Patients with cancer often have unmet needs for dietary advice.7,8 Various small studies have shown that nutritional counseling and education improves outcomes (i.e., quality of life and/or survival) for patients with head and neck,⁹ colorectal,¹⁰ and lung cancer.¹¹

Dietary Supplements

The term “dietary supplement” refers to “a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake.”¹²

Legal and Regulatory Issues

Since the passage of the Dietary Supplement Health and Education Act of 1994, companies seeking to market dietary supplements in the United States do not need to obtain prior approval from the U.S. Food and Drug Administration (FDA). By law, the advertisements and labels for such products can only make “structure and function” claims regarding a product’s effectiveness and cannot claim that the product should be used to cure, mitigate, prevent, or treat a disease.

Contamination and Adulteration

The FDA and various state and local drug regulatory authorities and academic researchers frequently find that dietary supplements that are sold in U.S. stores or are available through the Internet are contaminated with heavy metals ¹³ or adulterated with prescription medications.¹⁴ For example, PC-SPES was an herbal product manufactured and distributed by a U.S.-based company and advertised as preserving prostate health, but it was extensively used by patients with prostate cancer. PC-SPES was also being investigated as a potential prostate cancer therapy until the product was voluntarily withdrawn from the market in 2005 after the California Department of Health Services and the FDA published warnings indicating that several production lots were found to contain various amounts of warfarin and diethylstilbesterol.¹⁵

Adverse Effects

Adverse effects of a dietary supplement may be due to the labeled contents in the supplement or a contaminant or adulterant. In the case of herbal supplements, instances have occurred of the substitution of a different herb for one listed on the label, sometimes because of misidentification of the plant. The Natural Medicine Comprehensive Database ¹⁶ and Micromedex¹⁷ contain referenced information about the adverse effects of a large number of dietary supplement components. The following sections provide examples of some adverse effects that are relevant to patients with cancer.

Chaparral (Larrea divaricata Coville)

The leaves of chaparral, a desert shrub also known as the creosote bush, are reportedly used in Native American medicine.¹⁸ The plant contains nordihydroguaiaretic acid, a compound that is under investigation as an anticancer agent.¹⁹ Renal and hepatic toxicity have been associated with chronic use of products that contain chaparral.^22–22

Kava (Piper methysticum)

Kava is an herbal remedy generally recommended for the treatment of anxiety or to improve sleep.²³ Two randomized, controlled trials have confirmed evidence of its anxiolytic activity.²⁴ However, several cases of severe liver toxicity associated with the consumption of products labeled as containing extracts of kava have been reported. Consequently, kava is banned in several European countries,²⁵ and the U.S. FDA has issued a consumer advisory warning of the potential risk of hepatic toxicity from kava ingestion²⁶; however, products containing kava may still be legally sold in the United States as dietary supplements.²⁷

Laetrile

Laetrile, also known as amygdalin, is a cyanogenic glucoside found in the pits of many fruits, in raw nuts, and in other plants such as lima beans, clover, and sorghum.28,29 Although it is frequently called vitamin B17 in the lay literature, amygdalin is not recognized as a vitamin by the Committee on Nomenclature of the American Institute of Nutrition. Laetrile has been given orally and intravenously with different pharmacokinetics and toxicity profiles. Laetrile became a popular alternative cancer therapy in the 1950s and remained so through the 1980s. Currently, its sale in the United States is banned by the FDA; however, products labeled as containing laetrile can easily be purchased via the Internet. When orally ingested, laetrile can be hydrolyzed by intestinal beta-glucosidase to produce hydrogen cyanide, benzaldehyde, and glucose. The enzymatic activity of beta-glucosidase, and thus the rate of production of cyanide, can be increased under various conditions, including the presence of vitamin C.³⁰ Signs and symptoms of cyanide poisoning have been reported both from individual patients with cancer who ingested products containing laetrile^31,32 and from patients enrolled in clinical trials of oral laetrile.^33,34

Cesium Chloride

Cesium chloride has been promoted in books and on the Internet as a cancer therapy. No clinical trials of the use of cesium chloride have been published, but several case reports have described patients with cancer in whom QT prolongation and torsades de pointes ventricular tachycardia developed after they ingested products containing cesium chloride.35–40 In some of these reported episodes of toxicity, the patients also demonstrated hypokalemia and/or hypomagnesemia. In one case, the patient was successfully treated with 4 weeks of oral Prussian blue.³⁵

Aloe Vera

Leaves from aloe vera, a fleshy, cactus-like plant, contain a clear gel that is often used to soothe minor skin irritations, although a systematic review of the research failed to find firm evidence for a preventive effect with regard to radiation-induced skin reactions.⁴¹ Aloe latex is an extract of the inside of the outer lining of the leaves and is approved by the German Commission E for treating constipation.⁴² The gel can also be made into a juice that has been promoted as a cancer cure. In a male patient with HER2+ breast cancer who was taking capecitabine, trastuzumab, and 1 L a day of aloe vera juice for 2 weeks, severe hypokalemia developed that responded to potassium supplementation after ingestion of the aloe juice was stopped.⁴³ In clinical trials of smaller doses of aloe juice (i.e., 10 mL taken three times a day), hypokalemia has not been found to be an associated adverse effect.^44,45

Licorice (Glycyrrhiza species)

The root of the licorice plant has been used in TCM formulations for centuries. The now-banned herbal product PC-SPES reportedly contained Glycyrrhiza glabra,⁴⁶ as do some herbal products currently used by patients with prostate cancer. Glycyrrhizic acid, a component of licorice, inhibits 11β-hydroxysteroid dehydrogenase, thus resulting in mineralocorticoid excess, which can cause hypertension and hypokalemia.⁴⁷ Severe consequences of hypokalemia, including paralysis and torsades de pointes ventricular arrhythmia, have been reported in patients taking products that contain licorice.^48,49

Herbs Containing Aristolochic Acid

Aristolochic acid, a nephrotoxin that also may induce urothelial tumors, is found in herbs of the Aristolochiaceae family, as well as some from Bragantia and Asarum genera.⁵⁰ Some of these herbs are used in TCM (e.g., guan mu tong [Caulis aristolochiae manshuriensis], which is used for dysmenorrhea and breast disorders), and they are used in some weight-loss formulas found in Europe. Case reports have been published of patients in the United States who have experienced toxicities (e.g., renal failure and urothelial cancer) after ingesting supplements derived from these plants.⁵¹ The FDA has found that some botanical products labeled as containing “Aristolochia,” “Bragantia,” or “Asarum” contain aristolochic acid.⁵²

Adverse Interactions between Dietary Supplements and Drugs

Adverse effects resulting from interactions between a dietary supplement and a drug generally occur because of effects on the drug’s pharmacokinetic (PK) or pharmacodynamic (PD) properties. Many of the PK-related interactions are due to induced alterations in enzymes involved in drug metabolism or transport.

Cytochrome P450 Inducers and Inhibitors

The enzymes of the cytochrome P450 (CYP450) superfamily are responsible for the activation or inactivation of the vast majority of drugs currently in use.⁵³ Drugs or other exogenous chemicals ingested in the diet or via dietary supplements can affect the activity of CYP450 enzymes to a sufficient degree to meaningfully change the clinical effectiveness or toxicity of various chemotherapy drugs. Table 33-1 lists some herbs that have been shown to affect various CYP450 enzyme activities in humans and other herbs for which the effects on CYP450 enzymes have been predominantly determined by in vitro or animal studies, and thus are of uncertain clinical significance. Other herbs interfere with drug PK via effects on the activity of the P-glycoprotein multidrug transporter (e.g., curcumin) or other adenosine triphosphate–binding cassette drug transporters (e.g., genistein).⁵⁴

Table 33-1

Herb-Drug Interactions

Herb	Drug	Affect	Source
St. John’s wort	Irinotecan	Increases enzyme activity and decreases AUC of active metabolite SN38	Clinical trial⁵⁵
St. John’s wort	Imatinib	Increases clearance and decreases AUC of drug	Clinical trial⁵⁶
Green tea	Sunitinib	Decreases drug absorption	Animal study and case report⁵⁹
Ginkgo biloba	Teniposide	May decrease circulating concentration	Clinical trial (theoretical interaction based on known effects of herb on a similarly metabolized drug)¹⁸³
Black cohosh	Substrates of CYP2D6	Increases drug metabolism	Clinical trial¹⁸⁴
Garlic	Saquinavir	Decreases serum levels	Clinical trial¹⁸⁵

AUC, Area under the curve.

St. John’s Wort

A classic example of an herb affecting drug PK is St. John’s wort. Plasma levels of the active metabolite of irinotecan, SN-38, were decreased by 42% in five patients receiving irinotecan and a commonly used dose of St. John’s wort (300 mg three times daily), apparently because of induction of the CYP3A4 isoform.⁵⁵ Imatinib is also a CYP3A4 substrate, and a study using the same dosing schedule of St. John’s wort found a 43% increase in the drug’s clearance and a 30% decrease in the area under the curve of the plasma concentration.⁵⁶

Green Tea Extract and Epigallocatechin Gallate

Green tea and its polyphenols such as epigallocatechin gallate (EGCG) can affect drug metabolism and effectiveness via actions on either PK or PD. A PD-related dietary supplement–drug interaction has been noted in preclinical studies of the combination of green tea and bortezomib. EGCG blocked bortezomib’s anticancer effect on human multiple myeloma and glioblastoma cell lines in vitro by binding to the boronic acid component of the drug; this action occurred at concentrations achievable in the blood of humans after ingesting dietary supplements containing green tea.⁵⁷ In addition, the same research group reported that intragastric EGCG administration (50 mg/kg) completely abrogated bortezomib-induced apoptosis in plasmacytoma xenografts in nude mice. Another animal study also demonstrated that the antitumor activity of bortezomib on human prostate cancer xenografts in severe combined immune deficiency mice was completely eliminated with the very high plasma concentrations obtained after intravenous EGCG administration but not with the lower concentrations resulting from subcutaneous administration.⁵⁸ No human studies have been performed that directly address the clinical significance of this interaction.

A published case report describes a Chinese patient with metastatic renal cell carcinoma who was being treated with sunitinib and noted aggravated symptoms from a retro-orbital ocular metastasis at times when he increased the amount of green tea that he drank.⁵⁹ An animal study of the effects of coadministration of sunitinib and EGCG revealed the formation of a precipitate in the stomach, resulting in lowered sunitinib absorption.

Table 33-2 lists several other herb-drug interactions of potential relevance when advising and managing patients with cancer.

Table 33-2

Adverse Interactions between Dietary Supplements and Cancer Therapies

Anticancer Agent	Herb/Dietary Supplement	Interaction	Source
Rituximab	Bilberry; bitter melon	Hypoglycemia	Theoretical interaction based on shared adverse effects¹⁸³
Radiation therapy	dl-alpha-tocopherol (vitamin E)	Increased tumor recurrence rate	Randomized clinical trial result⁶⁴
Procarbazine	Ginseng	Mania	Theoretical interaction based on observed reaction with another MAO inhibitor, phenelzine^186,187
Imatinib	Ginseng	Transaminitis with biopsy evidence of hepatic injury	Case report¹⁸⁸
VEGF inhibitors	Licorice	Aggravated hypertension	Theoretical interaction based on shared adverse effects
Bortezomib	EGCG, green tea extract	Decreased anticancer effect	In vitro^57,⁵⁸
Sunitinib	Green tea	Decreased anticancer effect	Preclinical research and a case report⁵⁹
5-FU	Green tea	Increased 5-FU serum concentration and AUC	Animal research¹⁸⁹

AUC, Area under the curve; EGCG, epigallocatechin gallate; 5-FU, 5-fluorouracil; MAO, monoamine oxidase; VEGF, vascular endothelial growth factor.

Box 33-2 Dietary Supplements with Platelet Inhibitor Activity

Table 33-3

Supplements that May Interact with Warfarin

Supplement	Action	Source
CoQ10	Decreased warfarin effect	Animal studies and in vitro human microsomes studies
Dan shen (Salvia miltiorrhiza)	Increased warfarin effect	Animal study
Dong quai (Angelica sinensis)	Increased warfarin effect	Animal study
Fenugreek	Increased warfarin effect	Clinical case report
Green tea	Decreased warfarin effect	Clinical case report

Several observational studies have found that women who are overweight or obese at the time of breast cancer diagnosis have poorer clinical outcomes, including survival. Additionally, similar studies have shown better survival rates in women with breast cancer who undertake greater amounts of physical activity; however, the potential benefit of a “healthy” diet (i.e., low fat and high in fruit and vegetables) has been equivocal.

Two prospective studies have addressed the potential impact of dietary modification, and to a lesser extent physical activity, on the survival of women with early-stage breast cancer. The Women’s Intervention Nutrition Study randomly assigned 2437 women with stage I to III breast cancer and who had completed their adjuvant chemotherapy, when given, to either a diet low in fat (15% of calories) and high in fruits and vegetables or a control group that received general dietary advice from a dietician.⁶⁶ After a median of 60 months of follow-up, women following the low-fat diet experienced a statistically significant 24% reduced risk of relapse. The primary end point of relapse-free survival, however, was not statistically different (P = .07) for the entire study group, although women with estrogen receptor–negative tumors did have a significantly longer relapse-free survival (P = .03). Another similarly designed and sized study, the Women’s Healthy Eating and Living trial, failed to find a significant difference in recurrence rate for women on the low-fat diet, although a better recurrence rate was seen in the subgroup of women who adhered to the low-fat diet and undertook a greater degree of physical activity.^67,68 Another notable difference between the two trials was that women following the low-fat diet in the Women’s Intervention Nutrition Study trial lost weight, whereas women following the investigational diet on the Women’s Healthy Eating and Living trial did not lose weight.