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Complementary and Alternative Medicine: The Role of the Cancer Center

From the Departments of Medicine, Urology, Surgery, and Pediatrics, College of Physicians and Surgeons; Department of Epidemiology, Mailman School of Public Health; and Herbert Irving Comprehensive Cancer Center, Columbia University and New York Presbyterian Hospital, New York, NY.

Address reprint requests to Karen Antman, MD, MHB 6N 435, 177 Ft Washington Ave, New York, NY 10032; email: kha4{at}columbia.edu

IN THE 1980s, MANY astute physicians began to realize that public education, legislative action, and medical advances had failed to deter many patients from seeking unorthodox treatments for cancer and other diseases. Serious research efforts began to determine the scope of complementary and alternative medicine (CAM) used by patients and their motivations for its use.¹ An Office of Alternative Medicine (OAM) was established within the National Institutes of Health in 1992. In 1998, with substantially increased funding, the OAM became the National Center for Complementary and Alternative Medicine. During this period, the National Cancer Institute (NCI) also established its own OAM.

By the end of the 20th century, surveys showed that treatments without proven efficacy were widely used. The prevalence of CAM use among cancer patients ranges from 7% to 64% of patients sampled in 26 studies conducted worldwide.² The wide range of estimates reflects different inclusion criteria for unconventional cancer therapies as well as differencesin patient groups surveyed and in the country of origin of the study³ (Table 1). Many patients with cancer use diet modification, supplementary vitamins, and support groups. A smaller proportion use crystals, therapeutic touch, or shark cartilage, and a relatively small percentage use homeopathy and coffee enemas. Patients who reported using CAM do not conform to the stereotype of poorly educated, end-stage patients who had exhausted conventional treatment but are instead relatively well educated and well off. Furthermore, of 138 unorthodox practitioners studied in one report, 60% were physicians.¹

Patients often seek alternative therapies because of widespread beliefs that cancer can be cured or its outcome improved by sheer determination, metabolic therapies (nutrition, vitamins, or internal cleansing of industrial pollutants), immune-enhancing regimens, and therapies that are difficult to categorize, such as shark cartilage, homeopathy, crystals, therapeutic touch, or electromagnetics (Table 2). Given that plants have been the source of digitalis (the flower) and aspirin (the willow tree), some CAM treatments are biologically plausible. Many conventional cancer drugs are, in fact, natural products (eg, paclitaxel from the Yew tree, vincristine from Vinca, and tetrahydrocannabinol for nausea from Cannabis). Sheer determination actually does result in an aggressive search for the best treatments (but sometimes leads patients to blame themselves for a recurrence). Certainly, family and support groups improve nutrition and compliance, because patients are fed even when too ill to cook and are driven to treatments on time even when ill.

Potential risks for drug interactions exist. St John’s Wort, a herbal remedy for depression, interacts with several important drugs metabolized by the p450 system, such as warfarin. PC-SPES (literally prostate cancer hope in Latin), a mixture of 8 herbs based on a traditional Chinese formula, is weakly estrogen, which, if taken by patients with prostate cancer already taking estrogens, may result in estrogen-associated cardiovascular complications, such as myocardial infarction and pulmonary emboli.

The efficacy of antimetabolites against cancer suggests that vitamins use may actually be counterproductive. Folate, a vitamin, is also an antagonist of methotrexate, a drug that can be curative in childhood leukemia and in adjuvant breast cancer regimens. Whether methotrexate is equally effective in patients with high dietary folate intake, which is common in some cultures (eg, bean-based Hispanic diets), is unknown.

PUBLISHED CONTROLLED TRIALS
Published trials ofvitamin supplements for cancer prevention and treatment (Table 3) have not been particularly promising. Vitamin C therapy in colon cancer showed no advantage over placebo therapy in either time to disease progression or patient survival.¹⁹ Antioxidant vitamins (beta-carotene and vitamin E) do not decrease the risk of lung cancer in smokers or of colon polyps.^20-25

To determine the efficacy of a combination of antioxidant vitamins (vitamins C and E and beta-carotene) for lung cancer prevention among heavy smokers, Columbia University investigators conducted a randomized clinical trial using DNA damage as the end point. Immunological methods were used to measure polycyclic aromatic hydrocarbon-DNA adducts and oxidative DNA damage (8-oxo or hydroxydeoxyguanosine) in mononuclear and oral cells. A total of 121 subjects were randomized to the 6-month intervention and received either vitamins or placebo. Plasma levels of all three antioxidants rose significantly in the vitamin group but not in the placebo group, demonstrating adherence to treatment. Both groups appeared to have less DNA damage at the end of the study than at baseline, but the differences between the vitamin and placebo groups in level of DNA damage were not statistically significant. These results suggest that DNA damage may be a useful end point in chemoprevention trials, but they do not support the hypothesis that antioxidant supplementation can prevent DNA damage.²⁶

In a matched control study of patients with advanced cancer receiving conventional treatment with or without unorthodox treatment, the median survival for both groups was 15 months. Quality-of-life scores were consistently better among conventionally treated patients from enrollment on.³⁵ In patients with breast cancer randomized to group therapy versus standard care, the patients in the group survived longer,^36-38 but these results have not been reliably reproduced.

ONGOING CAM RESEARCH AT COLUMBIA UNIVERSITY’S HERBERT IRVING COMPREHENSIVE CANCER CENTER
Faculty at Columbia University in New York City have grant support for a variety of programs and studies of CAM. The Table that follows is a partial listing of CAM-related centers and their leadership (Table 4).

David Cobrinik, MD, evaluated the effect of putative cancer chemopreventive polyphenols in green tea to inhibit mammary tumorigenesis in mice and to define the compound’s cell-cycle effects. He found that the maximum tolerated doses of green tea polyphenols did not inhibit c-neu–induced mammary tumorigenesis but that the tea polyphenol EGCG inhibited the cell cycle in MCF10A and MCV10A/c-neu mammary epithelial cells. Cell-cycle inhibition was accompanied by increased expression of p21Cip1, but these effects were apparent only at concentrations substantially higher than are generally achieved by extensive drinking of tea.⁴⁰ These studies highlight the need to evaluate the effects of alternative agents in clinically relevant contexts and at physiologically achievable concentrations.

The polyphenolic compound resveratrol can be found in numerous plant species, including food products like grapes, peanuts, and various herbs. Red wine and grapes are probably its main sources in Western diets, and one of its richest sources is the herb Polygonum cuspidatum, which has been used in Asian folk medicine. Andrew Joe, MD, examined its antitumor activity using six human cancer cell lines and found that it induces growth inhibition, cell-cycle arrest, apoptosis, and changes in the expression levels of several cell-cycle control proteins.⁴¹

In clinical studies, John Chabot, MD, director of the pancreatic cancer surgical service, undertook a National Institutes of Health–supported study comparing nutritional therapy (the Gonzalez Regimen, described in a February 5, 2001, article in The New Yorker) with standard gemcitabine-based chemotherapy among patients with metastatic and unresectable pancreatic cancer. The end points are survival and quality of life. The conduct of this study has not been easy, because most patients are already firmly committed to nutritional therapy or standard therapy at the time of referral. For this reason, the study is not a randomized controlled trial but a phase II trial with a concurrent comparison group. The analysis of outcomes will use propensity scoring and sensitivity analysis to control for known and unknown confounders.

In a randomized clinical trial of black cohosh, an herb originally used by American Indians to treat menopausal symptoms, versus placebo for hot flashes among patients with breast cancer funded by Schaper & Brümmer with Victor R. Grann, MD, as principal investigator, Judith S. Jacobson, MD, et al found that both treatment and placebo groups experienced an improvement in symptoms during study participation but that the groups did not differ significantly in the degree of improvement.⁴² With funding from the National Foundation for Alternative Medicine, Grann and Jacobson are presently conducting a best-case series study of patients treated at the Hufeland Klinik in Germany.

Mind-body interventions, such as hypnosis, mental imagery, and relaxation, may be beneficial as adjuvants to mainstream care in cancer patients. No randomized studies have examined the effect of integrating the mind-body approach Hatha yoga during treatment for breast cancer. In a pilot study funded by the Department of Defense Breast Cancer Research Program, Amy Tiersten, MD, and Donna Russo, MS, are conducting a randomized clinical trial of 10 weekly sessions of Hatha yoga or support group participation versus standard care among women receiving chemotherapy for breast cancer. Outcome report measures include scores on the Functional Assessment of Cancer Therapy–Breast Cancer, Profile of Moods States, and Mental Adjustment to Cancer instruments, as well as laboratory results and the NCI common toxicity criteria. Analyses will be conducted using t tests and analysis of variance.

Aaron E. Katz, MD, is conducting of a pilot study of genistein-concentrated polysaccharide, a nutritional supplement made from a mixture of a mushroom and soybean extract, for men with prostate cancer before radical retropubic prostatectomy. The study will determine if the ingestion of genistein-concentrated polysaccharide will induce cell death within the prostate gland and reduce the number of blood vessels within the gland at the time of surgery using markers for angiogenesis.

The Southwest Oncology Group Selenium and Vitamin E Cancer Prevention Trial (SELECT, S0000) is available for healthy men at risk for prostate cancer. Both selenium and vitamin E as single agents have been linked with reduced prostate cancer. No combinations have been studied in large numbers of men. About 32,400 healthy men without prostate cancer will be enrolled onto this study and followed for 7 to 12 years. African-American men aged 50 years or older and men of other ethnic groups aged 55 years or older are eligible (because African-American men have been found to have a younger age at diagnosis of prostate cancer). Study participants will be randomly assigned to take selenium (L-selenomethionine), vitamin E (alpha-tocopherol), selenium plus vitamin E, or placebo to see if supplements can prevent or reduce the occurrence of prostate cancer. Participants will have office visits every 6 months and a limited medical examination every year. If participants wish, they may also have a yearly examination of their prostate (digital rectal examination) and a yearly blood test (prostate-specific antigen) to screen for prostate cancer.

Children with cancer are frequent consumers of CAM. In a survey conducted at the Herbert Irving Pediatric and Adolescent Oncology Center, 84% reported the use of at least one therapy.¹⁰ In the subgroup of patients enrolled onto clinical trials for the treatment of cancer, 85% were using CAM, including 34% reporting use of herbs and 25% taking nutritional supplements, which potentially interact with chemotherapy. Kara Kelly, MD, evaluated a large cohort of children undergoing therapy for acute lymphoblastic leukemia (ALL), investigating antioxidant levels and oxidative status (as measured by the oxygen radical absorbance capacity, the formation of DNA adducts, and polymorphisms of drug detoxification enzymes) and how these measures relate to diet and to treatment-associated toxicity. Preliminary analysis shows that administration of chemotherapy does not significantly affect antioxidant levels (vitamins C and E and beta-carotene) but that total antioxidant capacity declines significantly with more intensive chemotherapy.⁴³ The G&P Foundation is funding extension of these analyses of chemotherapy-antioxidant/flavonoid interactions in a transgenic mouse model of ALL. The center will also evaluate the efficacy of milk thistle in reducing the hepatotoxicity associated with maintenance chemotherapy for ALL in a placebo-controlled randomized trial funded by the American Institute for Cancer Research.

In Population Research Studies, Victor Grann has begun a cohort study of ethnic disparities in CAM use, preventive behavior and preferences, and risk factors for breast cancer (funded by the Avon Products Foundation Breast Cancer Program and the Sindab Breast Cancer in African Americans Endowment).

Staten Island, the least populous of New York City’s five boroughs, has both the highest lung cancer incidence rates in the city and the largest landfill in the world. The New York City Department of Health has contracted with Columbia University to conduct a 3-year Comprehensive Cancer Research, Health Promotion, and Risk Reduction Campaign in Staten Island. Some Staten Islanders are said to use CAM detoxification treatments, such as milk thistle, to protect them from the adverse effects of their environment. Judith Jacobson, the principal investigator, will therefore assess CAM use, along with known risk factors, among lung cancer cases and controls in Staten Island.

PRESENT ISSUES IN MEDICAL POLICY
Experimental drugs are typically evaluated individually, in highly standardized form, on a tightly specified schedule. Nutritional supplements and herbal products often consist of a mixture of active compounds that varies from batch to batch. Various analyses have shown that the content of food supplements can vary substantially from that claimed on the label. In some cases, no active compound could be detected; in others, the dosage was highly variable or active contaminants were detected, leading to toxic effects in a small percentage of patients. However, since 1994, United States law has forbidden Food and Drug Administration (FDA) regulation of food supplements.

Thus, at this time, drugs are evaluated and advertised differently from food supplements. Drug advertising is supervised by the FDA, but producers have rather wide latitude for food supplements, typically using suggestion (eg, "may improve memory") rather than claims that could be disputed.

The argument against regulation is basically that food supplements are foods, not drugs, and that requiring standardization of a supplement is like requiring that all oranges contain the same amount of vitamin C. Advocates for CAM often maintain that unlike experimental drugs, which must show efficacy within a limited time frame to be approved for commercialization, CAM treatments have a natural variability that contributes to their long-term benefits. Evaluation of CAM is additionally complicated by the fact that many CAM treatments are difficult to study by means of randomized controlled double-blinded trials. For some CAMs, placebo controls are not feasible; for others, treatment is customized to the patient. Furthermore, patients tend to use multiple forms of CAM simultaneously or sequentially before, during, or after conventional treatment. Given these patterns and the high prevalence of CAM use, the lack of evidence for harm is perhaps more surprising than the lack of evidence for benefit. Most experimental chemotherapeutic agents prove to be either ineffective or too toxic for clinical use. Findings of no benefit for specific CAM treatments should therefore not discredit all CAM.

WHERE DO WE GO FROM HERE?
Health care providers need to categorize treatments as proven versus unproven, not conventional versus CAM. We need to obtain data about patients’ use of CAM and assess any adverse events that may be CAM-related. We also need to evaluate all promising therapies in appropriately designed clinical trials. FDA regulation of the medication contents and advertising of food supplements would certainly substantially benefit consumers. The high prevalence of CAM use makes research on its effects both feasible and imperative.^{4-9,11-15,27-34}

ACKNOWLEDGMENTS

Supported in part by Cancer Center support grant no. P30-CA13696, Department of Defense grant no. BC996480, Avon Products Foundation, Sindab Endowment, New York City Department of Health, Schaper & Brümmer, and the National Foundation for Alternative Medicine. A.I.N. is the recipient of a K05 Award from the National Cancer Institute (CA89155). D.C. was supported by the American Institute for Cancer Research and by the United States Department of Defense (USAMRMC 17-98-1-8051). K.K. is supported by the American Institute of Cancer Research, Pediatric Cancer Foundation, G&P Foundation, the Lerner Foundation, and "A Mother’s Kiss."

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