ALTERNATIVE "TREATMENTS" IN CANCER

Complementary and alternative medicine (CAM) is associated with a wide variety of treatments and procedures. However, the use of herbs and supplements as medication is often a cause of concern when a patient is being treated by an oncologist.^[1,2]

According to the National Institutes of Health, approximately 40% of American adults used some form of CAM over the past decade, with use highest among women and those with higher education and income levels.^[3] Use of CAM alongside conventional medicine is even more common among patients with cancer, with some studies suggesting up to 83% of patients with cancer in the United States have tried some form of alternate therapy.^[4]

A recent study from the Yale Cancer Center found that patients with cancer who initially chose an alternative medicine treatment without conventional cancer treatment were more likely to die.^[5]

For patients with cancer who choose to use CAM alongside conventional treatment, oncologists must consider the impact of CAM on the narrow therapeutic window of oncolytic drugs, particularly when CAM use increases the risk for clinically relevant herb-anticancer drug interactions.^[6]

1. Common Herbs and Supplements: Mechanism of Interaction With Chemotherapy 

CAM-anticancer drug interactions can occur at the pharmaceutical, pharmacodynamic, or pharmacokinetic level. Interactions at the pharmacokinetic level are the most likely and involve changes in the absorption, distribution, metabolism, or excretion of the chemotherapeutic drug, via cytochrome P450 (CYP) metabolizing enzymes or phase II enzymes, especially uridine diphosphoglucuronosyl transferase (UGT).^[6] Of the CYP enzymes, CYP3A4 is the most important in the metabolism of anticancer drugs.

Many chemotherapeutic agents (such as cyclophosphamide, ifosfamide, docetaxel, paclitaxel, vincristine, vinblastine, vinorelbine, irinotecan, and etoposide) are CYP3A4 and/or P-glycoprotein substrates. Similarly, several supportive care agents (such as granisetron, fentanyl, and oxycodone) are CYP3A4 or P-glycoprotein substrates, and patients taking opioids to manage pain relief could also experience altered pharmacokinetics with CAM components.^[7]

Most anticancer drugs undergo phase I and/or II metabolism and are substrates of P-glycoprotein, breast cancer resistance protein, multidrug resistance-associated proteins, and/or other transporters. Because many CAM supplements are also metabolized in the liver, patients on certain chemotherapy drugs should avoid them, as induction and inhibition of these enzymes and transporters is considered an important mechanism for herb-anticancer drug interactions^[8] and can cause serious issues for patients.

Owing to the large numbers of patients with cancer who have tried herbal remedies, Memorial Sloan Kettering Cancer Center has taken a proactive approach and created a website containing an encyclopedia-type listing of common drug and herb mechanisms of action and interaction, as well as additional information for oncologists to be aware of.

2. The Most Common Herbs and Supplements Known to Interact With Chemotherapy Drugs 

Although acute medical problems caused by herb-drug interactions are rare, complications and death have been reported. In a systematic review of 890 pairs of herb-drug interactions,^[9] CAM products containing St John's wort, magnesium, calcium, iron, and ginkgo, in that respective order, had the greatest number of documented interactions with medications.^[10]

Of the scientific literature that studies herb-drug interactions, St John's wort in particular is known to have many (if not the most) drug interactions. A plant-based supplement used to treat depression, as well as ginseng, ginkgo biloba, and milk thistle, should not be used with many chemotherapy drugs. Like certain antidepressants, these over-the-counter supplements interfere with how the body metabolizes the CYP2D6 enzyme, diminishing the chemotherapy drug's effectiveness by causing it to break down too quickly, or otherwise poisons the body by blocking the drug from breaking down at all.^[8]

St John's wort can cause potentially dangerous interactions with the anticancer drugs irinotecan and imatinib.^[8] A clinical study in patients with cancer reported that treatment with St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%. In healthy participants, 2 weeks of treatment with St John's wort at 900 mg/day significantly decreased the systemic exposure of imatinib by 32%.^[8,11,12]

Grapefruit juice is another common supplement that renders many drugs ineffective, by increasing the absorption of various medications that are substrates for cytochrome P450 3A4 and P-glycoprotein (eg, etoposide). Of note, in vitro data are not consistent with the predicted in vivo interactions. Grapefruit juice would be expected to lower intestinal CYP3A content and hence increase the absorption of CYP3A substrates, such as etoposide, but a study in patients with cancer has demonstrated the opposite effect in that concomitant grapefruit juice administration decreased etoposide absorption.^[7]

In women with advanced breast cancer, coadministration of garlic supplement reduced the clearance of docetaxel by 23.1%-35.1%, although the difference did not achieve statistical significance. In addition, commonly used herbs, such as gingerand garlic, can interfere with anticoagulant drugs, such as warfarin, and increase the risk for bleeding after surgery.^[13]

3. Herbs That Are Known to Pose a Risk With Specific Cancer Treatments 

Reports of CAM products that had contraindicators for use among patients with specific disease states include alfalfa, black cohosh, chasteberry, dehydroepiandrosterone (DHEA), red clover, soy, and wild yam in breast cancer; alfalfa, chasteberry, DHEA, red clover, soy, and wild yam in gynecologic cancer; chasteberry, DHEA, flaxseed, and saw palmetto in prostate cancer; and Echinacea in leukemia.^[10]

Of particular note are herbs that contain hormone-like properties. Barrie R. Cassileth, MS, PhD, chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York, New York, pointed out in an article in the ASCO Post that phytoestrogens are herbal compounds that mimic estradiol. Foods containing phytoestrogens, such as soy, have been shown to confer protective effects against breast cancer. However, genistein, an isoflavone present in soy, may stimulate the proliferation of breast tumors and interfere with the action of tamoxifen.^[14]Cassileth stated these herbs are best avoided by patients with hormone-sensitive cancers.^[9]

Anticoagulants are commonly used to prevent deep vein thrombosis and pulmonary embolism in bedridden patients with cancer. Warfarin is from an older generation of anticoagulants that has a narrow margin of safety and requires careful monitoring. Earlier studies showed that such botanicals as dang gui may have additive effects, thereby elevating the risk for bleeding and hemorrhage.^[13]

In addition to herbs, antioxidants and vitamins can also interact with cancer treatments. Several studies have shown that antioxidants can protect cancer cells and normal cells, if dietary antioxidants or their derivatives or endogenously made antioxidants are given at doses that do not affect the proliferation of these cells are administered only one time shortly before cancer therapeutic agents. Vitamin E(alpha-tocopherol) or vitamin C, when given in a single low dose shortly before X-irradiation, reduced the effectiveness of irradiation on cancer cells in in vitro and in vivo models.^[15]

4. When CAM Does Not Have Negative Effects 

Naturally, not all data on CAM combined with cancer is negative. A large study of combined data on US and Chinese women showed that post-diagnosis soy food consumption ≥ 10 mg isoflavones was associated with a nonsignificant reduced risk for breast cancer-specific mortality and a statistically significant reduced risk for recurrence.^[16] This study contradicts some previous studies on soy interactions, so clearly research is ongoing in this field.

Herbs with antioxidant activity in particular have drawn a great deal of media attention and are suggested for use with anticancer drugs, such as anthracyclines, platinum compounds, and alkylating agents that generate free radicals via their cytotoxic effects. In theory, antioxidants may render these drugs less effective, but a review of studies showed mixed results that suggest a potential for reducing toxicities without affecting survival times.^[13]

A study by Wassertheil-Smoller and colleagues^[17] showed that women already diagnosed with invasive breast cancer who took multivitamins with minerals supplements had lower breast cancer mortality than nonusers.

5. NDs Working With MDs and Patients 

The trend of using CAM for cancer treatments has been steadily increasing in recent years. Without knowledge of what a patient is doing, a doctor cannot accurately provide a treatment plan. Oftentimes, patients pursue CAM treatment owing to symptoms from chemotherapy and radiation, so it is important to find solutions that patients find tolerable.

In the Pacific Northwest, schools including the National University of Natural Medicine and Bastyr University have been training naturopathic physicians and providing ND, or naturopathic doctor, degrees for students for over 50 years. NDs often work in collaboration with MDs to jointly care for patients, though they can also prescribe some medications on their own.

The Future of Herbal Remedies in Cancer Care 

Cancer survivors are more likely than the general population to be CAM users.^[18]The reasons for this are complex but include a desire to manage chemotherapy side effects and take a more holistic approach to managing health, gain a sense of control of what happens to their bodies, and address concerns that conventional medicine are not helping them manage all aspects of health.

On the other hand, numerous studies have been conducted regarding the effect of CAM on cancer survival, and according to a recent study in the Journal of the National Cancer Institute,^[5] use of alternative medicine for curable cancer without any conventional cancer treatment is associated with greater risk for death.

Patients with cancer in particular are a vulnerable population, so by increasing communication and contacting the correct medical care providers, they can be provided the safest, proven methods of holistic care.