mortality (1·06, 1·02-1·10), unlike the random-effects meta-analysis (1·06, 0·98-1·15). Low-quality trials showed no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high-quality and low-quality trials was significant (Z=2·10, p=0·04 by test of interaction).ß-carotene and vitamin A (1·29, 1·14-1·45) and ß-carotene and vitamin E (1·10, 1·01-1·20) significantly increased mortality, whereas ß-carotene alone only tended to increase mortality (1·05, 0·99-1·11). In four trials (three with unclear or inadequate methodology), selenium showed significant beneficial effect on the incidence of gastrointestinal cancer.

Interpretation We could not find evidence that antioxidant supplements can prevent gastrointestinal cancers; on the contrary, they seem to increase overall mortality. The potential preventive effect of selenium should be studied in adequate randomised trials.

ANH Comment

In reviewing this study, it is worth looking at the limitations given by the Lancet paper's own authors with respect to their meta-analyses:

"Our review had several potential limitations. We analysed a group of trials, which by nature of the topic—ie, preventive efforts for years—could have inherent weaknesses. We saw several inconsistencies in the different reports of the individual trials. Although we tried in all cases to obtain reconfirmation from the authors, we could not always do so. In several trials, the dropout rate was high, and this rate might have affected the results of individual trials and thereby our meta-analyses. Diagnostic criteria and timing of screening differed between trials or were not always well defined. Moreover, the examined populations varied. Generally, the risk of cancer was less than one in 100, which could make it difficult to detect any effects—beneficial or harmful.

In nine trials, the effect of antioxidant supplements was assessed in people with a high risk of cancer (ie, smokers, patients with oesophageal dysplasia, patients with previous history of skin cancer, hepatitis B surface antigen carriers, or relatives of patients with liver cancer), whereas three trials investigated healthy participants. One trial assessed the incidence of cancer as a secondary outcome in patients at high risk for cardiovascular disease. This variable risk to develop cancer could have affected our results. Likewise, the fact that occurrence of gastrointestinal cancers was not the primary objective of some of the trials might have affected the detection rate, but this factor would probably have affected both arms of the trials equally. The methodological quality of some of the trials could only be assessed by use of published reports, which might not have indicated the actual design of the trials. Not all authors responded to our requests for further information. Because we had to rely mainly on the published reports, the association between reported methodological quality and overestimation of intervention effect was very important.[23] Our data for the effect of antioxidant supplements on mortality were based on a select sample of trials assessing antioxidants for gastrointestinal cancers. We are in the process of identifying all trials investigating mortality after exposure to antioxidants. Finally, supplementation only lasted 1–12 years, which could be thought too short a period (compared with the length of time needed for cancers to develop) to draw definitive conclusions. In this respect, the fact that selenium seemed to be effective after only 2–4 years is noteworthy. We emphasise that our review analysed only the effect of certain antioxidant supplements. Therefore, the results should not be translated to the potential effects of vegetables and fruits, which are rich in antioxidants and other substances. Many substances in fruits and vegetables have been postulated to have anticarcinogenic properties. The most extensively investigated constituents of fruits and vegetables (acting as antioxidants) are micronutrients, dietary fibre, and various phytochemicals. [60–63] Some of these constituents, acting independently or in combination, might have protective effects."

In addition, the trials were reliant on treatments that could hardly be regarded as state-of-the-art antioxidants. The treatments involved synthetic antioxidant vitamins, BUT excluded key phytonutrients (e.g. oligomeric proanthocyanidins / OPCs, curcuminoids, Co-Enzyme Q10)that are well established from ORAC, FRAP and other assays as being considerably more potent as antioxidants than vitamins used alone. To assess antioxidant supplements properly, a 'cocktail' approach should be used, in line with leading-edge antioxidants presently on the market.

Additionally treatment times were often short, sometimes only 12 months, adn treatments are in many cases likely to have commenced prior to the onset of pre-clinical symptoms which lead to gastro-intestinal cancer.

Furthermore, even with these problems, the meta-analysis showed evidence of benefit of antioxidants with regard to gastro-intestinal cancer. However, there are numerous other areas for which there is good evidence of positive effects associated with antioxidants.

A summary, focusing particularly on OPCs and vitamins, is given below:

Some of the key studies in peer reviewed scientific journals supporting the use of OPCs with or without vitamin synergists are given below.

Capillary weakness, venous insufficiency and skin conditions

Numerous studies have demonstrated the ability of OPCs to strengthen capillaries, even at doses of 100 mg /day. It is has been proposed that OPCs assist in the stabilisation of two key proteins, collagen and elastin, in connective tissues that support blood vessels, organs, joints, muscles and skin.[1],[2] Accordingly, OPCs have been shown to assist in the wide range of conditions associated with chronic (and peripheral) venous insufficiency (see below), as well as a variety of skin conditions, including premature ageing of the skin caused by excessive exposure to the sun (ultra-violet radiation).2

An Italian clinical study reported improvement or disappearance of symptoms of venous insufficiency in the majority of subjects studied, measured both objectively by videocapillaroscope examination and subjectively by interviewing patients for symptoms (e.g. swelling, itching, heaviness, pain).[3] This effect has been demonstrated in numerous other studies (especially in France),[4] and is thought to be the result of OPCs' ability to stabilize collagen in the basal epithelium of capillaries or through the compounds' radical scavenging abilities, or a combination of both processes.[5]

Atherosclerosis

There are a number of animal studies that demonstrate that OPCs are effective in reducing the risk of atherosclerosis[6],[7] (caused by the build up of plaque in arteries), the leading form of heart disease in western countries. Atherosclerosis is considered the underlying cause of approximately 50% of all deaths in these countries.[8]

A series of studies have recently been conducted showing the cardiovascular protective effects of OPCs to both animals and humans.[9]

The key mechanisms for this effect are thought to be the role of OPCs in inhibiting oxidation of low density liprotein (LDL) “bad” cholesterol in blood vessels, as well as inhibiting cyclooxygenase and lipoxygenase in platelets and macrophages, and decreasing thrombotic events.[10]

It is for these reasons that a number of epidemiological studies have demonstrated the ability of red wine consumption to reduce the risk of coronary heart disease.[11]

Cancer

The potent oxygen radical scavenging abilities of OPCs would suggest that their consumption could reduce the risk of cancer. Accordingly, there is an increasing body of evidence to support the beneficial role of OPCs and other polyphenols in the diet against diseases such as cancer and metastasis.[12]

Although such effects have yet to be demonstrated for supplemented OPCs in clinical trials, there is evidence for anti-carcinogenic effects from both animal and in vitro studies. When transgenic mice were fed supplemental red wine solids in their diet, the rate of tumour onset was delayed compared with controls,[13] while apotopsis in non-malignant human liver cells exposed to chemotherapeutic agents was reduced following administration of OPC extracts.[14]

Vision

Supplemental consumption of OPCs has been shown to have a range of beneficial effects on vision including substantial improvements in glare tolerance and night vision.[15] Such effects are likely to be caused by the OPCs' selective affinity to collagen and elastin proteins. In a review of 26 case studies on retinopathy, OPCs were found to significantly improve vascular lesions, microaneurisms, and exudates associated with diabetic retinopathy.[16]

Other conditions

By virtue of the oxygen radical scavenging and collagen/elastin support functions of proanthocyanidins, OPCs have been found to support a wide range of other conditions.[17] OPCs have, for example, been found to have anti-inflammatory[18] and anti-viral properties, with evidence that grape seed derived OPCs can inhibit HIV infection in vitro.17

Antioxidant vitamins

Vitamins A (notably carotenoids such as beta-carotene), C and E (tocopherols and tocotrienols) are well known for their free radical scavenging (antioxidant) properties. In a placebo-controlled, double blind trial with athletes, beta carotene (30 mg/day), Vitamin C (1000 mg/day) and Vitamin E (500 IU/day), were shown to markedly reduce antioxidant stress caused by intensive physical training, as well as preventing serum iron reduction, compared with controls.[19]

However, scientific studies have demonstrated that the radical scavenging capacity of OPCs may be up to 20 times greater than vitamin E and 50 times greater than vitamin C.17

Unlike OPCs that are able to scavenge in both the water and lipid phases, Vitamin C scavenges hydrophilic radicals in the water phase, such as within the blood, while Vitamin E and A (including beta-carotene) scavenge lipophilic radicals in the lipid phase, such as within membranes.[20]

Although Vitamin C is unable to function in the lipid phase, it may act as a synergist of Vitamin E, reducing lipid peroxyl radicals within the lipid phase by reacting with tocopheroxyl radicals and regenerating active tocopherol.20

Vitamin C is known to act as a potent synergist of phenolic compounds such as the OPCs.[21],[22]


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[2] Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, Voorhees JJ. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature, 1996; 379: 335-9.

[3] Costantini A, De Bernardi T, Gotti A. Clinical and capillaroscopic evaluation of chronic uncomplicated venous insufficiency with procyanidins extracted from Vitis vinifera [Article in Italian]. Minerva Cardioangiol., 1999; 47:39-46.

[4] Schwitters, B. Dr Masquelier's Mark on Health: Masquelier's Original OPCs. Alfa Omega Editrice, Rome, 373 pp.

[5] Petrassi C, Mastromarino A, Spartera C. Pycnogenol in chronic venous insufficiency. Phytomedicine, 2000; 7: 383-8.

[6] Gendre PMJ, Laparra J, Barraud E. Procyanidolic oligomer preventive action on experimental lathyrism in the rat. Annales Pharmaceutiques Francaises, 1985; 43: 61-71.

[7] Uchida S, Edamatsu R, Hiramatsu M, Mori A, Nonaka G, Nishioka I, Niwa M, Ozaki M. Condensed tannins scavenge active oxygen free-radicals. Medical Science Research – Biochemistry, 1987; 15: 831-832.

[8] Lusis AJ. Atherosclerosis. Nature, 2000; 407: 233-241.

[9] Bagchi D, Sen CK, Ray SD, Das DK, Bagchi M, Preuss HG, Vinson JA.
Molecular mechanisms of cardioprotection by a novel grape seed proanthocyanidin extract. Mutation Research, 2003; 523-524: 87-97.

[10] Frankel EN, Kanner J, German JB, Parks E, Kinsella JE. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet, 1993; 20: 454-7.

[11] Sato M, Maulik N, Das DK. Cardioprotection with alcohol: role of both alcohol and polyphenolic antioxidants. Annals of the New York Academy of Sciences, 2002;957: 122-35.

[12] Cao Y, Cao R, Brakenhielm E. Antiangiogenic mechanisms of diet-derived polyphenols. Journal of Nutritional Biochemistry, 2002; 13: 380-390.

[13] Clifford AJ, Ebeler SE, Ebeler JD, Bills ND, Hinrichs SH, Teissedre PL, Waterhouse AL. Delayed tumor onset in transgenic mice fed an amino acid-based diet supplemented with red wine solids. American Journal of Clinical Nutrition, 1996;64: 748-56.

[14] Joshi SS, Kuszynski CA, Bagchi D. The cellular and molecular basis of health benefits of grape seed proanthocyanidin extract. Curr Pharm Biotechnol., 2001; 2: 187-200.

[15] Corbe C, Boissin JP, Siou A. [Light vision and chorioretinal circulation. Study of the effect of procyanidolic oligomers (Endotelon)] [Article in French] . J Fr Ophtalmol. 1988; 11: 453-60.

[16] Froantin M. Procyanidolic oligomers in the treatment of capillary fragility and retinopathy in diabetics. Med Int 1981;16: 432-434.

[17] Shi J, Yu J, Pohorly JE, Kakuda Y. Polyphenolics in grape seeds - biochemistry and functionality. Journal of Medical Food 2003; 6: 291-9.

[18] Li WG, Zhang XY, Wu YJ, Tian X. Anti-inflammatory effect and mechanism of proanthocyanidins from grape seeds. Acta Pharmacol Sin 2001; 22: 1117-1120.

[19] Aguilo A, Tauler P, Fuentespina E, Villa G, Cordova A, Tur JA, Pons A. Antioxidant diet supplementation influences blood iron status in endurance athletes. Int J Sport Nutr Exerc Metab. 2004; 14: 147-60.

[20] Niki E. Action of ascorbic acid as a scavenger of active and stable oxygen radicals. American Journal of Clinical Nutrition, 1991; 54 (6 Suppl): 1119S-1124S.

[21] Doba T, Burton GW, Ingold KU. Antioxidant and co-antioxidant activity of vitamin C. The effect of vitamin C, either alone or in the presence of vitamin E or a water-soluble vitamin E analogue, upon the peroxidation of aqueous multilamellar phospholipid liposomes. Biochem Biophys Acta. 1985; 835: 298-303.

[22] Ward NC, Hodgson JM, Croft KD, Clarke MW, Burke V, Beilin LJ, Puddey IB. Effects of vitamin C and grape-seed polyphenols on blood pressure in treated hypertensive individuals: results of a randomised double blind, placebo-controlled trial. Asia Pac J Clin Nutr., 2003;12 Suppl: S18.