Nutrition & Food Science

Can dietary intervention alter prostate cancer progression?

Robert Thomas, Mabel Blades, Madeleine Williams,
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NFS
37,1
Can dietary intervention alter
prostate cancer progression?
Robert Thomas
Addenbrooke’s and Bedford Hospitals,
24 Cambridge University NHS Trusts, Cambridge, UK
Mabel Blades
Nutrition and Dietetic Services, Rushden, UK, and
Madeleine Williams
The Primrose Oncology Unit, Bedford Hospital NHS Trust, Bedford, UK
Abstract
Purpose – Research has shown that dietary factors can mediate the transformation of latent
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prostate cancer into clinically apparent cancers. This paper aims to review the evidence from studies
on nutrition and prostate cancer.
Design/methodology/approach – A literature review of studies on nutrition and cancer was
undertaken.
Findings – The data showed that deficiencies in trace elements and vitamins may lead to an
increased risk of prostate cancer.
Originality/value – The paper shows that there appears to be a clear link with aspects of vitamin
and mineral deficiencies and prostate cancer and the area merits more work.
Keywords Diet, Cancer
Paper type General review

Nutrition & Food Science
Vol. 37 No. 1, 2007
pp. 24-36
# Emerald Group Publishing Limited
0034-6659
DOI 10.1108/00346650710726922
Of the 39,000 new patients with prostate cancer presenting in the UK each year at least
33 per cent can be classified as indolent which carries an excellent prognosis even in
many cases without therapeutic intervention (Albertsen et al., 1995). Finding a safe,
patient acceptable lifestyle alternative strategies to avoid or delay conventional
therapies would reduce the risks of their associated side effect; hormone therapy can
increase risk of cardiac death, osteoporosis, lethargy and hot flushes. Surgery carries
immediate peri-operative risks, late incontinence and potency problems, which also
occur to a lesser extent with radiotherapy but with the added risk of rectal damage
(Dearnly, 1999). Furthermore, the financial implications for health care providers are
also significant. The immediate cost of radical interventions can be up to £10,000 per
patient notwithstanding the follow up, adjuvant hormones and management of side
effects. Although, the role of active surveillance for asymptomatic, non-progressive
disease can been firmly established, patients with slowly progressive disease are less
satisfied with this approach (Parker, 2004).
Data is emerging from epidemiological and prospective studies, discussed in this
review, that dietary factors can mediate the transformation of latent prostate cancer
into clinically apparent cancers (Chan et al., 2005; Sonn et al., 2005; Wilkinson and
Chodak, 2003).
Randomised data on a reduction of cancer progression in men with establish
prostate cancer is currently scant, but a recent study has generated scientific and
media attention (Ornish et al., 2005). In this study, 93 volunteers with early prostate
cancer, who had opted not to undergo conventional therapies, where randomly
assigned to intensive lifestyle counselling, or not. This included a vegan diet
supplemented with soy, vitamin E, fish oils, selenium and vitamin C, together with a
 stress management and exercise. The PSA decreased at 12 months in the intervention Dietary
group (4 per cent) but increased in the control group (6 per cent, p ¼ 0.016). As a
secondary end point, serum taken from patients from the intervention group and
intervention in
introduced to prostate cell lines in vitro were eight times more likely to inhibit their prostate cancer
growth than the controls (70 per cent vs 6 per cent, p < 0.001) (Ornish et al., 2005).
These data are encouraging but need to be substantiated in larger multicentre studies,
which are likely to be welcomed (Thomas et al., 2000; Thomas and Williams, 2004;
Thomas et al., 2005). At the present time, most of the other evidence of benefits of a 25
lifestyle change in men with established prostate cancer are derived from case-
controlled and cohort studies. Nevertheless this article attempts review the evidence
and separates the components of diet for individual discussion.

Dietary salicylates
Prostate cancer over-expresses Cyclooxidase-2 in approximately 75 per cent of cases
(Gupta et al., 2000) with higher expression correlating to a higher grade (Madaan et al.,
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2000). In vitro, inhibitors of COX-2 such as non-steroidal anti-inflammatory (NSAID)

have been shown to induce apoptosis, inhibit proliferation, impair adhesion and
signal angiogenesis in prostate cancer cell lines and xenographs (Hsu et al., 2000;
Liu et al., 1998).
In humans several retrospective analyses have found an association with use of
NSAID and a lower incidence of prostate and other cancers (Greenberg et al., 1993;
Harris et al., 1996; Logan et al., 1993; Reeves et al., 1996; Suh et al., 1993; Thun et al.,
1991). It has been found that people with diets rich in fruit and vegetables, particularly
vegetarians have serum salicylate equivalent to a dose of 80 mg a day – more
than enough to initiate COX’s conversion of arachidonic acid to prostaglandins
(Blacklock et al., 2001). In the UK, a small pilot study, investigated dietary intervention,
combination with a salicylate compound (CV247) (Thomas et al., 2005) demonstrated
disease stabilisation in a subgroup with prostate cancer. A double blind randomised,
multicentre, controlled trial is underway under the registration of the NCRN.

Carcinogens
Dietary chemical such as polycyclic aromatic hydrocarbons and aromatic amines can be
converted to products, which can directly or indirectly oxidise water or oxygen
into short lived but highly energetic free radicals. These cause double or single DNA
strand breaks allowing cancer promoting genes to escape from the influence of
their suppressor gene guardians (Chan et al., 2005). Numerous environmental studies
have linked carcinogens to cancers and the USA Food and Drug Association (FDA)
regularly publishes list of foods containing high levels of acrylamides and other
potential carcinogens such as pesticides, toxic additives, chemical contaminants (FDA,
2006). Although patients with established cancer have already sustained the DNA
damage in order to mutate from benign to malignant cells, avoiding carcinogens, may
avoid further mutation of indolent prostate cells into more aggressive phenotypes
(Chan et al., 2005; Sonn et al., 2005; Wilkinson and Chodak, 2003).
The primary enzymic defence against oxygen reduction metabolites are the Copper,
manganese and zinc-containing mitrochondrial superoxidase dismutase enzymes
(SOD), together with catalase, and glutathione S-tranferase enzymes (Chan et al., 2005;
Markland et al., 1982), colloquially termed the free radical scavengers or antioxidants.
The FDA have published league tables relating to foods ability to induce these
defence enzymes, know as their Oxygen Radical Absorbance Capacity (ORAC)
 NFS (Administration UFAD, 2006). Dark greens, cruciferous, prunes and brightly coloured
vegetables and fruits generally provide the highest scores (Table I) but antioxidants
37,1 can be found in less obvious sources such as coffee (Svilaas et al., 2004). Although data
on alcohol consumption remains generally equivocal (Platz et al., 2004), apples and
particularly those which make cider have high levels of strong antioxidant quercetin
(Lee, 2002). Red wine consumption in one case control significantly reduced the relative
risk of prostate cancer (Schoonen et al., 2005).
26

Food Advice

Reduce saturated fats
Reduce meat intake
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Avoid processed fatty foods, cream, fried foods. Check serum
cholesterol and discuss taking a statin if elevated
Use meat for its taste preferably not >once a day. Excess fat
should be removed and should be gently grilled rather than

fried to further reduce the fat content and avoid burning.

Increase all fish intake
Reduce exposure to
potential carcinogens
Increase dietary selenium
Avoid excessive calcium and zinc
Increase dietary vitamins
Increase phytochemicals
Polyphenols
Phytoestrogens
Non-oestrogenic polyphenols
Table I.
Dietary and lifestyle Lignans and Stilbens
advice – practice Increase carotenoids (lycopene)
summary
If extra oil needs to be used in cooking, use olive oil rather
than animal fat
All fresh fish but particularly the oily varieties such as
mackerel and sardines. Fresh water fish such as trout have
the advantage of avoiding the potential heavy metal
contamination of tuna and sword fish which some suggest
should not be eaten more than twice/week
Try to avoid heavily processed foods, which often contain
high concentrations of fat, salt sugar and food additives.
Reducing the amount of time that vegetables are cooked
should maintain the flavour. Wash salads and vegetables
thoroughly to avoid pesticides and airborne chemicals, which
may have settled on them. Organic foods reduce the pesticide
exposure further. Avoid excessive amounts of foods
containing high levels of aromatic hydrocarbons and
acrylamides such as smoked food or those associated with
high temperature cooking processes such as deep fried foods,
crisps, chips barbecued and heavily fried meats
Brazil nuts, Sardines, Prawns. 60-75 mcg/day. No more than
200 mcg/day
Unless prescribed for other reasons avoid supplements which
give more than 1,500 mg of calcium and 11 mg zinc per day.
Fresh fruit, raw and calciferous vegetables, grains, oily fish,
nuts and salads. Unless you have diarrhoea try to increase the
amount of ripe fruit you eat each day, ideally by eating the
whole fruit. Freshly squeezed fruit juices are recommended
See Table II
Onions, leeks, broccoli, blueberries, red wine, tea, apricots,
chocolate. Coffee, blueberries, kiwis, plums, cherries, ripe
fruits. Parsley, celery, tomatoes, mint, citrus fruit
Soybeans, other legumes, including peas, lentils, pinto (baked
beans), other beans and nuts
Skin of colourful foods cherries, strawberries, tannins
(red wine) blackcurrant, blackberries. Dates, cranberries,
red grapes, White button mushrooms
Flaxseed, linseeds, hemp nuts, grains
Tomatoes, tomato source, chilli, carrots, green vegetables
and dark green salads
 Carotenoids Dietary
Lycopene and beta-carotene, are naturally occurring pigments. As well as inducing
antioxidant enzymes, there is growing evidence related to cell differentiation and
intervention in
proliferation independent of this mechanism of action (Stivala et al., 2000). Lycopene, prostate cancer
predominant in tomatoes, concentrated in processing, has been shown to have a
protective benefit on prostate cancer risk among US health professionals (Giovannucci
et al., 2002). For men with established cancer, two small non-randomised studies looked
at lycopene and tomato sauce intake and demonstrated a decreased PSA progression
27
(Chen et al., 2001; Kucuk et al., 2002). Beta-carotene found in carrots and green leafy
vegetables has also demonstrated in vitro reduction of proliferation in prostate cancer
cell lines (Williams et al., 2000). However, trials of supplemented beta-carotene, in
patients at high risk of lung cancer, showed an elevated risk of lung and prostate
cancer (Heinonen et al., 1998). Another large chemoprevention study combined beta-
carotene with retinol, and showed a lower risk of prostate cancer in those with
pre-intervention low plasma levels of beta-carotene, but those with high levels had a
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higher risk (Omenn et al., 1996).

Vitamins
Vitamin A is a fat-soluble essential vitamin found in fish and dairy food in the
preformed isoform retinol. It can also be ingested in fruits and vegetables that contain
carotenoid provitamins such as beta-carotene. Prostate cell line data have
demonstrated an increased apoptosis and reduced proliferation when exposed to
synthetic retinoids such as fenretinide (Huieh and Wu, 1997). Likewise in genetically
susceptible mice fenretinide reduced the incidence of prostate cancer by 49 per cent
(Slawin et al., 1993). However, in a subsequent prospective study involving 10,472 US
men, no reduction in prostate cancer incidence has yet been demonstrated, although
there have only been 93 events so far in the five years follow up period (Paganini-Hill
et al., 1987).
Vitamin C acts as a natural antioxidant by preventing the inhibition of gap-junction
intercellular communication (GJIC) induced by hydrogen peroxide. Inhibition of GJIC is
related to carcinogenesis and tumour promotion (Lee, 2002). Vitamin C is involved, in
the mechanism, which enables DNA to ‘‘sense’’ free radicals by integrating with the
iron imbedded in DNA, thereby facilitating DNA repair and is therefore and important
factor in immune surveillance against cancer as according to estimates, each cell in the
body can be expected to suffer approximately 100,000 DNA-damaging events per day
(Fraga, 1991).
Vitamin C has shown some in vitro dose dependent decrease in prostate cell line
proliferation (Maramag et al., 1997). Case-controlled studies have also shown a
protective association between diets deficient in vitamin C deficiency and risk of
prostate cancer (Deneo-Pellegrini. et al., 1999; Du et al., 1997; Ramon et al., 2000).
However, three large placebo-controlled studies patients, with advanced disease,
showed no consistent benefit from vitamin C (Cregan et al., 1979; Tschetter et al., 1983).
Furthermore, reports of toxicity such as diarrhoea and renal tubular damage occur
with very high doses (LeMarchand et al., 1991).
Vitamin D is converted to the active metabolite calciferol in the kidney. Calciferol
exposed to prostate cell lines reduce proliferation, promote differentiation, inhibit
invasion and loss of adhesion (Campell et al., 1997; Peehl et al., 1994; Schwartz et al.,
1994) and promote apoptosis (Blutt et al., 2000). It has also be shown to interact with
the androgen signalling pathway in vivo inhibiting angiogenesis (Hsieh and Wu, 1997;
 NFS Zhao et al., 1999). Clinical studies of calcitriol can dangerously increase serum calcium
but vitamin D analogs have been developed without this risk and are being
37,1 investigated in an ongoing multicentre study (Wilkinson and Chodak, 2003).
Vitamin E in its eight naturally occurring isoforms, tocopherols (Wilkinson and
Chodak, 2003) have been linked to a reduction in prostate cancer risk (Chan et al., 1999).
The Alpha-tocopherol beta-carotene cancer prevention study trial (ATBC), involving
29,133 male smokers, reported a statistically significant reduction of prostate cancer
28 incidence and mortality although the primary end point, lung cancer was higher
(Heinonen et al., 1998). In the Health Professional Follow up Study (HPFS) vitamin E
intake was also associated with decreased risk of prostate cancer in smokers but not
overall (Chan et al., 1999). The serum based Cancer Prevention II (CPII) Nutrition
Cohort study showed inverse correlation between plasma vitamin E levels and prostate
cancer, again mainly among smokers and mostly the gamma-tocopherol isoform
mainly found in the diet rather than over the counter supplements (Rodriguez et al.,
2004). In a further trial involving 5,000 patients with diabetes or cardiovascular
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disease, alpha-tocopherol demonstrated no reduction in cancer, and the incidence of

heart disease was slightly worse (Lee et al., 2005). Likewise, in the ATBC study cerebral
haemorrhage risk was also higher in smokers with hypertension who took alpha-
tocopherol. The ongoing National Cancer Institute sponsored, double blind,
randomised select study comparing selenium and vitamin E supplementation against
placebo will provide data on completion in 2013.

Phytochemicals
Phytochemicals are plant chemicals that contain protective, disease-preventing
compounds. They include the oestrogenic Phytoestrogens (flavones, isoflavones and
flavanones) and the other polyphenols of which the commonest are the phenolic acids
namely benzoic acid (hydroxybenzoic acid, gallic acid) and cinnamic acid (caffeic and
quinic acid). Other polyphenols include the non-oestrogenic flavanoids including
anthocyanidins and the flavanols (catechins and proanthocyanidins) together with the
lignans and stilbens (Chan et al., 2005; Sonn et al., 2005; Wilkinson and Chodak, 2003).
Phytoestrogens display oestrogen like activity. High dietary intake could potentially
create a more favourable hormonal milieu for prostate cancer by inhibiting 5 alpha-
reductase, the enzyme responsible for converting testosterone to the more active
metabolite dihydrotestosterone (Evans et al., 1995). Genistein, daidzein and equaol are
isoflavones in human diet derived mainly from soybeans, legumes, including peas,
lentils and beans (Wilkinson and Chodak, 2003). Lignans, do not act via a hormonal
route but have been shown to have some direct antioxidative, antiproliferative
activities (Wilkinson and Chodak, 2003). They are the most common phytochemical of
western diets found in flaxseed, linseeds, nuts and grains. Some epidemiological
studies have shown that soy or its active phytochemicals have been associated with a
lower prostate cancer risk (Herbert et al., 1998; Lee et al., 2003) although not all studies
have been statistically significant (Nomura et al., 2004).

Metals and salts

Manganese, copper and zinc, are dietary trace elements essential for the production of
amino acids and factors leading to a healthy immune system and wound healing. They
also act as antioxidants as they are essential elements in the formation and function of
SOD. This together with catalase, and glutathione peroxidase form enzymic defence
against toxic oxygen reduction metabolites (Marklund et al., 1982). There is in vitro
 evidence of an increased risk of carcinogenesis in the presence of cooper, manganese or Dietary
zinc deficiencies particularly under conditions of high carcinogenic attack where more
SOD is needed (Chan et al., 2005; Sonn et al., 2005; Wilkinson and Chodak, 2003). This
intervention in
theory is partially supported by animal studies that deficiencies can impair SOD prostate cancer
activity. For example, feeding adequate copper to copper-deficient rats and cattle
raised, initially low levels of defective erythrocyte SOD, to normal functioning values
(DiSilvestro, 1989; Levieux, 1991; Merli et al., 1995; Westman and Marklund, 1981).
In humans manganese SOD (MnSOD), has also recently been identified as a
29
potential tumour suppressor gene Genetic MnSOD impairment, prevalent in 25 per
cent of the controls of a large cohort study had higher prostate cancer risk in subjects
found to have low dietary antioxidant levels (selenium, vitamin E, lycopene) but not if
antioxidant levels where adequate (Venkataraman et al., 2005; Li et al., 2005; Woodson
et al., 2003). This gene-diet interaction an interesting consideration for future
prevention studies (Li et al., 2005).
Zinc is abundant in many food sources and the average person usually obtains
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sufficient zinc through a well balanced diet (RDA, 11 mg/day). Zinc tends to
accumulate more in the prostate, and one in vitro study suggested that this may offer
some protection against prostate cancer cell growth (Liang et al., 1999). However, in the
HPFS, men who took supplemental zinc of more than 100 mg/day or for long durations
were more than twice as likely to develop advanced prostate cancer compared with
controls (Leitzmann et al., 2003).
Selenium enters the food chain via plants and nuts (particularly Brazil nuts). It has
been postulated that intensive farming techniques may reduce selenium in the soil
(Coombs, 2004; Jackson et al., 2004). Selenium is essential for glutathione peroxidase,
one of the oxygen metabolites defence enzymes (Wilkinson and Chodak, 2003). Human
prostate cell lines have demonstrated growth inhibition with selenium (Metha and
Moon, 1991). A statistically significant reduction in prostate cancer has been
demonstrated in a double-blind trial of dietary selenium in a trial in which the
incidence of the primary end point, non-melanoma skin cancer was not reduced (Clark
et al., 1998). Several large ongoing prostate prevention studies including the select
study are underway internationally (Costello, 2001; Millier, 2001).
Calcium: The RDA of calcium is 1,200 mg/day for men over 50 years. Four
prospective cohort studies, relating to calcium and prostate cancer, have been
published (Sonn et al., 2005). Two with a mean intake between 1,330-1,840 mg/day
showed no associated risk. Two others, one involving 86,404 men in the CP II Nutrition
cohort, with mean intake of >2,000 mg/day from food and supplements, showed a
significantly higher risk of prostate cancer (Rodriguez et al., 2004). Five of nine further
questionnaire surveys associated high intake of dairy food with an increased risk of
prostate cancer but in these surveys high diary was associated with high fat intake
(Sonn et al., 2005). Excessive dietary calcium reduces vitamin D which has
demonstrated antiproliferative benefits which in theory are therefore lost with calcium
excess (Campell et al., 1997).

Fats, statins and fish

Fats and meat, usually red, have generally been associated with greater risk of
developing prostate cancer (Gann et al., 1994; Norrish et al., 1999a). A history of high
saturated fat (Harvei et al., 1997; Kristal et al., 2002) and alpha-linolenic fatty acid (Chan
et al., 1994) have been particularly associated with greater risk of advanced disease.
Although the mechanism remains unclear, a small dietary experiment in men
 NFS suggested that a low-fat diet correlated with lower testosterone and insulin-like growth
factor-I levels (Barnard et al., 2003; Chan et al., 2002; Pollak et al., 2004).
37,1 Statins: Statin may have a preventive role over and above their ability to reduce
cholesterol. Lovastatin and simvastatin has been shown to trigger apoptosis in cancer
cell lines (Keyomarsi, 1991). Five randomised trials have demonstrated fewer colon,
breast and melanoma in long term users of statins compared to controls (Sonn et al.,
2005). The data for prostate cancer however, is non-conclusive as two other large
30 clinical cohort studies did not demonstrated a reduce risk with statin intake. A further
cohort study of 16,976 subjects showed a 63 per cent reduction of prostate cancer
although this was not statistically significant (Graaf et al., 2004).
Fish: Evidence from two large prospective studies (Augustsson et al., 2003; Terry
et al., 2001) and a smaller case-control study (Norrish et al., 1999b) suggests a protective
effect of fish intake on prostate cancer incidence and mortality (Terry et al., 2003).
A unique nutritional component of fish is the long-chain marine omega-3 fatty acids.
Cell line, xenografts and small human studies have suggested that marine omega-3
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fatty acids or the ratio of marine omega-3:omega-6 fatty acid can modulate the
cyclooxygenase-2 pathway, a potentially potential route for prostate cancer
development (Chaudry et al., 1994).

Other dietary factors

Green tea – contains the polyphenol, epigallocatechin gallate, which in prostate cell
lines and mice has been shown to induce apoptosis (Ahmad et al., 1997; Mettlin et al.,
1989). In one case controlled study in China, tea drinking was associated with a reduced
risk of prostate cancer ( Jian et al., 2004) although others have shown mixed results
(Schoonen et al., 2005).
Garlic has demonstrated some inhibitory capacity on androgen-dependent prostate
cell lines (Pinto et al., 2000). In one case-controlled clinical study supplements but
particularly dietary garlic were associated with a lower risk of prostate cancer (Key
et al., 1997).
PC-SPEC was a mixture of eight herbs demonstrating PSA reduction in one small
clinical study. As it was found to contain contaminants of diethylstilboestrol and
indomethacin the FDA has advised recommended its withdrawal by the manufacturer
(Sovak et al., 2002).
Shark cartilage: Although sharks can develop cancer, the avascular nature of
cartilage led to the discovery of a number of angiogenesis inhibitors, but so far in the
few small clinical trials involving men with metastatic prostate cancer no benefit has
been demonstrated (Leitner et al., 1998).

Conclusion
The theme emerging from these data is that deficiencies in trace elements and vitamins
may lead to an increase risk or progression of prostate cancer especially under
circumstances of high carcinogen exposure. On the other hand, over correction of trace
elements may be counter productive. The levels of supplementations for each
individual are likely to differ considerably depending on patients dietary history and
genetic susceptibility (Li et al., 2005). Ideally future trial design should include bespoke
analysis and supplementation. As simple vitamin, mineral and essential fatty acid
levels have not always been found to reflect the true status of individual requirements
( Joosten et al., 1992) more complex tests may be required in addition to detailed dietary
questionnaires. These may include an analysis of their genetic signature (Li et al.,
 Food ORAC Score (per once) Dietary
intervention in
Prunes 5,770 prostate cancer
Raisins 2,830
Blueberries 2,400
Blackberries 2,036
Kale 1,770
Strawberries 1,540 31
Spinach 1,260
Raspberries 1,220
Brussels sprouts 980
Plums 949
Alfalfa sprouts 930
Broccoli florets 890
White onion 860
Beets 840
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Tomato 770
Oranges 750
Red grapes 739
Red bell peppers 710
Cherries 670
Carrot 650 Table II.
Pea 360 The oxygen radical
absorbance capacity
Note: The FDA have recommended over 3,000 ORAC units a day of common foods

2005), measurement of serum metabolites that accumulate in vitamin deficiencies

(Slater et al., 1987); serum lipid peroxide levels as an indicator of oxidative free radical
damage (Slater et al., 1987); or markers relating too the function of the primary defence
enzymes, catalase, glutathione S-tranferase glutathione and SOD (One to one Health
Excercise and Nutrition, 2006).
In view of the enthusiasm among patient with indolent prostate cancer for previous
and ongoing dietary supplementation studies this increasingly motivated group, are
likely to welcome much needed further nutritional research trials (Thomas et al., 2005;
Kristal, 2002). In the mean time a logical, albeit pragmatic advice sheet, summarized in
Table II, essentially ensures adequate amounts of fresh healthy foods whilst avoiding
excessive unregulated over the counter supplementation, particularly of high dose
calcium and zinc and foods with potentially high carcinogen content.

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Further reading
Schmidt, K. and Ernst, E. (2004), ‘‘Assessing websites on complementary and alternative
medicine for cancer’’, Annals of Oncology, Vol. 15, pp. 733-45.

Corresponding author
Mabel Blades can be contacted at: mabel@qmnds.demon.co.uk

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