By Howell Sasser, PhD
A diagnosis of cancer is a life-changing event. Many newly diagnosed patients who have not previously devoted much attention to their health now begin to show an intense desire to learn about the disease and potential treatments. This often includes changes in diet, exercise, stress reduction, and other lifestyle factors. Conversely, those who already took an active approach to health management before diagnosis may be concerned about what practices to modify or stop during cancer therapy. In both cases, it is important for the physician to be able to offer reliable advice and reassurance.
One such area of advice that has been controversial is the use of antioxidant supplements during adjuvant chemotherapy and radiation therapy. Use of vitamins A, C, and E, and beta-carotene for a variety of indications is very popular. Among the health benefits proposed for such agents are improved capacity for healing and immune system function, both of which would appear attractive for cancer patients. However, there is also at least an intuitive case why such agents should not be used. This article reviews recent published evidence for and against use of antioxidants during adjuvant therapies for cancer. Much of the difference in findings appears to arise from differences in definitions and procedures, such as dose and timing of administration. Also, few clinical studies have been reported to date, and those that have been reported usually have very small sample sizes. These conditions are worth bearing in mind when weighing the evidence.
Evidence of Harm
The arguments of those on all sides of the antioxidants during chemotherapy and/or radiation therapy issue revolve around the interaction of these agents with reactive oxygen species (ROS). Antioxidants reduce oxidative stress by functioning as free radical scavengers. Radiation therapy and some chemotherapeutic agents act by selective induction of oxidative stress through free radical production, which in turn mediates apoptosis.1 Selective induction of apoptosis in cancer cells is a key goal of treatment. It could be argued that antioxidant supplements might interfere with this process by quenching the ROS that have been deliberately created.
A few studies dealing with specific aspects of this subject have been published. Witenberg and colleagues reported in 1999 that ascorbic acid (vitamin C) inhibited apoptosis in vitro in irradiated leukemia cells.2 Salganik and colleagues showed in an animal model that depletion of antioxidants in the diet led to a predictable rise in observed reactive oxygen species.3 From this they inferred that higher levels of antioxidants might interfere with cancer treatment by reducing levels of the necessary mediators of apoptosis. They further reasoned that high levels of antioxidants could be cancer-promoting in people exposed chronically to high levels of environmental carcinogens, by inhibiting normal apoptotic clearance of precancerous or cancerous cells. Wells and colleagues found in an in vitro model that treatment with ascorbic acid increased resistance to specific anticancer drugs in cell lines already known to be resistant.4 There is a dearth of clinical studies to corroborate these laboratory findings.
A variation on the antioxidant-ROS model holds that while antioxidants may not have a positive or negative impact on the effect of cancer therapies, they might help to prevent incidental damage to healthy tissue. Blasiak and colleagues reported on an in vitro model in which vitamins C and E were used as a means of protecting normal cells during idarubicin therapy.5 At fairly low concentrations (10 mM for vitamin C and 50 mM for vitamin E), lymphocytes treated with vitamin C showed significantly less DNA damage, but those treated with vitamin E did not.
Blanke and colleagues reported a case series in which nine patients with advanced malignancies were treated prophylactically with high doses of vitamin E (3,200 IU/d or about 2,100 mg/d) for 14 days prior to and during chemotherapy.6 There was no measurable reduction in chemotherapy toxicity. Indeed, the authors noted that the most their findings could support was the conclusion that a maximal dose of vitamin E, when combined with chemotherapy, did not lead to a meaningful increase in symptoms of toxicity.
Wagdi et al randomized 25 patients, 13 receiving chemotherapy and 12 receiving radiation therapy, and with a variety of cancer types, to 1 g vitamin C and 600 mg vitamin E, or placebo.7 The principal outcome of interest was cardiotoxicity. Neither group showed a significant drop in left ventricular ejection fraction (EF) (defined as > 10%). Although overall EF declined in the placebo arm and rose slightly in the active arm, the difference was not statistically significant. This replicated an earlier finding by Legha et al, in which a similar dose of vitamin E was used during adriamycin therapy.8
Weijl et al conducted a randomized study of the effects of vitamins C and E and selenium during cisplatin therapy.9 Forty-eight patients with various kinds of cancer (not specified as to stage) received nutritional drinks twice a day beginning one week before the first chemotherapy dose. In the active arm, the drinks contained 1,000 mg vitamin C, 400 mg vitamin E, and 100 mg selenium. The main outcomes were reductions in nephro- and ototoxicity. No significant difference was noted in either dimension. They speculated that the lack of effect might have been dose-related.
Evidence of Benefit
The bulk of recent published opinion in favor of antioxidant use relies on a lack of clear evidence that antioxidant supplementation during chemo- and radiotherapy interferes with ROS-related therapeutic processes.10 A few studies have even been interpreted to suggest that some antioxidants may enhance cancer cells’ susceptibility to chemotherapeutic agents and/or radiation. Proponents of the use of antioxidants during chemotherapy suggest that antioxidants have a benefit over and above that of mitigating oxidative damage to normal tissue. They also argue that the benefit of such agents is only apparent with chronic treatment, beginning some time before chemotherapy. However, there remains considerable debate over which agents to use, in what doses, and during which stage of treatment.
Blumenthal et al administered a cocktail of vitamin A (3.5 IU/d), vitamin C (4 mg/d), and vitamin E (0.107 IU/d) to mice who were subsequently exposed to a single dose of radiation of varying sizes.11 Treatment began 14 days before irradiation, and outcomes were assessed at seven and 14 days after exposure. Mice who received vitamin supplementation had a higher maximum sub-lethal dose of radiation and showed less loss of body weight. White blood cell counts were higher in the supplemented mice as early as day 7 post-exposure. A complicating factor with this study was the concomitant use of bone marrow transplantation in some of the mice. Another animal study, by Olas et al, used a pig blood model to test the protective effect of vitamin C on cells exposed to cisplatin.12 They found that at a fairly high dose of vitamin C (3 mM), there was a significant reduction in oxidative damage to platelets.
There is some evidence of benefit from observational studies. Branda et al collected questionnaire data from 49 women with breast cancer, irrespective of stage.13 Although the focus of the study was vitamin B12 and folate, information about other micronutrients also was recorded. Forty-seven percent of respondents reported taking a multivitamin, 22% reported taking vitamin C, and 37% reported taking vitamin E. Both those reporting multivitamin or vitamin E supplementation, and those in a historical control group showed a drop in neutrophils during chemotherapy, but the drop in those reporting supplement use was attenuated to a statistically significant degree. This result is interesting, but somewhat limited by the way the data were collected and by the use of non-contemporaneous controls.
Another observational study followed 103 children in treatment for acute lymphoblastic leukemia for a period of six months.14 Assessment of antioxidant intake was made by 24-hour food recall and food frequency questionnaires, and by serum analysis at three-month intervals. Substances reported included vitamins A, C, and E, as well as beta-carotene and types of cholesterol known to mediate inflammation. Vitamin A intake declined significantly (P = 0.04) over the study period from 724 ± 29 mg to 645 ± 31 mg. Average vitamin C intake declined from 92 ± 5 mg/d to 83 ± 6 mg/d, though the change was not significant. Vitamin E intake also declined from an average of 6.7 ± 0.2 mg to 6.3 ± 0.2 mg. Interestingly, plasma concentrations increased (vitamin A and total carotenoids) or were static (all others) over the course of the study.
At various measured intervals, intake of all agents was associated with a statistically significant reduction in chemotherapy-related side effects. However, when intake was averaged over the whole study period, only the association with beta-carotene remained significant. Very few of the studied patients (< 4%) took supplements at any time, so the majority of antioxidant intake was in the form of food. The nausea and other digestive disturbances associated with chemotherapy would suggest that these findings are better described as correlative than causative.
A number of small clinical studies also have lent support to the "protective" camp. Ludwig et al reported that in a series of eight patients, a cream containing DMSO and vitamin E appeared to minimize skin ulceration secondary to extravasation of chemotherapy agents known to cause such irritation.15
Wadleigh and colleagues used a topical vitamin E preparation to treat oral mucositis in patients receiving chemotherapy.16 Sixty-seven percent of patients (6/9) on active therapy showed complete resolution of oral lesions, as compared to 11% (1/9) of those using placebo cream. Although the difference was statistically significant, the small sample size combined with the heterogeneity of cancer types makes the result difficult to generalize.
Pace et al randomly assigned 47 patients with solid tumors to cisplatin therapy, or cisplatin plus vitamin E (300 mg/d).17 Vitamin E supplementation began between one and eight days (mean = 4) before the start of cisplatin therapy. The cumulative incidence of neurotoxicity, measured by the neurological symptom score, was the main outcome. Incidence in the vitamin E group was significantly lower than in the control group (30.7% vs. 85.7%, P < 0.01).
One published report lends support to the notion of an anticancer role for antioxidants independent of other agents. An in vitro study by Piyathilake and colleagues used human tissue collected from 22 individuals with primary cancers of the lung and larynx.18 They reported the intriguing finding that cancer cells appear to accumulate vitamin C at higher rates than normal cells. Further, there was a statistically significant inverse association between vitamin C concentrations and DNA methylation, a marker of malignant change.
Limitations of the Available Evidence
None of the reports published to date meets all of the requirements of convincing scientific evidence—an adequately powered study, conducted in a homogeneous group of human subjects, testing a single intervention while holding everything else as constant as possible. It is perhaps unreasonable to expect this, given the nature of cancer treatment. Few if any kinds of cancer are invariably treated with a single compound or the same combination of compounds, in the same doses, on the same schedule. The challenge of finding a large enough group of patients with the same kind of cancer, at the same stage, in a reasonable time, is daunting for most single-center studies. The lack of a well-funded and research-oriented industry (as exists for pharmaceuticals and medical devices) to back vitamin research is a limiting factor to the setting up and running of large-scale multicenter trials. Yet these practical factors leave the literature in this area without a clear consensus.
It would appear that in medio stat virtus is the best guiding principle for clinical advice. There does not seem to be strong evidence that antioxidant supplements in moderate quantities interfere with the action of chemo- or radiotherapy. If anything, the evidence suggests that cancer treatment depletes the body’s normal levels of these agents. Super-dietary supplementation may be indicated just to maintain daily recommended intake levels. At the same time, the evidence that antioxidants have a positive interactive relationship with cancer therapies, or that they have independent anticancer properties, is still more suggestive than demonstrative. Very large doses of antioxidants (and other micronutrients) have toxicities that may make them dangerous for anyone, not just cancer patients.
Vitamin supplements are readily available over the counter. Both patients with newly found and long-standing interest in their health may seek out such products as part of a response to the diagnosis of cancer. It is important for the clinician to establish and maintain communication with his/her patients about what they are taking. Because supplements vary widely in potency, purity, and formulation, it is also important for the clinician to be familiar enough with brands and their reputations to give sound advice when asked.
Ultimately, the primary care physician’s recommendations must be guided by patient preference and by deference to the opinion of the treating oncologist. It is not fair to involve the patient in a tug-of-war between physicians with differing philosophies. Although conventional chemotherapeutic agents are far from perfect, there is as yet no micronutrient with a comparably large body of experimental evidence. Until there is, when a choice must be made, the conventional therapies should take precedence.
Dr. Sasser is Director, Research Epidemiology, R. Stuart Dickson Institute for Health Studies, Carolinas HealthCare System, Charlotte, NC.
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