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Home > FACT > FACT contents > Volume 9 2004 > Volume 9:2 June 2004 > Focus

Focus Altern Complement Ther 2004; 9: 96–106

Antioxidants during anticancer therapy

Stephen M Sagar

Keywords

  • Antioxidants
  • cancer
  • radiation therapy
  • chemotherapy
  • interactions
  • micronutrients
‘Opinions based upon theory, superstition, and ignorance are not very precious.’

Mark Twain (1900)

‘I am not one of those who in expressing opinions confine themselves to facts.’

Mark Twain (1907)

Introduction

The debate over the usefulness and contraindication of antioxidants during conventional anticancer therapy is currently based more on opinion than on scientific fact. A Medline search reveals that there is no level I evidence (i.e. prospective RCTs) that proves antioxidants to be either beneficial or detrimental to the outcome of anticancer treatment. To be of benefit, an antioxidant therapy should increase the therapeutic gain, in other words either improve tumour control or reduce normal tissue toxicity. A therapy that equally reduces both tumour control and normal tissue toxicity has not produced a therapeutic gain and is therefore not clinically useful. Speculation on clinical benefit has been extrapolated from a combination of interventional laboratory studies (usually based on cell culture) and observational studies of cancer prevention. Opinion on clinical detriment is based on some conflicting laboratory studies and the fundamental teaching of clinical oncologists that free radicals (or reactive oxygen species) are the major weapons of cancer destruction and should never be suppressed for fear of reducing tumour control. Pundits on both sides of the debate make good points, but these are mainly based on opinion rather than fact.

Part of the controversy arises from the futile attempt to compare apples and oranges. Many biochemicals have either oxidant or antioxidant activity that varies under different metabolic conditions.1–4 The human population is heterogeneous in relation to levels of reactive oxygen species (ROS) and the ability to moderate them.5 It has also been assumed that it is the antioxidant activity alone that is responsible for any interventional benefit. This is clearly naive since all antioxidants have many additional biochemical and pharmacological effects.6 Any discussion of antioxidants needs to be very specific when defining both the intervening chemical and the measured effect. For example, the carotenoids are generally regarded as antioxidants, but they also interact with cell membrane receptors to initiate differentiation.7–10 The efficacy of antioxidants in preventing cancer should be differentiated from their contribution during anticancer therapy. For example, epidemiological studies indicate that lycopene can inhibit the development of prostate cancer,11–16 but laboratory experiments show that it reduces the ability of radiation to destroy prostate cancer cells.17 Synthetic beta-carotene can increase the risk of lung cancer in people who have previously smoked cigarettes, hence proposing a paradox between cancer promotion and prevention.18–23 On the other hand, another antioxidant, vitamin E, seems to promote the destruction of cancer cells in vitro by radiation, whilst enhancing the normal healing of tissue following completion of radiation therapy.24–40 The source of the antioxidant may affect its biological activity. Synthetic and natural beta-carotenes manifest different biological effects.41 This differential response implies that the effects of antioxidant activity are dependent on the metabolic environment or that the effects are totally unrelated to their antioxidant activity.42,43

This review focuses on the limited evidence available for combining antioxidants and anticancer therapy, with a view to providing the best current evidence for designing an RCT. I will direct attention towards dietary antioxidants, especially vitamins (rather than the multiple herbal derivatives touted for their antioxidant activity), and evaluate whether or not there is a role for pharmacological intervention with micronutrients above the recommended supplement dose. Non-vitamin antioxidants include sulphydryl compounds (such as glutathione) and antioxidant enzymes, whose major effects are to quench free radicals and reduce radiation damage to both normal and tumour tissues. The micronutrient selenium is an essential component of glutathione peroxidase, an enzyme that quenches ROS. Other non-vitamin antioxidants include melatonin, pycnogenol and Coenzyme Q10, all of which have pharmacological properties that can inhibit cancer, but are not necessarily related to their antioxidant activity. They may also have a role in counteracting the long-term toxicity of conventional anticancer therapies.44–49

Observational surveys that report associations of antioxidant levels and outcome may provide leads and hypotheses but cannot replace the data of prospective clinical trials.50–52 For example, people who ingest diets rich in fruit and vegetables have a decreased chance of developing cancer and an increase in the concentration of beta-carotene in their blood.22,53–61 However, supplements of beta-carotene do not have an anticancer effect and actually increase cancer in smokers.21,23,62–67 The beta-carotene level may simply be a surrogate for the activity of an associated compound. Despite the beneficial effect of fruit and vegetables in decreasing the free radical damage from environmental pollutants (including radiation) in human observational studies, supplements of vitamins C, E and beta-carotene generally do not decrease DNA damage from irradiation in many in vitro and animal studies.68–73 In contrast, lycopene does reduce DNA damage from ROS.17 Other studies have shown that levels of vitamin C below the recommended dietary allowance (RDA) are associated with increased free-radical damage to DNA and greater tissue sensitivity to radiotherapy, whereas moderate vitamin C supplementation can reduce free-radical damage from radiation treatment and enhance cancer cell survival.68,74 Paradoxically, treatment with very high doses of vitamin C can inhibit cancer cell division and increase the sensitivity of tumours to radiotherapy.42 The effects of antioxidants are multi-factorial and dependent on initial conditions. Their actions are indeed a tangled web.

The paradox of dietary antioxidants

The effect of dietary antioxidants on tumours is dose dependent. High doses inhibit the growth of cancer cells without affecting the growth of normal cells.5,42,43,75 Prasad has defined a ‘high dose’ as more than the RDA but not enough to cause toxicity. A high dose of vitamin C is up to 10 g/day, of vitamin E up to 1000 IU/day, of vitamin A up to 10 000 IU/day and of natural beta-carotene up to 60 mg/day.6 Prasad’s research has defined the equivalent doses in tissue cultures. The results from tissue cultures suggest that high doses of the dietary antioxidants A, C, E, D-alpha-tocopheryl succinate (alpha-TS) and beta-carotene inhibit the growth of cancer cells without affecting the growth of normal cells and actually enhance the effect of irradiating cancer cells, whilst protecting normal cells.3,7–10,26–28,31,37,38,40,76–87 In addition, a critical factor is to ensure that the dose of these vitamin antioxidants is within the high-dose range and that the cells are exposed to the high dose of antioxidants for a prolonged treatment time before and after irradiation. In contrast, doses of the vitamin antioxidants that are intermediate between the RDA and high level reduce the efficacy of X-irradiation in destroying cancer cells.88–92 This in vitro and animal tumour research suggests that these specific antioxidants can quench the toxic effects of free radicals on normal tissues whilst increasing the cell kill in tumours via mechanisms unrelated to their antioxidant activity. Also, the efficacy of this combination of antioxidants is synergistic. They inhibit the growth of tumours by causing differentiation and apoptosis in cancer cells.24,30,93–95 This is reflected by their ability to down-regulate genes involved in the proliferation of cancer cells. However, the issue is complicated by the fact that the growth-inhibitory doses vary between species and tumour types. In addition, the relative degree of uptake of the dietary antioxidants between tumour and normal cells is highly variable, and does not seem to define the therapeutic gain.82,96–100

Laboratory experiments indicate that a mixture of dietary antioxidants is more effective in reducing the division of cancer cells than individual antioxidants.91 Since each of the dietary antioxidants has different modes of action, a combination of dietary antioxidants should be considered for a clinical trial.

Another paradox is that although total antioxidant status declines during cancer treatment, the serum levels of specific antioxidants may increase. A systematic review of patients with cancer who were receiving chemotherapy revealed that there was no consistent pattern in the changes in the amounts of vitamins C and E, selenium and beta-carotene.101 Total antioxidant status is depleted prior to treatment, perhaps because cancer cells use antioxidant vitamins more efficiently than normal cells, or simply because cancer patients become malnourished through reduced appetite. The initiation of anticancer therapy may further lower levels of antioxidants through poor diet, but levels of individual antioxidants may improve as the cancer burden is reduced.102 Supplementation with individual antioxidants inconsistently affects serum levels. It is not known whether the standard RDA is sufficient for supplementation during anticancer therapy.103–105

Antioxidants during chemotherapy

Specific antioxidants have been proposed as anticancer agents. One of them, vitamin C, has been highly publicised since Linus Pauling (the Nobel laureate) postulated its anticancer activity when it was prescribed at a high dose (5–10 gm/day).106,107 Plausible data have been presented that suggest that vitamin C has no effect on cancer,55,59,108–115 that lower doses can stimulate tumour growth97,116 and that both low and high doses can inhibit tumour cell formation and progression.98,117–125 There is reasonable evidence that a deficiency of vitamin C in the diet is a factor in carcinogenesis and that replacement may prevent the development of some tumours, such as gastric and oesophageal cancers.122,123,126–129 In contrast, the evidence for a therapeutic role of vitamin C in treating established tumours is weak. At least two double-blind RCTs have failed to find a significant effect on improving outcome.130,131

Serious concerns have been raised regarding the potential of antioxidants to antagonise the activities of certain chemotherapy drugs, especially the alkylating agents.132 Proponents of high-dose antioxidants during chemotherapy often cite amifostine as being a conventional agent that is an antioxidant widely used to protect normal tissues from the toxicity of cisplatin. However, amifostine has specific pharmacological properties that increase its therapeutic ratio towards normal tissues. Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite that can reduce the toxic effects of cisplatin in conventional oncology.133–135 The ability to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumour tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake. The higher concentration of free thiol in normal tissues is available for binding to, and thereby detoxifying, reactive metabolites of cisplatin. Even so, most oncologists exercise caution and do not utilise amifostine when treating highly curable cancers, such as germ cell tumours. In addition, mesna is also touted as an example of a pharmaceutical antioxidant that is acceptable for use with chemotherapy. However, this ignores the important pharmacokinetic advantage that mesna has in improving therapeutic gain. It is rapidly metabolised in vivo to mesna disulfide, which undergoes rapid renal excretion. Its high antioxidant activity is concentrated in the renal pathway, where it reacts with acrolein, the highly oxidant metabolite of the alkylating agent iphosphamide, thereby limiting the chemotherapy’s renal and bladder toxicity without affecting tumour cytotoxicity.136

There is no clear evidence in the literature that individual dietary antioxidants reduce toxicity from chemotherapy at RDA doses.101,132 On the other hand, studies have been inconsistent in evaluating various combinations of micronutrients, their doses, their timing and the lack of appropriate controls, and usually there is no validation of covert antioxidant supplementation. The most promising studies propose that selenium (a component of glutathione peroxidase) is an effective antioxidant in preventing cisplatin-induced nephrotoxicity.47 Laboratory experiments suggest that some antioxidants may potentiate the cytotoxicity of specific chemotherapy agents on some tumours.137,138 The cytotoxicity of some chemotherapy drugs, such as etoposide and cisplatin, may not depend solely on ROS production.139

However, many concerns have been raised over potential pharmacokinetic and pharmacodynamic interactions between chemotherapy agents and higher than supplemental doses of dietary antioxidants.132 In general, alkylating agents and anthracyclines create ROS, which can react with the nucleic acids to incapacitate the function of DNA and RNA.140–143 Thiols, such as cysteine, are endogenous antioxidants that neutralise ROS.144 Higher levels of free thiol groups can be associated with tumours that have a greater resistance to alkylating agents.145 On the other hand, some studies show that thiols and other endogenous antioxidants, such as superoxide dismutase, can potentiate the activity of some alkylating agents.146–150 Dietary antioxidants can quench free radicals generated from both endogenous sources, as well as chemotherapy agents.151 In summary, interactions are complex and unpredictable since different kinds of free radicals are produced, pharmacokinetics are variable, multidrug resistance gene induction is highly conditional, and the distribution, metabolism and excretion of metabolites of the chemotherapy agent may differ from the parent compound.

The potential for reducing the efficacy of certain categories of chemotherapy agents that owe their cytotoxic activity to the formation of ROS is clear. On the other hand, high doses of some antioxidants themselves have cytotoxic activity in vitro and may contribute to therapeutic gain. Only a RCT will provide clinical useful answers.138 Of more concern is the influence of high doses of antioxidants on the sensitive pharmacokinetics of chemotherapy drugs. These drugs are often administered near their maximum tolerated dose, such that toxicity may occur following a small effect on their pharmacokinetics. Patients are cautioned about taking aspirin with high-dose methotrexate, since even a low dose can reduce excretion and cause major toxicity. The same advice should apply to higher than RDA doses of antioxidants until we know more about their influence on the pharmacokinetics of specific chemotherapy drugs.

Antioxidants during radiotherapy

The inference of laboratory experiments is that high doses of some specific dietary antioxidants enhance the effect of irradiation selectively on cancer cells whilst protecting normal cells.42 In contrast to the effect of high doses of dietary antioxidants, in vitro experiments suggest that low doses either have no effect on cell proliferation or may even stimulate the growth of cancer cells.6,43 It is important to be specific, since high-dose vitamin E and retinoic acid enhance the effect of X-irradiation on tumour cells (through preventing the repair of potentially lethal damage in cancer cells more than in normal cells), whereas lycopene inhibits its effect.3,17,32,33,89,152–155 Laboratory studies have established that vitamins A, C and E, and carotenoids can protect normal cells but not cancer cells.29,32,152,156–161 In contrast, elevated levels of endogenous antioxidants, such as thiols and superoxide dismutase, enhance radio-resistance.162–165

The situation with radiotherapy may be quite different from chemotherapy. Radiotherapy produces extraordinarily high levels of ROS within milliseconds inside the targeted volume. It seems implausible that such high levels of ROS could be significantly quenched by dietary antioxidants. On the other hand, high doses of micronutrient supplements could replenish the total antioxidant status, thereby reducing normal tissue toxicity. A rodent study showed that antioxidant vitamins reduce the normal tissue toxicity induced by radio-immunotherapy.156,166 Similarly, selenium and vitamin E reduce radiation-induced intestinal injury in rats.33 A randomised controlled study in patients with advanced squamous carcinoma of the mouth showed that beta-carotene reduced radiation and chemotherapy induced oral mucositis, with no significant effect on the tumour recurrence rate.167,168 Amifostine is often quoted as evidence that antioxidants do not antagonise the efficacy of radiotherapy on tumour cells. However, the therapeutic gain in treating head and neck cancers is because amifostine is concentrated and activated more efficiently by the parotid glands than adjacent tumour cells, thereby preventing the side-effect of xerostomia without compromising tumour control.135

The evidence of synergy between antioxidants and radiotherapy from human studies is limited. Advocates of antioxidant treatment sometimes quote two phase II studies that demonstrate an increased response of carcinoma of the cervix and advanced squamous cell carcinoma of the skin to 13-cis-retinoic acid combined with interferon-alpha.81,169 However, this protocol contains a synthetic carotene and is combined with interferon, a protocol that bares no resemblance to the dietary antioxidants investigated in the laboratory. Another study evaluated 18 non-randomised patients with small-cell lung cancer who received vitamins, trace elements and fatty acids.170 The conclusion was that patients receiving antioxidants showed an improved tolerance to chemotherapy and radiation treatment, and prolonged their survival compared to historical controls. Unfortunately, although promising, comparison with a historical control group introduces potential bias and cannot be considered a high level of evidence.

Antioxidants following completion of anticancer therapies – treatment of iatrogenic complications

Despite the uncertainties of combining high-dose antioxidants with conventional anticancer therapies, some progress has been made in evaluating antioxidants for reversing the side-effects of both chemotherapy and radiotherapy. An RCT evaluating the efficacy of antioxidant supplementation on the neurotoxic effect of cisplatin therapy showed a significant reduction of neuropathy when vitamin E (300 mg/day) was administered during chemotherapy.34 A small single-arm study suggested that alpha-lipoic acid (600 mg IV per week for 4 weeks, followed by 1800 mg oral tid for a maximum of 6 months) reduces docetaxel/cisplatin-induced polyneuropathy.171 A case report suggested that a combination of pentoxifylline (PTX) and tocopherol (vitamin E 1000 IU and PTX 800 mg for 18 months) may produce regression of radiation-induced fibrosis.39 A small phase II study showed that childhood radiation therapy-induced uterine dysfunction was reversed by vitamin E and PTX, resulting in increased measured uterine blood perfusion and increased embryo implantation rate.172 A recent RCT of 24 women with radiation-induced breast fibrosis showed that 6 months of treatment with combined vitamin E and PTX can significantly reduce radiation-induced fibrosis.173 Synergism between PTX and vitamin E was likely, as treatment with each drug alone was ineffective. An RCT of grape-seed extract (containing the proanthocyanidin antioxidants) is being initiated at the Royal Marsden Hospital in the UK.174 This will evaluate whether a 6-month course of grape-seed antioxidant following radiotherapy will prevent radiation-induced breast fibrosis. Despite the controversy over advocating high doses of specific antioxidants, a balanced diet rich in fruit and vegetables should be encouraged for all patients during (when tolerated) and following their anticancer therapies to reduce toxicity from nutritional deficiency and as an aid to prevent further cancer development.59,175

Conclusions

Free-radical and antioxidant activity exist within a complex physiological and biochemical framework in humans that cannot be duplicated by in vitro experiments. Surveys of patients undergoing cancer treatment have shown that 25–85% use nutritional supplements containing antioxidants at doses higher than the RDA.176,177 In light of both plausible benefits and potential adverse interactions with conventional therapies, further clinical studies are warranted.

Antioxidant studies need to focus on cancer patients receiving conventional treatments within the context of an RCT.178,179 Laboratory and observational studies have produced a plausible hypothesis that specific combinations of antioxidant micronutrients, at doses greater than the RDA, may improve tumour control and reduce toxicity when administered with some conventional anticancer therapies.107 The design of a clinical trial to evaluate the role of antioxidants in anticancer treatment should be very specific in selecting the interventional agents and measuring both benefits and toxicities. Mixtures of antioxidants can be synergistic, so preclinical and phase II studies are needed to affirm optimal combinations. Factorial phase III trials may provide greater efficiency in testing a variety of combinations.180 In reality, the evaluation can never be simply antioxidants, but the activity of specific agents with multiple biochemical effects, some of which may be antioxidant in certain circumstances. Important issues in designing a clinical trial include defining the appropriate patient population, measuring the total antioxidant status, in addition to serum and tissue levels of the specific interventional agents,5,100,181 and establishing well-defined endpoints.182 The study should measure both short- and long-term tumour control and normal tissue toxicities. The study must design the intervention to be over and above the standard dietary antioxidant supplementation.103 It would not be ethically appropriate to malnourish patients during their standard anticancer treatment since we already know that a depletion of antioxidants below accepted normal levels increases toxicity and is associated with the side-effects of malnourishment.103 A pilot study will be necessary to determine the variance of outcomes so that the appropriate number of trial participants can be calculated to avoid a beta error, namely not having sufficient patients to detect a statistical difference. In short, we require a randomised, double-blind, placebo-controlled trial of a specific antioxidant intervention for a defined tumour type, while realising that we cannot generalise the results of this specific intervention to alternative antioxidant combinations any more than we can generalise the effects of different categories of drugs.

A major challenge for the initiation of a clinical trial is deciding which combination of antioxidants to evaluate. For a radiotherapy study, a combination of high-dose vitamin E, vitamin C, vitamin A, beta-carotene and selenium (limited to 200 mcg) seems reasonable. A phase III trial will require large numbers of patients to detect the likely small differences in outcome. The number of potential combinations of different antioxidants is vast and the relative clinical efficacies of these combinations are unknown. There are definite limitations in the ability of clinical trials to evaluate varied treatment combinations, and funding of this endeavour is unlikely to occur until phase II studies have defined the most effective combination of antioxidant agents. Knowledge of the molecular mechanisms of activity of these agents is essential and methods are necessary for predicting their complementary and synergistic activity prior to initiating the RCT. Antioxidants may improve short-term toxicity but this could be followed by an increase in the long-term probability of recurrence. Clinically meaningful data should include long-term recurrence and survival rates. Ultimately only phase III trials can determine the relative advantage of one combination over another, and multi-arm and factorial designs may be a more efficient mechanism for testing multiple regimens at the same time. Until we can obtain valid clinical facts, opinions will be based on theory, superstition and ignorance.

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Stephen M Sagar, BSc Hons, MB, BS, MRCP, FRCR, FRCPC is Associate Professor at McMaster University in Hamilton and Radiation Oncologist at the Juravinsky Cancer Centre, 699 Concession Street, Hamilton, Ontario, Canada L8V 5C2. He is also a member of the International Editorial Board of FACT. E-mail: Stephen.Sagar@hrcc.on.ca
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