Herb-Drug Interactions in Cancer Care

Herbs have served as medicine throughout human history. Since the passage of the Dietary Supplement Health and Education Act (DSHEA), inconsistent regulatory practices have resulted in widespread, indiscriminate use of herbal supplements. Available data indicate that cancer patients use these products (along with standard treatments) more often than the general population. The reasons cited for such use include improving health, reducing the risk of recurrence, and reducing the side effects of cancer treatments. Herbs, however, contain biologically active compounds and can potentially interact with prescription medications, including chemotherapy drugs. We describe the mechanisms via which these interactions may occur, as divided into pharmacokinetics and pharmacodynamics. We highlight four popular herbs and a medicinal mushroom commonly used by cancer patients-turmeric, green tea, ginger, ashwagandha, and reishi mushroom-along with reports of their interactions with standard drugs. We conclude by emphasizing the need to inform patients and physicians about herb-drug interactions and how to advise patients on appropriate use of herbal supplements to minimize the risk for interactions.

Introduction

Before the era of modern pharmaceuticals, plants were the major source of medicine. Today, herbal products are classified as “dietary supplements” under the Dietary Supplement Health and Education Act (DSHEA), and are used as part of a complementary health approach by many in the United States.[1] Compared with healthy populations, cancer patients appear to be more frequent users of these supplements.[2,3] The majority employ them as adjuncts to chemotherapy or other cancer treatments to alleviate symptoms and to prevent recurrence. In addition, cancer survivors have reported greater use, with one-third having taken herbs.[4] This use is driven by specific health beliefs and as recommended by families and healthcare providers.[5,6] Herbal products typically are considered “natural” and “safe” compared with invasive treatments.

These products, however, are not regulated as drugs by the US Food and Drug Administration (FDA).[7] Poor manufacturing practices, lack of standardization, varied amounts of active ingredients, product contamination, and serious herb-drug interactions have been reported.[8] In this article, we focus on “herbs” used by cancer patients and survivors. These products are derived from botanical sources used as traditional medicine, dietary supplements, food, or spices.

Herb-Drug Interactions

Herb-drug interactions started appearing in the literature in the 1980s, when reports described the interactions of St. John’s wort and grapefruit juice with several prescription drugs. Despite increasing concerns, the term “herb-drug interactions” was only introduced as a Medical Subject Headings (MeSH) term in 2004. It was defined as “the effect of herbs, other plants, or plant extracts on the activity, metabolism, or toxicity of drugs.”

To fully appreciate the clinical impact, both the drug and the herb must be studied together in humans. Very few herbs and drugs have been studied in this way, however, and much of the current knowledge rests on data from in vitro, animal, and in silico models. Therefore, understanding the mechanisms of interaction is crucial in predicting the clinical effects.

The basic mechanisms of herb-drug interactions are similar to other drug interactions. They can be divided into pharmacokinetics, which describe how herbs can influence the absorption, distribution, metabolism, and excretion of other drugs; and pharmacodynamics, which define how herbs can alter the actions of other drugs when used concurrently.

Pharmacokinetic Studies

Studies of pharmacokinetics focus on the actions of microsomal enzymes of the cytochrome P450 (CYP) family and membrane transporters such as P-glycoprotein (P-gp), which play important roles in the absorption and metabolism of many prescription drugs. Compounds derived from botanicals are known to interfere with CYP enzymes and transporters, thereby affecting the way substrate drugs are metabolized. Early studies found that furanocoumarins from the rind of grapefruit irreversibly bind with CYP3A4, resulting in a sevenfold increase in the intestinal absorption of simvastatin.[9] Among the drugs used in cancer care, grapefruit juice can increase the blood levels of cyclosporine by 38%, tacrolimus by 110%, and oxycodone by 67%.[10]

Another compound, hyperforin, is a major constituent of St. John’s wort, an herb commonly used to treat depression. It induces both CYP and P-gp by activating the pregnane X receptor.[11] Studies in humans show that it can reduce the blood levels of irinotecan, a major CYP3A4 and P-gp substrate, by 40% when used concomitantly.[12] Tyrosine kinase inhibitors such as imatinib, osimertinib, and lapatinib, as a group, are also major CYP3A4 substrates.[13] Dose adjustments may be required when they are used concomitantly with another drug or herb that is a strong inducer or inhibitor of the CYP3A4 enzyme. Tamoxifen is another widely used medication that relies on CYP2D6 and CYP3A4 to be metabolized to its active form. Herbs that inhibit these enzymes can lower the drug’s efficacy. Genetic polymorphisms may also play a role in drug metabolism.

Pharmacodynamic Interactions

These comprise the interactions between drugs and herbs resulting in changes in their physiologic effects. In cancer care, medications that are prone to pharmacodynamic interactions include chemotherapeutic agents, anticoagulants, hormones, and immunosuppressive agents.

Chemotherapeutic agents vs herbs with antioxidant properties

As a class, chemotherapeutic agents have the potential to interact with many herbs, but their interactions with herbs that possess antioxidant activity have drawn much attention. Drugs such as anthracyclines, platinum compounds, and alkylating agents generate free radicals for their cytotoxic effects. Theoretically, antioxidants may render these drugs less effective. Reviews of studies, however, showed mixed results that suggest a potential for reducing toxicities but no impact on survival times.[14,15] The variation in forms and dosages of antioxidants and chemotherapy drugs used may contribute to the differences in these findings.

Some also argue that antioxidants can help minimize chemotherapy-induced adverse effects. Studies in which low-dose antioxidants were used following chemotherapy suggest that they may reduce toxicity and prolong survival.[16] Unlike prescription drugs such as amifostine and mesna, however, which can protect organs by neutralizing free radicals, no definitive data exist to show that antioxidant supplements can selectively protect the healthy tissues without reducing the cytotoxic effects of chemotherapy drugs. Until conclusive evidence becomes available, oncologists should advise patients to avoid supplements, including herbs, with antioxidant effects during cancer treatment.[17]

Anticoagulants vs herbs that have anticoagulant effects

Anticoagulants are commonly used to prevent deep vein thrombosis and pulmonary embolism in bedridden cancer patients. Warfarin is from an older generation of anticoagulants that has a narrow margin of safety and requires careful monitoring. Earlier studies showed that botanicals such as dang gui may have additive effects, thereby elevating the risk of bleeding and hemorrhage.[18] Patients who are thrombocytopenic secondary to cancer, or due to chemotherapy, should avoid herbs that have anticoagulant effects to decrease the risk of major bleeding. Those undergoing surgery should not use these herbs at least 2 weeks prior to avoid prolonged bleeding time or excessive blood loss during surgery.[19,20]

Hormonal therapies vs phytoestrogenic herbs

Hormonal therapies are often used as adjuvants for treating hormone-sensitive cancers. Tamoxifen, a drug that is widely used for treating estrogen receptor–positive breast cancer, acts by blocking the estrogen receptor, resulting in disease remission and prolonged survival. Botanicals such as red clover and soy products are known to have mild estrogenic effects and may stimulate the growth of hormone-sensitive cancers.[21,22] Furthermore, genistein, an isoflavone found in soy, has been shown to interfere with tamoxifen.[23,24] Data from clinical studies, however, have shown positive associations between soy food consumption postdiagnosis and a nonsignificant reduced risk of breast cancer–specific mortality, as well as a statistically significant reduced risk of recurrence.[25] Consumption of soy foods also reduced mortality and recurrence, regardless of tamoxifen use, in breast cancer patients.[26] For patients who wish to incorporate soy for cancer prevention, oncologists should recommend soy foods but not dietary supplements.

Immunosuppressive agents vs immunostimulant herbs

Transplantation patients often rely on immunosuppressive agents to minimize rejection of the transplanted organ. These drugs, however, are prone to interact with herbs. For instance, the commonly used herb St. John’s wort reduces the plasma level of cyclosporin and tacrolimus by more than 50%.[27] Astragalus, a well-known herb used for its tonic property in traditional Chinese medicine, can also potentially negate immunosuppressive drugs due to its immune-stimulatory effects.[28]

Common Herbs and Their Potential Interactions

Turmeric

Native to South Asia, turmeric (Curcuma longa, Curcuma domestica) has a long history of use. The “ginger-like” yellow-orange–colored rhizome is used as a spice. In traditional medicine, it is often used to improve circulation and digestion. Turmeric extracts are marketed as dietary supplements for arthritis and for cancer prevention. The active constituent is curcumin, which has been researched extensively. Preliminary data indicate that curcumin helps relieve adverse effects due to cancer treatments. A topical turmeric-based cream was reported to reduce radiotherapy-induced dermatitis.[29] Oral curcumin also improved cachexia and general health in colorectal cancer patients.[30] In a phase II trial involving 21 patients with advanced pancreatic cancer, curcumin demonstrated bioactivity by downregulating nuclear factor-ÎºB and cyclooxygenase-2. Despite limited absorption, antitumor response was seen in two patients.[31] Curcumin has been reported to be safe, but due to its antioxidant properties, it can interact with chemotherapy drugs such as cyclophosphamide and doxorubicin.[32] It is also known to interfere with CYP450 enzymes and may interact with substrate drugs.[33] In addition, because of its antiplatelet property, curcumin can increase the risk of bleeding when used with anticoagulants.[34]

Green tea

The leaves of green tea (Camellia sinensis) are used to prepare tea. With origins in Asia and now consumed worldwide, green tea and its extracts have been used to prevent and treat hyperlipidemia, hypertension, atherosclerosis, and cancer. The active constituent of green tea extract is epigallocatechin-3-gallate (EGCG).

Green tea extract has demonstrated chemopreventive activity by preventing formation of precancerous polyps, inhibiting proliferation of breast cancer cells, and by inducing apoptosis in bladder cancer cells.[35-37] A large case-control study reported a reduction in the risk of breast cancer following intake of mushrooms (both fresh and dried forms) and green tea in premenopausal and postmenopausal women.[38] It may also reduce the risk of myelodysplastic syndromes.[39] A meta-analysis, however, failed to find any benefits for prevention of gastric cancer.[40]

Topical application of green tea extract has been shown to be effective against external genital and perianal warts.[41] One such extract, sinecatechins, is approved by the FDA. Preclinical studies, however, have shown that the polyphenolic constituents in green tea can negate the therapeutic effect of bortezomib, an anticancer drug, while increasing the risk of toxicity when used with tamoxifen and irinotecan.[42-44] Elevated risk of hepatotoxicity has also been reported when used with acetaminophen and when consumed on an empty stomach.[45,46]

A clinical study showed that taking 800-mg EGCG is associated with elevated liver enzymes, which was reversible following cessation of consumption.[47] According to an observational study, intake may enhance the risk of breast cancer in postmenopausal women. Daily consumption of green tea varied between 1 and 3 cups. The risk appears to be modified by the age at onset of tea drinking, with a protective effect for women who started before age 20 years and an increased risk for those who started after age 50 years.[48] Green tea extract is also known to interfere with the CYP450 3A4 enzyme and may affect the intracellular concentration of drugs metabolized by this enzyme.[49]

Ginger

Ginger, the rhizome of the plant Zingiber officinale, has long been used as a culinary spice and medicine in Asian and Arabic traditions to treat the common cold, headache, and fevers, as well as gastrointestinal and inflammatory disorders. Clinical trials indicate that ginger can effectively reduce nausea and vomiting due to pregnancy, motion sickness, and following surgery.[50-53] Findings of its efficacy in preventing chemotherapy-induced nausea are also promising.[54,55] A systematic review of randomized, controlled, and crossover trials, however, found that data are inconclusive to recommend clinical use.[56]

A longitudinal study reported that in patients receiving warfarin, concomitant use of ginger elevated the risk of bleeding (odds ratio, 3.20; 95% CI, 2.42–4.24).[57] A common warning is to discontinue use of ginger supplements in the perioperative setting due to the potential risk for increased bleeding.[58] According to a recent systematic review, findings of platelet aggregation and coagulation properties of ginger are equivocal.[59] Future studies are needed for definitive data.

Ashwagandha

A shrub valued in Ayurveda for its medicinal effects, ashwagandha (Withania somnifera) is used to relieve stress, anxiety, and fatigue; to treat osteoarthritis and skin diseases; to rejuvenate; and to improve endurance. It is being widely promoted as an anxiolytic.

The active constituents include alkaloids, saponins, and steroidal lactones known as withanolides. Clinical studies show its utility in relieving anxiety; in producing analgesic, anti-inflammatory, and chondroprotective effects in patients with knee joint pain; and in mitigating chemotherapy-induced fatigue, along with improving quality of life, in a small study of breast cancer patients.[60-62]

Although it is generally considered safe, ashwagandha has been reported to potentiate the sedative effects of triazolam.[63] Future studies to evaluate safety are warranted because of the recent rise in the popularity of this herb.

Reishi mushroom

Although not a botanical, reishi (Ganoderma lucidum) is a medicinal mushroom that is commonly used by cancer patients. It is an important component of traditional medical systems in Asia and is used to strengthen the body, increase vitality, and to treat insomnia.

PERSPECTIVE BY

Donald I. Abrams, MD
Botanicals: Weighing Patients’ Individualized Needs Is Best

The use of complementary therapies is one way that cancer patients can empower themselves during their course of treatment. Rather than a blanket proscription against use of all supplements during treatment, it is best to keep each patient’s goals of care in mind when discussing the use of botanicals. If the goal is to cure the patient’s cancer or treatment is being given adjunctively to decrease the risk of recurrence, delaying most botanicals until after active treatment seems prudent. That said, while Yeung and colleagues caution against use of the reishi mushroom, a large body of literature, mostly from Asia, suggests that mushrooms are safe and effective to combine with both radiation and chemotherapy during active cancer therapy (See NCI’s PDQ Cancer Information Summaries: Integrative, Alternative and Complementary Therapies). However, because of their immune-enhancing potential, I recommend against their consumption by patients with lymphoproliferative malignancies or those on immunotherapies. This caution is based totally on theoretical concerns, without supporting evidence from the literature to date.

If treatment is palliative and cure is not likely, allowing the patient to experience some sense of control through judicious use of supplements during treatment seems acceptable. I am often faced with patients bringing in a shopping bag full of supplements that have been recommended to them. If they seem wedded to a regimen they are currently taking, trying to dissuade them seems inappropriate. If some of their botanicals seem unsafe or excessively expensive, I will advise they consider discontinuing those. Patients are frequently advised, most often by radiation oncologists, to eat only white foods. Although it is wise to avoid potent antioxidant supplements-vitamin C, vitamin E, and coenzyme Q10-during radiation and chemotherapy, eating antioxidant-rich foods is generally regarded as safe.Dr. Abrams is an Oncologist at Zuckerberg San Francisco General Hospital; Integrative Oncologist, UCSF Osher Center for Integrative Medicine; and Professor of Clinical Medicine, University of California, San Francisco

Preliminary data show that reishi is effective in enhancing immune responses in advanced-stage cancer patients.[64] Remission of hepatocellular carcinoma has also been reported in a few cases.[65] Extracts from the fruiting body as well as spores have been employed in clinical trials for cancer. Nevertheless, preclinical studies have led to concerns about its use. Because of its antiplatelet effects, reishi can increase the risk of bleeding when used with anticoagulant/antiplatelet medications.[66] Additionally, due to its antioxidant property, it may potentially reduce the effectiveness of some chemotherapeutic agents.[67] It can also alter immune responses.[64] Additionally, reishi has been reported to inhibit CYP450 enzymes and may increase the toxicity of substrate drugs.[68]

Advising Patients

Research suggests that patient–provider communication about herbal use is very rare in the oncology setting.[69] Although many oncologists are not trained in the use of herbs, they have an important role in advising and guiding patients as part of the overall treatment plan. Where scientific evidence is lacking, physicians often advise against supplementation by erring on the safe side. But such a conservative approach can also discourage communication about dietary supplement use.

For many oncologists, finding credible information about dietary supplements, especially herbs, can also be tricky. Standard drug databases (eg, Lexicomp) have comprehensive information on prescription drugs, but the entries on herbal supplements are often limited. On commercial websites that promote herbal products, information about potential adverse effects or interactions is often minimized or ignored. To address this issue, the Integrative Medicine Service at Memorial Sloan Kettering Cancer Center has developed the “About Herbs” website: www.mskcc.org/aboutherbs. It contains objective information on more than 280 dietary supplements and bogus treatments used by cancer patients. Mechanisms of action underlying the effects of these products and the drugs with which they can potentially interact are listed. This award-winning site, which has both healthcare professional and consumer versions, is available free of charge to clinicians and patients. Other databases that provide reliable information include the National Institutes of Health’s Office of Dietary Supplements (https://ods.od.nih.gov), which is free to access, and ConsumerLab.com and the Natural Medicines Comprehensive Database (www.naturaldatabase.com), both of which charge for their services.

Herbal product use by cancer patients has significantly risen in the last few decades. However, these agents lack governmental oversight and are biologically active, with a potential for interactions with chemotherapy and other cancer drugs. Fostering open communication on herbal product use between patients and physicians is therefore important. Physicians should discuss expectations with their patients, clearly communicating the potential benefits and risks involved.

How to Discuss Herb-Drug Interactions With Patients

ASK ABOUT HERBAL USE. Be aware that some patients may consider these products as food or spices. Many also use multiple products that have similar ingredients, making the cumulative effect more potent.

KEEP AN OPEN MIND. Even though very few herbs have been proven useful in treating cancers, some can help relieve symptoms.

EXPLAIN THE REASONS. If you think a product is not the right choice, tell patients why. For example, the herb may increase the risk of toxicity or it may reduce the effectiveness of chemotherapy drugs. If this is not discussed, the patient may continue to use these products, but refrain from divulging that information.

EDUCATE. Inform patients about the potential interactions with other drugs or lab tests.

MONITOR FOR ADVERSE EFFECTS. When you determine that an herbal product is suitable, encourage the patient to report any signs and symptoms following use.

CONSIDER RECOMMENDING NONPHARMACOLOGIC INTERVENTIONS. When herbal supplements are not appropriate, you can recommend therapies such as acupuncture, yoga, and meditation. These have been proven effective in mitigating symptoms and improving quality of life. More patients are beginning to be receptive to such suggestions.

REFER TO AN INTEGRATIVE MEDICINE SPECIALIST who has training in balancing the benefits and risks of herbal therapy and other integrative approaches to cancer treatment and survivorship.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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