International Research Conference

on Food, Nutrition, and Cancer

The Role of Dietary Supplements during Cancer Therapy1

Helen A. Norman,* Ritva R. Butrum,* Elaine Feldman,y David Heber,** Daniel Nixon,z
Mary Frances Picciano,yy Richard Rivlin,z Artemis Simopoulos,zz Michael J. Wargovich,#
Elizabeth K. Weisburger,§ and Steven H. Zeisel##
*American Institute for Cancer Research, Washington, D.C., † Medical College of Georgia, Augusta, GA,
**UCLA Center for Human Nutrition, Los Angeles, CA, ‡ American Health Foundation, New York, NY,

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††
Office of Dietary Supplements, National Institutes of Health, Bethesda, MD, ‡‡ Center for Genetics,
Nutrition and Health, Washington, D.C., # South Carolina Cancer Center, Columbia, SC, §Rockville, MD,
and ## University of North Carolina at Chapel Hill, Chapel Hill, NC

ABSTRACT This guide was compiled after recommendations by the American Institute for Cancer Research
(AICR) Cancer Resource Advisory Council. It encompasses the AICR position on current issues in nutrition for
cancer survivors during treatment and is intended to provide advice about dietary supplements for cancer survivors
who are still being treated. Current scientific findings about the safety and effectiveness of some commonly used
dietary antioxidants and nonantioxidant supplements during chemotherapy are presented and assessed. Use of
dietary supplements during cancer treatment remains controversial. Patients are cautioned that vitamin and mineral
supplements as therapies are not substitutes for established medicine. The current recommendation for cancer
patients is to only take moderate doses of supplements because evidence from human clinical studies that confirm
their safety and benefits is limited. A daily multivitamin containing supplements at the levels of the Dietary Reference
Intakes can be used safely as part of a program of healthy nutrition. In addition, the AICR Cancer Resource Advisory
Council concluded that further scientific research is needed to provide a set of firm guidelines for the use of vitamin
and mineral supplements by cancer patients during treatment. J. Nutr. 133: 3794S–3799S, 2003.

KEY WORDS:  dietary antioxidant  dietary supplement  micronutrients  chemotherapy

This guide is intended to provide advice about dietary as well as the various vitamins and minerals necessary to
supplements for cancer survivors who are still being treated, maintain good health (1). For cancer patients undergoing
their families, their physicians, other health care providers specific treatments, other nutritional regimens may be con-
(including dietitians), and the research community. It is sidered based on treatment status and disease stage.
concerned primarily with interactions among antioxidant Although nutrition has an important effect during treatment,
supplements during chemotherapy rather than with their oncologists often avoid giving advice, particularly about
possible chemoprevention activities before treatment. The supplements. Individualized dietary advice during treatment is
guide was compiled after recommendations by the American important so that undesirable weight loss or excessive weight
Institute for Cancer Research (AICR)3 Cancer Resource gain can be avoided. During cancer treatments with either
Advisory Council. It encompasses the AICR position on current chemotherapy or radiation, patients often experience nausea,
issues in nutrition for cancer survivors during treatment. vomiting, diarrhea, and loss of appetite, leading to a lower intake
AICR has always recommended a diet for cancer survivors of dietary constituents and weight loss. Supplemental intakes of
that is low in fat; is high in fruits, vegetables, and whole-grain essential vitamins and minerals may seem to be desirable but may
products; and has adequate levels of the major macronutrients not always be so. Before taking any supplements, patients should
discuss the matter with their physicians because dietary
1
interactions with the treatment may affect the outcome of
This paper is included in the proceedings of the symposium ‘‘International
Research Conference on Food, Nutrition, and Cancer’’ but was not presented at
therapy. Of special concern here are dietary supplements with
the symposium. It was compiled as a position paper by the American Institute for antioxidant properties, but supplements without antioxidant
Cancer Research (AICR) Cancer Resource Advisory Committee. The content of properties may also influence the efficacy of cancer treatments.
this paper is germane to those presented at the symposium in the session on
cancer survivorship issues. Authors not employed by the AICR received honoraria
Dietary supplements include macronutrients, vitamins, and
for serving on the Cancer Resource Advisory Committee. minerals that are essential to human health as well as a wide
2
3
To whom correspondence should be addressed. E-mail: h.norman@aicr.org. variety of nonessential nutrients, such as certain phyto-
Abbreviations used: AI, Adequate Intake; AICR, American Institute for
Cancer Research; DRI, Dietary Reference Intakes; RDA, Recommended Dietary chemicals, hormones, and herbs. The recommendation for
Allowance; UL, Tolerable Upper Intake Level. cancer patients is to take only moderate doses of supplements

0022-3166/03 $3.00 Ó 2003 American Society for Nutritional Sciences.

3794S
 DIETARY SUPPLEMENTS DURING CANCER THERAPY 3795S

because evidence from human clinical studies that confirm therapies (8). Dietary supplementation with antioxidants may
their safety and benefits is limited (2). Use of dietary supple- provide a safe and effective means of enhancing the response to
ments during cancer treatment remains controversial. chemotherapy and improving quality of life by reducing or
The source of a nutrient—that is, whether it is from preventing side effects (8–10). On the other hand, an argument
a supplement or a natural food—influences the recommended against using supplemental antioxidants during chemotherapy
level of intake. Fruits and vegetables eaten in the AICR is that they may interfere with the oxidative breakdown of
recommended amounts of 5/d or more are safe for cancer cellular DNA and cell membranes necessary for the agents to
patients during treatment except for patients with extreme work (11,12). A further argument for avoiding the addition of
sensitivity to potential infections, such as those undergoing large doses of antioxidants during cancer treatment comes from
bone marrow transplantation or aggressive chemotherapy while evidence that the apoptotic breakdown of tumor cells is
hospitalized under sterile conditions. Dietary Reference Intakes selectively increased by the presence of reactive oxygen species
(DRI) established by the Institute of Medicine include the within the tissue and that this process will be slowed down by
Recommended Dietary Allowance (RDA), Adequate Intake an antioxidant-replete diet (13).
(AI), and Tolerable Upper Intake Level (UL) (2). The RDA is Because of the widespread use of antioxidants by cancer
the average daily dietary intake sufficient to meet the nutrient patients, further research is needed to establish the clinical

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requirement of nearly all healthy individuals. An AI is set when implications of various doses. Effects may vary depending on
evidence is not sufficient to set an RDA. The UL is the highest the amount available to normal and tumor cells. Tumor cells
level likely to pose no risk to nearly all individuals; it may be are hypothesized to have impaired homeostatic control
affected by cancer as well as cancer treatment. mechanisms, which would allow excess uptake of vitamins
This guide complements the AICR booklet ‘‘Nutrition of the and minerals. This uptake could subsequently shut down
Cancer Patient’’ (3). The term ‘‘dietary supplement’’ as used oxidative reactions required for vital cellular functions and lead
here is distinct from nutritional complementary or alternative to cell death, reduced cell proliferation rate, or induction of
(integrated) medicines, including specific botanicals. Current differentiation that would override any protective effect of
scientific findings about the safety and effectiveness of some antioxidants (8). Theoretically, these effects overall would be
commonly used dietary antioxidants and nonantioxidant advantageous in the treatment of tumors, but the results must
supplements during chemotherapy are presented and assessed. be carefully examined, not only during and immediately after
cessation of chemotherapy, but over the long term (12,14). It
Dietary antioxidants should be remembered that so-called antioxidant nutrients
under certain circumstances may act as prooxidants.
AICR and the World Cancer Research Fund advise that five A large percentage of cancer patients undergoing active
or more servings of fruits and vegetables be consumed daily to treatment take supplemental antioxidants in addition to a daily
reduce the risk of certain cancers (1). The beneficial effects of multivitamin-multimineral preparation probably with the be-
fruits and vegetables for both healthy people and cancer lief that, at the very worst, they can do no harm. How-
survivors have sometimes been associated with the presence of ever, more research is needed before definitive positive or
various antioxidant micronutrients. It has been claimed that negative advice can be given about the use of antioxidant
oxidative processes are involved in various stages of carcino- dietary supplements as adjuncts to cancer chemotherapy or
genesis, that excessive antioxidants interfere with the cytotoxic radiotherapy. It is recommended that a daily multivitamin-
effects of antineoplastic agents on cancer cells, and that certain multimineral supplement containing quantities at the levels of
micronutrients affect cancer prevention and treatment through the DRI can be used safely as part of a program of healthy
their antioxidant properties. These micronutrients include nutrition. Taking dietary supplements containing levels of
vitamin E, vitamin C, b-carotene, and other carotenoids, which nutrients with antioxidant properties much greater than the
are available singly or combined. The trace element selenium DRI is not recommended during chemotherapy because higher
has an important role in antioxidant defenses as a crucial levels may have adverse effects and interfere with efficacy of
component of selenoproteins, such as glutathione peroxidase. treatment. Patients should not be discouraged from taking
Phytochemicals with antioxidant properties also include some folic acid at the level of the RDA because this has many other
flavonoids, such as quercetin, and some polyphenols. benefits for health.
Overall, there is no convincing evidence that antioxidant No good advice for cancer patients currently exists; a greater
nutrients in the amounts obtained from fruits and vegetables understanding of processes involved in the regulation of tumor
in the diet have any deleterious effects on human health (1). growth is needed. After reviewing the available scientific
However, trials in which selected antioxidants are taken in literature, AICR has concluded that supplementation of the
amounts or combinations much higher than those normally diets of cancer patients undergoing active treatments with
found in foods have yielded conflicting data regarding cancer individual or combined antioxidants above their DRI cannot be
risk (4–6). Cancer patients should try to eat sufficient fruits and recommended as safe or effective. A second overall conclusion
vegetables daily to provide adequate levels of antioxidants, from the available data is that use of high levels of antioxidants
with the addition of a daily multivitamin-multimineral pill. as the sole treatment protocols is not advisable because they
The benefits of eating fruits and vegetables may be much may be deleterious to normal cells via a prooxidant effect or
greater than are the effects of any of the individual antioxidants may confer an advantage to cancer cells. A recent compre-
they contain because the various vitamins, minerals, and hensive guide providing nutritional advice for patients at
phytochemicals in these whole foods may act synergistically different stages of cancer survivorship concluded that patients
(1,7). undergoing chemotherapy or radiotherapy should be advised
Two opposing views exist about the use of antioxidants in not to exceed the UL for vitamin and mineral supplements and
cancer therapy. One working hypothesis recently proposed is to avoid other nutritional supplements that contain large doses
a complementary approach in which multiple antioxidant of antioxidants (7). Specific recommendations for a particular
supplements together with a low fat, high fiber diet and lifestyle antioxidant remain controversial.
modifications, including physical exercise, may markedly Vitamin E. Vitamin E is a lipid-soluble antioxidant. It is
improve the efficacy of standard and experimental cancer naturally synthesized only by plants, and its various forms occur
3796S SUPPLEMENT

in different proportions. The main sources of vitamin E are that the recommendations for vitamin C intake should be
edible polyunsaturated vegetable oils. Vitamin E is the most several times higher to achieve tissue saturation in normal
important nutrient for preventing polyunsaturated fatty acid people (27). Adverse effects of vitamin C (diarrhea, gastroin-
peroxidation. a-Tocopherol is the form of the vitamin most testinal disturbances, abdominal bloating) are rare and are
commonly used as a supplement, but vitamin E succinate is also associated with an intake of several grams daily. A recent
used. The RDA for vitamin E is 15 mg/d; the UL is 1000 mg/d review of studies pointing to the dangers of consuming ex-
(15). cessive amounts of vitamin C noted that in large amounts,
Vitamin E may prove to be an important nutrient for vitamin C changes from a protective antioxidant agent to
enhancing antineoplastic activity because of its role in pre- a harmful prooxidant that may interfere with standard therapies
venting the peroxidation of lipids. This property maintains the (28). Vitamin C can induce the decomposition of lipid
rapid proliferation of cancer cells, which is essential to che- hydroperoxides in vitro, which theoretically could give rise to
motherapy, while preventing damage to normal cells and having DNA damage in vivo (29). The investigators used concen-
beneficial effects on immune function. Some evidence shows trations of vitamin C comparable with what they thought
that in cancer cells vitamin E has a synergistic effect with che- would be found in the human body with an intake of 200 mg/d.
motherapy and radiation (10). In animal studies, combina- Whether these same conditions actually prevail in the human

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tions of high doses of vitamin E and chemotherapy have had body remains uncertain (30). Many studies have shown that
beneficial effects, detrimental effects, and no effect (10). the amount of vitamin C that the body can store is limited, so
Vitamin E may be useful in the management of treatment for a question remains about what beneficial effect is possible with
some cancer patients because it has been shown to reduce pain large doses. Data are sufficient for people to be wary of taking
(16), prolong survival in conjunction with (n-3) polyunsatu- megadoses ($600 mg/d).
rated fatty acids (17), reduce fibrosis from radiation treatment One clinical study suggested protection against chemother-
(18), and decrease oral mucositis associated with chemotherapy apy-induced mutagenesis after daily supplementation with 1 g
(19). Vitamin E, although reported to reduce somewhat the vitamin C (31); supplementation with 100 mg vitamin C had
cardiotoxicity of doxorubicin, had no striking effect otherwise no significant effect. In another study vitamin C was believed to
(20,21). Treatment of oral leukoplakia with vitamin E was enhance immune function by increasing natural killer cells and
successful and well tolerated (22). Intensive topical treatment the function of T- and B-cell lymphocytes (32).
with vitamin E may facilitate the healing of chemotherapy- AICR recommends that cancer patients should follow
induced stomatitis (23). a reasonable diet sufficient in the fruits and vegetables that
In considering the possible use of supplementary vitamin E, provide vitamin C at least at the RDA level but that they
it is essential to remember that vitamin E may act as should not take more supplemental vitamin C than the amount
a prooxidant in cigarette smokers, particularly if they are obtained in a reliable daily vitamin-mineral pill containing
following a diet with high amounts of (n-6) fatty acids (24). In vitamin C at the level comparable with RDAs.
addition, vitamin E acting as a prooxidant in high concen- b-Carotene. b-Carotene is one of ;600 plant compounds
trations was shown to directly inhibit human prostate tumor classified as carotenoids. b-Carotene is the most abundant
growth via induction of tumor cell apoptosis without affecting carotenoid and is found in orange vegetables and fruits and in
surrounding tissues (25). 5-Fluorouracil is possibly the single dark-green leafy vegetables. It is widely used as a supplement
most effective treatment for advanced colorectal cancer; but its only defined role in nutrition is as a precursor for vitamin
vitamin E was shown to induce cell death in colorectal can- A. Although b-carotene is an antioxidant, its importance to
cer cells and to enhance growth inhibition of these cells by health in this role is not established. No DRI is proposed for
5-fluorouracil (26), suggesting an adjuvant therapy for colo- b-carotene or other carotenoids (15) but existing recommen-
rectal cancer. dations (1) for increased consumption of carotenoid-containing
Although vitamin E appears to be beneficial in some cases, fruits and vegetables are supported.
and some animal experiments have suggested that high doses of Because of evidence that b-carotene supplements have not
vitamin E may enhance the efficacy of chemotherapeutic drugs, been shown to confer any benefit for the prevention of cancer
AICR has concluded that the evidence is not sufficiently strong and may actually cause harm in certain subgroups, b-carotene
to warrant its routine use by patients receiving chemotherapy or supplements are not advised routinely for cancer patients. Four
radiation therapy. Oversupplementation with vitamin E is not large studies involving b-carotene supplementation have pro-
recommended during traditional therapies. The UL of vitamin vided no evidence of a protective effect against cancer and two
E should not be exceeded in supplements given to cancer studies showed an increased risk of lung cancer and overall
patients. The RDA may safely be provided for cancer patients mortality (1).
to prevent deficiency. If there is serious malabsorption, the Some data from studies in animal and human cancer cells in
amount of vitamin E has to be increased. culture suggest that b-carotene may increase the efficacy of
Vitamin C. Vitamin C is a water-soluble nutrient that has chemotherapy and radiation (10). Most studies have been done
antioxidant properties. It is common in a variety of fresh fruits with a combination of b-carotene and other antioxidants.
and vegetables. It is widely used by cancer patients but its effect Studies in patients, however, are too few and too fragmentary
on conventional treatment is not known. Limited preclinical to enable conclusions to be drawn about efficacy or to make
data suggest that vitamin C may either stimulate or inhibit definite recommendations or guidelines for patients and for
tumor growth depending on the form, dose, and timing of health professionals.
supplementation, cancer site, and type of chemotherapy (9). It has also been suggested that b-carotene is not an
The interactions of vitamin C with chemotherapy and ra- antioxidant exclusively and that its observed effects are related
diotherapy remain unclear in the absence of rigorous, com- to other biological properties (33). AICR therefore recom-
prehensive preclinical and clinical research, although vitamin mends that patients not take b-carotene in quantities unat-
C in high concentrations increased the toxicity of some che- tainable from a normal diet and that it is more beneficial to eat
motherapeutic drugs in animals (10). carotenoid-rich fruits and vegetables.
The RDAs for vitamin C are 90 mg/d for men and 75 mg/d Selenium. The trace mineral selenium is not itself an anti-
for women; the UL is 2000 mg/d (15). Some evidence shows oxidant but within cells it is incorporated into selenoproteins,
 DIETARY SUPPLEMENTS DURING CANCER THERAPY 3797S

some of which have antioxidant functions. The best charac- negative breast cancer cells in vitro (37). In a review of 26
terized antioxidant selenoprotein is glutathione peroxidase. studies of the effects of soy or soy isoflavones on eight cancer
Selenium occurs naturally in cereal products, a wide variety of sites in animals, soy had positive (inhibitory) effects in most
vegetables, and seafood. The richest source of selenium in cases (38). None of these studies indicated that soy increases
a supplement is a selenium-enriched brewer’s yeast. The RDA tumor development. However, as recently reviewed, the overall
for selenium is 55 mg/d; the UL is 400 mg/d (15). epidemiologic evidence relating soy and breast cancer risk
Recent studies with animals indicate that selenium sup- remains controversial (39).
plementation may enhance the effectiveness of various chemo- Isoflavones may exert antiestrogenic effects on breast tissue
therapeutic agents (10,34,35). Thus, there is great interest in and for this reason soy products and isoflavone supplements
selenium as a preventative agent for cancer at a variety of sites. are widely taken by breast cancer patients. However, recent
The suggested mechanism is that selenium (through gluta- concerns over the possible detrimental effects of soy isoflavones
thione peroxidase activity) acts as a scavenger for products of on breast cancer patients because of their estrogen-like
oxidation reactions induced by standard therapies. In addi- properties demonstrated in some experimental systems has
tion, selenium supplementation may directly cause tumor cell led to considerable controversy as to whether they should be
apoptosis. taken by these patients (39). Genistein, for example, inhibits

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The development of drug resistance is a major cause for the the growth of both hormone-dependent and -independent
failure of chemotherapy, particularly in ovarian cancer. Re- breast cancer cells in vitro, but at low concentrations
search has focused on reversing drug resistance and the alter- proliferation of at least one breast cancer cell line is stimulated
native approach of preventing the development of resistance. by genistein (39).
Selenium compounds were found to prevent the induction of A recent review of the available data addressed two extreme
drug resistance by cisplatin in human ovarian tumor xeno- and opposing claims: soy is effective against breast cancer and
grafts (35). because of this should be recommended for consumption by
Few studies in cancer patients have examined the extent to healthy women and breast cancer patients, and soy is harmful
which selenium supplementation protects patients during for women with a history of breast cancer or who are at high risk
chemotherapy and radiation. Oversupplementation is con- and therefore should be avoided by such women (39). The
traindicated because selenium is toxic at higher levels. Among authors concluded that the data are not convincing enough to
dietary nutrients, selenium has a particularly narrower dose support either claim and that strong conflicting data exist
range between efficacy and toxicity. Evidence is not sufficient regarding both.
for either broad or precise recommendations to the public for AICR concludes that at this time information is not
cancer patients during treatment. sufficient to make a recommendation about soy foods or soy
products. Supplements containing isoflavones are not recom-
Combinations of antioxidants during cancer treatment mended because the levels of the isoflavones contained are in
most cases much higher than what can be obtained in the diet.
More research is needed on the effects of different Polyunsaturated fatty acids. Two families of polyunsatu-
combinations of antioxidant supplements on cancer patients rated fatty acids are essential: the (n-6) and the (n-3) families,
during treatment. Because of extensive interactions—both which are grouped according to their chemical structures.
synergistic and antagonistic—that occur in vivo, the outcome Although plants can synthesize both the basic (n-6) and (n-3)
of their total action cannot be assumed to be equal to the sum structures, animals (including humans) cannot and must ob-
of the individual antioxidant actions. The lack of information tain them from dietary sources. Linoleic acid is the parent fatty
on such interactions raises concern about making recom- acid of the (n-6) family and a-linolenic acid is the parent of the
mendations for the indiscriminate use of these supplements. (n-3) family. The Western diet is rich in (n-6) fatty acids and
Therefore, the AICR recommendation of fruits and vegetables poor in (n-3) fatty acids because of the large amounts of vege-
in the diet rather than relying on large amounts of a multi- table oils and meats and relatively low amounts of fish in
vitamin-multimineral supplement is a sound strategy. In addi- the diet. Both (n-6) and (n-3) polyunsaturated fatty acids are
tion to consuming fruits and vegetables during the treatment of important components of animal and plant cell membranes.
cancer, patients should only take a daily multivitamin-multi- a-Linolenic acid comes from green leafy vegetables,
mineral pill containing antioxidants below the UL. flaxseed, rapeseed, and walnuts. Humans can form eicosap-
entaenoic acid and docosahexaenoic acid from a-linolenic acid
Dietary supplements without antioxidant properties or get them from eating fish. Most liquid vegetable oils, includ-
ing corn, are rich in linoleic acid. Humans can form arachidonic
Many nonantioxidant supplements are widely taken by acid from linoleic acid or get it from eating meat. Eicosapen-
cancer patients although their effects on the efficacy of taenoic acid and arachidonic acid are precursors of prostagland-
chemotherapy treatments are controversial. Among these are ins and leukotrienes.
soy foods and soy products, (n-3) fatty acids, and vitamin D. Indications are that dietary (n-3) fatty acids can significantly
Soy protein and isoflavones. Soy protein is the highest retard the growth of tumors whereas (n-6) fatty acids
quality protein found in the plant kingdom and is eaten as potentially can increase tumor development (40). However,
a staple by two-thirds of the world’s population. On the basis of the data are largely derived from animal experiments (41), and
numerous studies demonstrating that soy protein reduces regulation of the growth of human cancers is still a controversial
serum cholesterol levels, the U.S. Food and Drug Admin- issue. Mechanisms of fatty acid effects on tumorigenesis and
istration approved the health claim that eating 25 g/d of soy tumor growth are not well defined, but evidence exists that
protein reduces the risk of heart disease (36). high levels of prostaglandin E2, derived from (n-6) fatty acids,
A lot of evidence suggests that soy consumption may promote tumor growth. Fish oil–enriched diets containing
decrease breast cancer risk. This decrease has been largely eicosapentaenoic acid and docosahexaenoic acid decrease the
attributed to isoflavones in the soy protein, primarily the formation of prostaglandin E2, which coincides with retarded
phytoestrogens genistein and daidzein. Soy isoflavones inhibit growth of tumor cells. An alternative mechanism proposed
the growth of both estrogen receptor–positive and receptor– is that oxidative damage of the polyunsaturated fatty acids
3798S SUPPLEMENT

in fish oil enhances lipid peroxidation in the tumor to toxic D-2 (calciferol; of plant origin) and D-3 (animal origin), both of
levels. which are biologically relatively inert and first have to be
Fish oil supplementation enhanced the efficacy of the cancer metabolized to the active form 1,25-dihydroxyvitamin D.
chemotherapeutic agent CPT-11 (irinotecan) against MCF7 Vitamin D-3 is biologically largely inactive until it is converted
breast carcinoma xenografts and ameliorated intestinal side to 1,25-dihydroxyvitamin D-3. This active form not only plays
effects in MCF-7–bearing mice (42). The explanation given a central role in bone and calcium metabolism but also has been
is that the combination of fish oil and CPT-11 leads to the shown to suppress the growth of tumors of different origins,
selective accumulation of lipid peroxidation products to cyto- including breast cancer cells (48). The AI for vitamin D are 5
toxic levels in the MCF7 xenografts. mg/d for ages 19–50 y, 10 mg/d for 51–70 y, and 15 mg/d for
Experimental studies indicate that very-long-chain poly- $70 y. The UL is 50 mg/d (49).
unsaturated fatty acids, in particular docosahexaenoic acid, A series of studies suggested a possible role for increased
may increase the sensitivity of mammary tumors to several dietary calcium and vitamin D in the chemoprevention of colon
cytotoxic drugs, including doxorubicin (43). Omega-3 (n-3) and breast cancer (50,51). A major drawback to a clinical
fatty acid supplementation for breast cancer chemoprevention application in cancer therapy is that high doses of di-
is strongly supported by epidemiologic and experimental hydroxyvitamin D-3 are needed; such high doses can lead to

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studies. Experimental data and data from a case-control study hypercalcemia and death (52). A major focus of chemopre-
conducted on a homogeneous population in France suggest vention research has been the synthesis of analogs of dihydroxy-
that a-linolenic acid may have a protective effect in breast vitamin D-3 that have antiproliferative and prodifferentiation
cancer (44). The association between levels of fatty acids stored effects against cancer cells without resulting in hypercalcemia.
in breast adipose tissue and the response of the tumor to The results are new synthetic vitamin D-3 analogs that are
chemotherapy in patients with an initially localized carcinoma potent inhibitors of cancer cell growth (53,54). Their exact
was studied (45); primary chemotherapy combined mi- mode of action remains largely unknown.
toxantrone, vindesine, cyclophosphamide, and 5-fluorouracil. The synergistic effects of dihydroxyvitamin D-3 analogs with
The results suggested that docosahexaenoic acid could increase retinoids, antiestrogens, and conventional chemotherapeutic
the response of the tumor to the cytotoxic agents used. Dietary drugs may result in enhanced response rates and reductions in
supplementation with (n-3) fatty acids was evaluated in several the concentrations of conventional anticancer drugs, thereby
clinical trials, and the results suggest some benefits to cancer reducing side effects (55,56). These analogs are still in an ex-
patients (17,46). perimental stage. Definitive recommendations for vitamin D-3
Recommendations made by AICR and other official and its analogs cannot be made for cancer patients at this time.
organizations are that energy from dietary fat should be The benefits of ample consumption of fruits and vegetables
#30% of the total energy intake. Research indicates that the in their entirety may be much greater than the positive effects
type of dietary fat is also important for normal growth and of any of their micronutrient components because individual
development and for treatment of cancer and other diseases. components may act in synergy during treatment. No evidence
The ratio of (n-6) to (n-3) fatty acids seems to be critical in exists that fruits and vegetables are harmful to the cancer
some cases. It is recommended that cancer patients and healthy patient during treatment.
people should consume the recommended AI for polyunsatu- Patients are cautioned that vitamin and mineral sup-
rated fatty acids (47). plements as therapies are not substitutes for either sound
Vitamin D-3. Biological modifiers of cancer cells that are nutrition or established medicine. Taking a daily multivitamin-
designed to retard proliferation; induce differentiation of these multimineral supplement containing essential nutrients at the
cells to a quiescent, nondividing stage; and promote cell death levels of the DRI can be used safely as part of a program of
have been intensively studied in recent years. Several research healthy nutrition. Further scientific research is needed to
studies have used a combination of vitamin D-3 (cholecalcif- provide a set of firm guidelines for use of additional vitamin and
erol) analogs with radiation. mineral supplements by the cancer patient during treatment.
Vitamin D-3 is a hormone produced in the skin by the AICR presents specific recommendations in Table 1. Animal
action of sunlight. Supplements of vitamin D contain vitamins studies and cell culture studies often use relatively high levels of

TABLE 1
Dietary supplements during cancer treatment: specific recommendations from the American Institute for Cancer Research

d Supplementation of the diets of cancer patients undergoing active treatments with individual or combined antioxidants above their Recommended
Dietary Allowances (RDA) or Adequate Intakes (AI) cannot be recommended as safe or effective.
d Use of high levels of antioxidants as the sole treatment protocol is not advisable because they might be deleterious to normal cells via a prooxidant
effect or may possibly confer an advantage to cancer cells.
d Evidence is not sufficiently strong to warrant routine use of vitamin E supplementation in patients receiving chemotherapy or radiation therapy.
Oversupplementation is not recommended during traditional therapies.
d Cancer patients should follow a reasonable diet that provides vitamin C at the RDA or no more than double that amount.
d Patients should not take large amounts of b-carotene.
d Evidence is not sufficient at this time for either broad or precise recommendations about selenium.
d The lack of information on antioxidant interactions raises concern about making recommendations for the indiscriminate use of combinations of
antioxidants.
d Information is not sufficient to make a recommendation about soy foods or soy products. Supplements containing soy isoflavones are not
recommended because the levels of the isoflavones contained are in most cases much higher than can be obtained from the diet.
d Cancer patients and healthy people can consume the recommended AI for polyunsaturated fatty acids.
d Recommendations for vitamin D3 cannot be made for cancer patients.
d A daily multivitamin containing supplements at levels of the DRI can be used safely as part of a program of healthy nutrition including 5–10 servings of
fruits and vegetables daily.
 DIETARY SUPPLEMENTS DURING CANCER THERAPY 3799S

supplements to achieve a positive effect, but few clinical trials 29. Lee, S. H., Oe, T. & Blair, I. A. (2001) Vitamin C-induced de-
composition of lipid hydroperoxides to endogenous genotoxins. Science 292:
with high doses have been conducted. Without clinical trials, 2083–2086.
no firm basis exists for constructing guidelines. 30. Rosenthal, D. & Ades, T. (2001) Vitamin C promotes genotoxic lipid
metabolites: in vitro-in vivo significance remains uncertain. CA Cancer J. Clin. 51:
316–320.
31. Pohl, H. & Reidy, J. A. (1989) Vitamin C intake influences the bleomycin-
induced chromosome damage assay: implications for detection of cancer
LITERATURE CITED susceptibility and chromosome breakage syndromes. Mutat. Res. 22: 247–252.
32. Heuser, G. & Vojdani, A. (1997) Enhancement of natural killer cell activity
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