Nutrition and Cancer
Micronutrient Supplementation for Patients With Metastatic Cancer
James J. Stark, Cancer Treatment Research Foundation, Gary T. Anderson,
Cancer Treatment Research Foundation, Timothy C. Birdsall, Cancer Treatment Centers of America, Daniel Nixon and Edith Zang, American Health Foundation, and Gerald M. Haase, University of Colorado School of Medicine
[Nutrition and Cancer 38(2):296-298, 2000. © 2000 Lawrence Erlbaum Associates, Inc.]
A large percentage of Americans use some form of complementary and alternative medicine to improve their health. The public perceives the vitamin, mineral, and food supplements that constitute much of alternative medicine to be free of toxicity or harm (1).
Our personal experience with scores of colleagues leads us to conclude that many physicians, when faced with a cancer patient who wants to know whether taking supplements is a good idea, will shrug their shoulders and say something to the effect that they probably will do no good but should do no harm. Various recent studies have demonstrated that 23-72% of cancer patients undergoing active treatment use alternative therapies, probably with the belief that, at the very worst, they can do no harm (2-4).
Support for the use of vitamin and mineral supplements has been incorporated into the treatment approach of at least one major cancer program without supporting data. At least one other major cancer center is incorporating concepts of complementary and alternative medicine into its program on the basis of a perceived need from the public at large (5,6).
Many dietary supplements act as antioxidants. Labriola and Livingston (7) recently delved into theoretical reasons why antioxidants might interact adversely with cancer chemotherapy drugs in a comprehensive review of the subject. The likely site of interaction involves removal of free radical oxygen from the milieu of the tumor cell with reduction in free radical-mediated cytotoxicity.
Subsequent editorials and rebuttals have enlivened the debate (8-11). Agus and colleagues (12) recently helped elucidate a mechanism by which tumor cells sequester and accumulate high levels of intracellular vitamin C, which in theory could interfere with the effects of chemotherapy.
On the other side of the debate, Lamson and Brignall (13,14) reviewed the published data on antioxidant-chemotherapy interactions and concluded that the vast majority of studies have demonstrated increased or no effect on chemotherapy efficacy. Other proponents argue that several chemoprotective agents such as mesna and amifostine are themselves antioxidants.
Smyth and colleagues (15) allege that glutathione, when added to cisplatin in the treatment of ovarian cancer, leads to reduced chemotherapy-related toxicity and an enhanced quality of life.
Ascorbic acid is said to reduce the toxicity of doxorubicin without affecting its anti-tumor properties (16). Green tea, a potent antioxidant, may enhance the effectiveness of doxorubicin as well (17). In vitro studies shed some light on these issues. Prasad and co-workers (18) reported their results and those of others in a review of this subject. Among other observations, they showed that neuroblastoma cells cultured in the presence of various concentrations of vitamin E suffered synergistic cell kill when exposed to ionizing radiation.
Taper and colleagues (19) showed in ascitic liver tumor-bearing mice that the addition of vitamins C and K3 to standard chemotherapy resulted in a prolongation of survival in the animals so treated. Kurbacher and associates (20) demonstrated that vitamin C increased the cytotoxicity of doxorubicin, cisplatin, and paclitaxel against MCF-7 and MDA-MB-231 breast carcinoma cell lines.
Certain antioxidants have been shown to possess potent anticancer properties in the laboratory when used in combination, whereas when they are given singly they have no effect.
The experiments by Prasad and co-workers (18) using ascorbic acid, carotenoids, -tocopherol, and retinoic acid in melanoma cell lines in vitro show a synergistic antitumor effect without the use of chemotherapy and further synergism when chemotherapy is added.
Although the relevance of such in vitro observations to the clinical setting is not clear, these findings represent the best available evidence of potential in vivo interactions and their relevance should be clarified by this and similar trials. Circumstances in which vitamins alone have anticancer properties have also been reviewed.
Human in vivo data on the interaction of micronutrients and chemotherapy are sparse. Jaakkola and colleagues (21) attempted to show that patients with small-cell lung cancer who ingested micronutrients in addition to their chemotherapy program enjoyed a better outcome.
Their study was, however, uncontrolled, the number of subjects was small (n = 18), and the median survival of their study group was virtually identical to that published contemporaneously elsewhere. Furthermore, their claim of reduced chemotherapy-associated toxicity was unsubstantiated in the body of the paper.
There are thus no adequately performed studies of the interaction of antioxidants and standard chemotherapy in the treatment of metastatic malignancy.
We believe that the time is right to study this issue and have launched a project to attempt to further elucidate the nature of the interaction between standard cancer chemotherapy and antioxidants and its impact on the lives of patients with metastatic cancer.
Issues to be addressed include responsiveness to chemotherapy, duration of survival, and quality of life. The ultimate goal of the project is to show a prolongation of life with micronutrient supplementation, to show a shortening of life if Labriola and Livingston (7) are correct, or to have the power to show no difference.
A pilot study is being launched first to look at tolerability of this micronutrient complex, compliance in this group of patients (given their altered sense of well being and perception of taste), and evidence of oxidative damage (as measured by urinary 8-OH-deoxyguanosine) before and during supplementation (22).
We will measure levels of vitamins A, C, and E and -carotene before and during supplementation to assess our ability to raise these levels with doses of supplements utilized and to measure overall compliance with the regimen in patients receiving cancer chemotherapy.
The optimal content for a program of micronutrient supplementation is unknown. After much discussion, the combination of micronutrients, chosen empirically, is as follows: a high-potency multivitamin (2 capsules twice a day), calcium ascorbate (vitamin C, 4 g twice a day), mixed natural carotenoids standardized to -carotene (30 mg twice a day), and d--tocopheryl succinate (vitamin E, 400 IU twice a day).
The combination will be administered as several different commercially available preparations.
Calcium ascorbate was chosen, rather than ascorbic acid, because there is no associated gastrointestinal toxicity and no problem of solubility in the urine with the calcium salt (23). As to the choice of vitamin E preparation, -tocopheryl succinate has been found to be the most active form of vitamin E in terms of inducing growth inhibition and cell differentiation in malignant melanoma cell lines (24). Carini and colleagues (25) reported that -tocopheryl succinate is more effective as an antioxidant than -tocopherol.
Patients will be surveyed for quality of life in addition to the objective data, for compliance with the program, and for the ad hoc addition of supplements off study. If the pilot study shows that the program is tolerable and compliance is good, a large prospective randomized study will be done looking at outcome (survival and quality of life) in patients so treated vs. patients given placebo.
Patients with metastatic breast, colon, and lung cancer on conventional chemotherapy will form the patient base; we estimate that several hundred patients will be accrued over two to three years before the questions framed above can be answered with certainty.
As part of the planning for this trial, some in our working group argued that because the optimal combination is unknown, we should delay doing this trial until more basic science work was accomplished. In light of the very public and somewhat acrimonious nature of the debate, we believed that there was more to be gained by initiating the study than by waiting.
Chemoreception Sciences Meeting
Cancer Causes and Control, 6/02
Cancer Epid, Biomarkers
& Preventtion, 6/02
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