Introduction  

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Oral cancer has been identified as a significant public health threat. It has been defined by the WHO International Classification of Diseases as a malignancy arising within the lips, oral cavity, oropharynx, nasopharynx, hypopharynx, and other sites within lip, oral cavity and pharynx. Oral cancer is the sixth most common cancer in the world, and its prevalence continues to increase globally (3).  The British Dental Health Foundation reports that in the last 10 years the percentage of males under the age of 45 with mouth cancer has risen by almost a third (4) .      

 

Although globally oral cancer has a prevalence of 3% in males and 2% in females of all malignant neoplasms, it is considered to have one of the lowest 5-year survival rates of around 50%. The World Health Organization reported oral cancer as having one of the highest mortality ratio amongst all malignancies.  Oral cancer is largely a preventable disease, related to behavioural and lifestyle factors. The aetiology of oral cancer is multifactorial, with alcohol, tobacco products, a diet low in fruit and vegetable intake, and possibly human papilloma virus, the main risk factors considered responsible for inducing this malignancy. (5,6)    Prevention and early detection of oral cancer remain the goals of the dental profession in our efforts to reduce the impact of this disease on the public.  

 

Treatment  

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The treatment of oral cancer is often complicated requiring multiple procedures, including surgery, radiotherapy and less commonly chemotherapy. The chosen treatment depends on clinical staging, lymph node involvement and presence of metastases. Surgical treatment is the mainstay of therapy for patients with oral cancer, particularly in advanced stages of cancer. External beam radiation therapy and brachytherapy have been used successfully as the primary modality for treating patients with early stage oral cancer, and they are standard adjunctive therapies in postoperative cases of patients with advanced stages of oral cancer.(7)     

 

Nutritional Influences  

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There is a large body of evidence showing that an increase in fruit and vegetable consumption is related to a lower incidence of oral cancer. In addition to this a number of valuable micronutrients have been identified as having preventive and therapeutic roles in oral cancer. This two part review article will provide current information on nutrition, including antioxidant nutrients and their possible role as chemopreventive agents in the development and treatment of oral cancer. In addition, recommendations will be made for incorporating nutritional education into our daily practice.    

 

Recent studies suggest that patients treated for early-stage oral carcinoma, and at risk for second primary cancers, have a statistically significant deficiency in dietary sources of antioxidant nutrients when compared with both historic control subjects and current recommendations (8).  More recent studies have shown how additional foodstuffs and micronutrients may also be indicated in oral cancer prevention.  There is evidence that the consumption of cereals, fruits, dairy products, and added lipids (mostly olive oil) are associated with an inverse risk of oral carcinoma . Only meat and meat products were positively associated with increased risk of oral carcinoma (9).  Other recent studies concur with these findings.   Frequent consumption of fish, eggs, raw green vegetables, cruciferous vegetables, carrots, pulses,  and overall consumption of vegetables and fruit decreased oral cancer risk (10).   

 

Components of fruits and vegetables such as  vitamin C and E, carotenoids, dietary fibre, and flavanoids may be responsible for this protective effect. Possible mechanisms through which these components may act include antioxidant effects, inhibition of nitrosamine formation and dilution and binding of carcinogens.(11, 12)     

 

Antioxidants  

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The pathogenesis of oral cancer is influenced by deficiencies of antioxidant nutrients, and there is also evidence for diminished DNA methylation, disruption of DNA integrity, and increased DNA damage.  Many classes of agents including anti-oestrogens, anti-inflammatories, and antioxidants have shown promise in chemoprevention(13) . Oxygen free radicals are extremely reactive chemical species that can damage DNA, proteins, and cell membranes (lipid peroxidation). Consequently, the most widely used chemopreventive agents against oral cancer  are antioxidants and free radical scavengers. These antioxidants neutralize reactive oxygen species, interfere with activation of pro-carcinogens, prevent binding of carcinogens to DNA, inhibit chromosome aberrations, restrain replication of the transformed cell, suppress actions of cancer promoters, and it has been suggested that they may even induce regression of pre cancerous oral lesions such as leukoplakia and erythroplakia.(14)     

 

A diet rich in fruits and vegetables should provide sufficient antioxidants like vitamin A and carotenoids, vitamin C, vitamin E, selenium and zinc, but inflammatory conditions, alcohol, and smoking may tip the balance in favour of oxidative stress and risk of cancer. (15)      

 

Vitamin A   

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Vitamin A is essential for growth, and since cancer is a disease involving disturbances in normal tissue growth and cell differentiation, it was one of the first vitamins, which  was evaluated with respect to carcinogenesis. For over two decades the efficacy of retinoids, natural and synthetic, has been studied and  demonstrated. It has, however, been difficult to translate this into a recommendation for prevention because of the toxicity of retinoids.

 

The synthetic retinoid most often used in these trials is 13-cis-retinoic acid. This compound is toxic even at very low doses (0.1 mg/kg/day), particularly when given over several weeks to months. Hence, although effective, it cannot be advocated for prevention of oral cancer. Later studies suggested that protective effects were only observed for dietary vitamin A from plant sources (beta-carotene) (16)   Studies with non-toxic antioxidants, such as beta-carotene, are much more recent. Early results are promising in that beta-carotene, alone or in combination with other nutrients, can reverse oral leukoplakia without toxicity in short-term trials.

 

Carotene  

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Beta-carotene belongs to the carotenoid family, which include compounds such as xanthophylls, carotenes, and lycopene. These compounds have been identified as possible chemopreventive agents for oral cancer, and as such their effects may be partly due to suppression of cell proliferation(17)  Experimental and epidemiological data suggest that carotenoids, particularly lycopene and beta-carotene, can reduce the risk of certain cancers. In a recent study lycopene strongly and dose-dependently inhibited proliferation of human oral tumour cells. The results of this study further support the hypothesis that carotenoids in general, and lycopene in particular, may be effective anti-carcinogenic agents for oral cancer (18) It has been suggested that lycopene may exert its chemopreventive effects by modulating lipid peroxidation and enhancing the activities of the enzymes in the glutathione redox cycle. More research including long-term evaluation is needed.     In 1994 two studies were  published on the effect of beta carotene in lung cancer(19, 20)  These  studies  found patients taking beta carotene  had an increase in lung cancer among smokers and those previously exposed to asbestos.

 

Two further large-scale studies, however, did not find such an association (21, 22) . The problem seems to be with the synthetic form of beta-carotene used in the earlier studies. There are two types of beta-carotene found in food supplements and they are very different substances. Natural beta-carotene as found in foodstuffs is also referred to as “Mixed Carotenoids”, to which there are no reported adverse effects. Mega dose supplementation of singular  antioxidants is not recommended.  The review of the literature, therefore, strongly suggests food state mixed carotenoids as the  choice in terms of safety.

 

Vitamin C 

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Vitamin C has specific antioxidative properties with possible cancer preventive potential by acting as a free radical scavenger, preventing carcinogenic nitrosamine formation (23). These protective mechanisms may explain the observation that consumption of vegetables and fruits is associated with a reduced risk of cancer.

 

Vitamin C prevents the inhibition of gap-junction intercellular communication (GJIC) induced by hydrogen peroxide, which is essential for maintaining normal cell growth. Inhibition of GJIC is strongly related to carcinogenesis, especially to tumour promotion.(24)

 

A well publicised  study in Science journal  (25) , however,  suggested that lipid hydroperoxides (rancid fat molecules) can react with vitamin C to form products that could potentially harm DNA, although the reaction of these products with DNA was not demonstrated in the study.  However, it was suggested that vitamin C can form genotoxins (DNA-damaging agents) from lipid hydroperoxides, the implication being that vitamin C may enhance mutagenesis and the risk of cancer.  

 

What this in vitro study did not evaluate was that in vivo, lipid hydroperoxides are very rapidly reduced to harmless “alcohols” by a number of antioxidant systems, thus, when human plasma is exposed to oxidizing conditions, vitamin C forms the first line of antioxidant defence, and no lipid hydroperoxides are formed.  This study however, demonstrates the problems with mega dose supplementation of singular antioxidant micronutrients.  

 

Care should be taken with megadose supplementation. Generally excess nutrient is excreted but some micronutrients accumulate in the body and are toxic in excess. There are a number of physiological factors to be aware of with high ascorbate doses. Recent research has suggested that malignant tumours may use the specific glucose transporter molecules responsible for transporting vitamin C into the cell to obtain the energy they need to grow (26). The researchers state, however, that more studies need to be done to determine what the tumour cells do with those intracellular ascorbate doses.   It is advised that care should be taken in patients receiving chemotherapy when recommending supplemental amounts greater than 200 - 500mgs daily.   

 

Vitamin E

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Vitamin E acts as a free radical scavenger to prevent lipid peroxidation of polyunsaturated fatty acids and block nitrosamine formation (27). Vitamin E supplementation can increase production of humoral antibodies and has been hypothesised to have anti tumour proliferation capacities, possibly by modulating gene expression (28). Vitamin E has also been shown to inhibit the production of pro inflammatory prostaglandins in human gingival fibroblasts and therefore suppress the growth of oral tumours (29).  This becomes more significant in the review of the role of inflammation and essential fatty acids in Part two.      

 

The possibility that high intake of antioxidants may allow protection against cancer has drawn much attention in the last decade (30) . When recommending supplements to our patients, particularly those undergoing treatment for cancer, care must be taken to avoid drug interactions and possible micronutrient accumulation. Dietary advice should include the intake of fresh fruit and vegetables, cold pressed unsaturated oils and adequate protein.

 

Part Two will focus on the micronutrients needed for endogenous antioxidant synthesis, prostaglandins and anti inflammatory metabolites, protein malnutrition and practical advice in avoiding weight loss and cachexia linked to cytokine production.

 

References

 

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2 www.dentalhealth.org.uk

 

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21 Hennekens et al: Lack of long term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.  US Physicians Health Study. 1996 .  NEJM 1996 May 2 : 334 (18) :1145-9.

 

22 MRC/BHF Heart Protection Study of antioxidant vitamin supplementation. Heart Protection Study Collaborative Group. 2002. Lancet 2002 Jul 6:360(9326):23-33.

 

23 Hanck AB. Vitamin C and cancer. Progress in Clinical and Biological Research 1988;259:307-20. 88203700.

 

24 C.Y. Lee, Ki Won Lee, Hyong Joo Lee and Kyung-Sun Kang Jan. 12, 2002, issue of The Lancet , (Vol. 359, No. 9301),

 

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26  Agus D.B., Vera J.C., Golde D.W.: Stromal Cell oxidation: a mechanism by which tumours obtain vitamin C.  Cancer Res 1999 Sept15:59(18):4555-8.

 

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