Hardy ML. Dietary supplement use in cancer care: help or harm. Hematol Oncol Clin N Am. 2008;22: 581-617.

Studies consistently show that most cancer patients use dietary supplements (DS) in all phases of treatment, most often without revealing use, or revealing it only partially, to oncologists. Most oncologists recommend complete avoidance of DS, reducing patients’ willingness to disclose use and thereby potentially increasing risks. Overall, physicians and patients do not share the same perceptions of possible benefits from complementary and alternative medicine (CAM) or agree on what evidence to use for CAM therapy.

Some risks cited by oncologists for CAM use are not fully supported by research. These include fears that patients using CAM may refuse or delay conventional treatment or that CAM products may be contaminated or adulterated, and risk of liver toxicity from DS. The author states that these risks are relatively small and would be best guarded against by physician-patient communication. In one study, only 8% of advanced cancer patients were receiving alternative care alone. According to the author, contaminated or adulterated DS should be substantially reduced under new rules from the Food and Drug Administration. Not all evidence of liver toxicity for herbs is equally compelling; in particular, reports involving black cohosh (Actaea racemosa syn. Cimicifuga racemosa) were insufficiently persuasive for the National Institutes of Health to halt or modify clinical trials.

Herb-drug interactions, another risk cited by oncologists, have been the subject of several reviews, but only two studies. In one, of 76 chemotherapy patients, three were using botanical DS that could interfere with the chemotherapeutic agent: St. John’s wort (SJW; Hypericum perforatum) and garlic (Allium sativum). In another, of 318 chemotherapy patients also taking herbs, 11% took DS in higher-than-recommended doses. Potential interactions were inferred for 12%, mostly with echinacea (Echinacea spp.) on the presumption that it might adversely affect immune stimulation. However, neither study confirmed any interactions. In screening tests, herbal preparations have shown the ability to up- or down-regulate activity of P450 isoenzymes, but relatively few clinical trials have verified this. One review assessed in vitro, in vivo, and human data for common herbs concluding that, in chemotherapy, interactions with black cohosh, milk thistle (Silybum marianum), saw palmetto (Serenoa repens), cranberry (Vaccinium macrocarpon), and bilberry (Vaccinium myrtillus) were not expected. Mostly preclinical research suggests that for garlic, ginkgo (Ginkgo biloba), soy (Glycine max), Asian ginseng (Panax ginseng), valerian (Valeriana officinalis), and kava (Piper methysticum), precautions should be taken. Human studies with SJW and imatinib found reduced levels and increased clearance of the drug; similar results were found for SJW and irinotecan. Induction of CYP450 enzymes is thought to be caused by hyperforin, one constituent of SJW. In no pharmacokinetic study cited was composition of the SJW extract described or independently confirmed by investigators.

Reduced blood coagulation, perhaps due to antiplatelet action or interference with warfarin, is also cited as a risk for cancer patients using DS. Evidence for either effect is mixed with mostly poor quality case reports unsupported by in vivo research.

Some herbs’ phytohormonal effects cause concern for oncologists with regards to hormone-sensitive cancers, particularly breast, ovarian, endometrial, or prostate. Research has focused on estrogenic activity in menopause. Both soy and red clover (Trifolium pratense) extracts are phytoestrogenic, with uncertain significance for estrogen receptor-positive breast cancer patients. Black cohosh, however, does not appear to be estrogenic. Activity on serotonergic neutrons in the hypothalamus may account for its effects on symptoms of menopause.

While eating antioxidant-rich foods is associated with reduced risk of many cancers, using antioxidant DS to prevent cancer is not supported by large randomized trials and has at times been found to increase risk. However, a large amount of preclinical data and some human trials support use of some antioxidants, e.g., high-dose vitamin C for possible tumor response; and vitamins C, E, and coenzyme Q10 to reduce chemotherapy-related toxicity. Some evidence for harm exists for vitamin E use in head and neck cancers.

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While most perceived risks remain theoretical or even unlikely, benefits are found for cancer patients from many CAM products in overall quality of life and reduced side effects of conventional treatment. The author omits discussion of lectin compounds from mistletoe (Viscum album), and a polysaccharide extract from shiitake mushroom (Lentinus edodes), because both are delivered parenterally or intravenously, and therefore are not DS by US standards; and omits whole-herb cannabis (Cannabis sativa) extracts and isolated compounds because of “legal ambiguity and challenges with standardization.”

Among immunomodulators, mushrooms and mushroom-derived polysaccharides improved quality of life, modified tumor response, and boosted immune response in several cancer models and some clinical trials, mostly in patients with solid tumors. A proprietary extract of turkey tail mushroom (Trametes versicolor syn. Coriolus versicolor), PSK® (JHS Natural Products; Eugene, Oregon), showed those benefits and lower relative risk of regional metastases, in trials of over 1200 subjects with colorectal cancer and over 8000 with gastric cancer. Another turkey tail extract, together with danshen (Salvia miltiorrhiza), improved immunological parameters in nasopharyngeal cancer patients having radiation therapy and in breast cancer patients. A polysaccharide extract of a proprietary hybrid mushroom identified as Basidiomycotina (probably Agaricus blazei), has shown beneficial immune effects in clinical trials, and a highly significant statistical increase in survival in some advanced liver cancer patients. An A. blazei extract given to gynecological cancer patients increased natural killer cell activity and decreased chemotherapy side effects from carboplatin, etoposide, or taxol. Other promising immunomodulators include a proprietary fermented wheat (Triticum spp.) germ extract standardized to methoxy-substituted benzoquinones (Avé® or Avemar®; American BioSciences; Blauvelt, New York), and probiotics. Unexpected and still unexplained deaths in a recent trial of probiotics in patients with severe pancreatitis mandate caution.

Stomatitis or mucositis, a common side effect of cancer therapy, reduces quality of life and caloric intake. Simple natural interventions, such as ice (plain or flavored), honey, and topical vitamin E oil, reduce stomatitis. There is strong evidence, in several cancers and with a variety of chemotherapeutic agents, for glutamine as an oral rinse that is then swallowed; however, results with 5-fluorouracil (5-FU) chemotherapy were generally negative. Zinc supplementation, a proprietary homeopathic remedy (Traumeel®; Heel, Inc.; Albuquerque, New Mexico) containing arnica (Arnica montana), and proteolytic enzymes have all shown benefit. Aloe (Aloe vera) and chamomile (Matricaria recutita) rinses have had mixed results. Chamomile fared better in uncontrolled cases with heterogenous chemotherapy and radiation than in a controlled study with 5-FU. Stomatitis is often associated with disruption of gut mucosa leading to diarrhea or leaky gut syndrome. Glutamine benefited 5-FU-induced intestinal toxicity and diarrhea associated with irinotecan in some studies, but not diarrhea from doxifluridine or neo-adjuvant chemotherapy or radiation in others. Even when no benefit was found, there was no interference with chemotherapy. Probiotics decreased diarrhea when given concurrently with 5-FU chemotherapy or radiation; again, caution is currently warranted. Both glutamine and vitamin E have shown promise in alleviating chemotherapy-induced neuropathies, caused especially by platinum-based drugs and taxanes. Ginger (Zingiber officinale), in doses as low as 1 g/d powdered root, reduces chemotherapy-induced nausea, with no serious adverse effects, and fewer side effects than metoclopramide.

Radiation therapy damages skin contributing to morbidity. So far, few herbal agents have shown benefit. Aloe is often used for radiation-induced burns, but trials have not confirmed a strong benefit. It has delayed onset of damage briefly. A proprietary chamomile cream, compared to almond (Prunus dulcis) oil, delayed onset of dermatitis and reduced damage, though the differences were not statistically significant. Those using a homeopathic calendula (Calendula officinalis) cream compared with trolamine during radiation had significantly less dermatitis and were more satisfied with the calendula cream despite its being more difficult to use.

Reviews and meta-analyses confirm the usefulness of omega-3 fatty acids in preventing cancer-related cachexia, but relatively high doses are required for efficacy: 7.5 g/d fish oil or eicosapentaenoic acid (EPA). Combining fish oil with celecoxib gave significantly more improvement in appetite, fatigue, body weight, and muscle strength than fish oil alone in a small group of patients with advanced lung cancer.

Edema after conventional cancer treatments can be a serious issue and difficult to treat. One randomized trial with selenium selenite reduced upper extremity edema and improved function of breast cancer patients, while an uncontrolled trial showed its benefit for head and neck radiotherapy. Several small studies with flavonoid-rich preparations have shown benefit, including one using a proprietary ginkgo formula.

DS studied for cancer-related fatigue have generally been ineffective, but supplementation with up to 3000 mg/d carnitine decreased fatigue and improved quality of life in carnitine-deficient patients during chemotherapy.

Black cohosh – as discussed earlier, effective against symptoms of menopause but not estrogenic – has been suggested for vasomotor symptoms in cancer therapy, especially in younger women. Not all trials have shown benefits in women with breast cancer, but some have, without serious adverse effects. And, far from increasing breast cancer risk, two studies found a possible protective effect of black cohosh extract (BCE). In a case-controlled study of 949 menopausal breast cancer patients and 1524 menopausal controls, women who took BCE had 50% less risk of developing breast cancer. In a retrospective cohort study comparing 1102 breast cancer survivors who took BCE with a small group who did not, those who used BCE had longer disease-free intervals.

While DS are inappropriate as primary cancer treatments, some show promise in pre-malignant lesions, early cancers usually treated with watchful waiting, and specific treatment-resistant cancers. Subjects with oral leukoplakia received 3 g tea (Camellia sinensis) or placebo. After six months, the treatment group had smaller lesions and fewer micronucleated exfoliated cells. High-grade intraepithelial neoplasia of the prostate (HG-PIN) has responded to oral administration of a green tea extract. Pomegranate (Punica granatum) juice (POM Wonderful®; POM Wonderful, Inc.; Los Angeles, California), given to men with rising prostate-specific antigen (PSA) after surgery or radiation, increased mean PSA-doubling time from 15 to 54 months. Another DS with soy, lycopene, silymarin, and antioxidants increased PSA-doubling time from 445 to 1,150 days. Some tumor response was seen in a trial of 10 mg/d lycopene (Lycored®; LycoRed Natural Product Industries; Beer Sheva, Israel) supplementation, for three months, in men with hormone-resistant or refractory prostate cancer (HRPC). Most were able to reduce the amount of analgesics used. Lycopene with orchiectomy improved outcomes of men with metastatic HRPC. However, given to HRPC patients as tomato (Lycopersicon esculentum) paste or juice, it showed no effect.

Oncologists are urged to become familiar with literature on DS in cancer and to accept that the majority of their patients will use DS, with or without their knowledge or approval. Being able to discuss well-characterized, well-tested products can help minimize risks. Finally, it is critical that additional research examine benefits and risks of DS use in cancer.

 —Mariann Garner-Wizard

Karppi J, Kurl S, Nurmi T, Rissanen TH, Pukkala E, Nyyssönen K. Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. Ann Epidemiol. 2009 Jul;19(7): 512-518.

Cancer is a leading cause of death worldwide, second only to mortality associated with heart disease. It is thought that nutritional factors play an important role in the prevention of chronic diseases, such as cancer, and it has been estimated that nearly one-third of all cancer deaths in the United States could have been prevented through dietary modification. For example, diets rich in fruit and vegetables have been shown to be associated with a lower risk of many cancers. Among various phytochemicals the carotenoids in fruit and vegetables have shown “considerable promise” in preventing cancer because of their antioxidative ability to reduce oxidative stress—a risk factor for cancer. Of the many carotenoids, lycopene’s ability to reduce the risk of prostate cancer has been studied the most. Dietary lycopene is derived primarily from tomatoes (Lycopersicon esculentum) and tomato products, but is also found in small amounts in pink grapefruit (Citrus x paradisi), watermelon (Citrullus lanatus), rose hip (Rosa spp.), apricot (Prunus armeniaca), guava (Psidium guajava), and papaya (Carica papaya). Lycopene is a potent antioxidant, and its anticancer activity has been shown both in vivo and in vitro. Its likely anticarcinogenic mechanisms of action include free radical scavenging, upregulation of detoxification systems, interruption of cell proliferation, and inhibition of cell cycle progression. The objective of the present study was to evaluate the association between serum lycopene concentrations and the risk of cancer in middle-aged eastern Finnish men in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study.

 The KIHD study is an ongoing, population-based, prospective study designed to investigate cardiovascular disease risk factors and related outcomes in middle-aged men from eastern Finland. Residents of Kuopio and the surrounding rural communities (n = 2682) aged 42, 48, 54, or 60 years were enrolled for the baseline examinations between March 1984 and December 1989. Reexaminations took place every 4 years thereafter. Nine hundred ninety-seven men from the Finnish cohort had serum lycopene data available from the reexaminations that took place between 1991 and 1993 and comprised the study population for the present study. During the examinations, blood samples were collected for the measurement of serum lycopene, retinol, a-tocopherol, a-carotene, b-carotene, and folate concentrations. Physical activity, smoking habits, alcohol consumption, education level, and family history of cancer were assessed. In addition, waist-to-hip ratio and body mass index were measured. All cancers diagnosed in Finland are recorded in the National Cancer Registry. The incidence and type of cancer that developed in the Finnish cohort were derived from this registry. All cancers diagnosed in the cohort between the time of study entry (March 1991 to December 1993) and 31 December 2006 were included in the analysis.

 Over an average follow-up period of 12.6 years, 141 cancers were diagnosed: 55 prostate cancers, 17 lung cancers, 16 intestinal cancers, 10 urinary bladder cancers, and 43 cancers of other origin (e.g., stomach, lymphoma, skin, liver, kidney, and pancreas). The mean serum lycopene concentration was 0.12 mmol/L in the subjects who developed cancer and was 0.16 mmol/L in the subjects who did not develop cancer. Of the vitamins and carotenoids measured, serum lycopene was the only serum antioxidant that was significantly higher in men without cancer than in men with cancer and was the only carotenoid to have a negative correlation with cancer (r = -0.10, P = 0.003). More men with cancer than without cancer were smokers, and the duration of smoking was longer in the men with cancer than in those without cancer; smoking duration was inversely associated with serum lycopene concentration (r = -0.11; P < 0.0001). Men in the highest tertile of serum lycopene concentration had a 45% lower risk of overall cancer (risk ratio [RR] = 0.55; 95% confidence interval [CI] = 0.34–0.89; P = 0.015) and a 57% lower risk of other cancers (RR = 0.43; 95% CI = 0.23–0.79; P = 0.007) than did those in the lowest tertile of serum lycopene concentration after adjustment for the covariates age, examination years, family history of cancer, waist-to-hip ratio, duration of smoking, physical activity level, education level, alcohol consumption, and serum folate. No association between serum lycopene and prostate cancer was observed.

The results suggest that high serum lycopene concentrations may lower the risk of cancer, except for prostate cancer, in middle-aged men. However, the relatively small number of cancer cases in the cohort reduced the possibility of studying the risk of site-specific cancers. Also, the limitations to this study include obtaining only a single serum sample that simply demonstrates short-term dietary intake of lycopene due to its half-life of only a few days; multiple measurements would have been more precise.

 —Brenda Milot, ELS

By Stephen Daniells, 31-Jul-2009

Supplement users may have better cancer survival: Study

By Stephen Daniells, 31-Jul-2009