It is recommended that patient supplement treatments be limited to those whose actions and interactions are understood; when there is doubt, one should err on the side of caution. The potential benefits of reduced side effects frequently do not outweigh the potential risk of a poor outcome.
—Dan Labriola, ND, and Robert B. Livingston, MD
Many potential drug-nutrient interactions can affect cancer treatment. It is important to consider these interactions given the significant use of supplements and other self-treatment options during cancer care. Antioxidants account for a large portion of the $32 billion in supplement industry sales,1 and thus, patients frequently have questions about them. The challenges for oncology professionals are to determine which supplement–cancer treatment combinations are safe and to explain the risks to patients.
The solution is not to rely on drug-nutrient interaction references, as these are not as mature or reliable as drug-drug interaction science reports for consistently accurate answers. Moreover, telling the patient to stop all supplements or even to just stop antioxidants is problematic, since patients are reluctant to give up agents that they believe will produce better outcomes and reduced adverse effects, as typically cited in aggressive marketing.
Understanding the Controversy
The numerous contradictory reports about antioxidants in the cancer treatment setting are understandable and more easily explained to patients if we revisit the pharmacology of these agents. We focus here solely on the interactions between antioxidants and those cancer treatments that utilize reactive oxygen species for their cytotoxic effects. Characterized by an unpaired set of electrons in their outer orbital ring, reactive oxygen species are a well-known mechanism by which radiotherapy and some chemotherapy agents preferentially induce apoptosis in cancer cells.
Antioxidants gained their fame with cancer patients as a result of their ability to quench reactive oxygen species, the free radicals that can result in some cancers. It is also well recognized that they can quench the reactive oxygen species created by cancer treatments.2 These interactions, however, occur only when the antioxidant and chemotherapy are matched. If the molecules do not match, the antioxidant will not interact and therefore will not affect treatment.
Different cancer treatments utilize a variety of different, unique reactive oxygen species for their cytotoxicity, even though they are frequently referred to as if all chemotherapy or cancer treatments were the same. The antioxidants from dietary, botanical, and other available sources come in many different forms as well. Some combinations of antioxidants and cancer treatments will interact, some will not, and as of today, we are not able to accurately predict which do or do not interact.
When an interaction occurs, it has the net effect of reducing the dosage by reducing the number of reactive oxygen species delivered by the treatment. Since most of these treatments have a narrow therapeutic index and efficacy that is proportional to dose, even a modest decrease in reactive oxygen species can have a significant effect on outcome including reduction in disease-free survival,3 especially where long-term outcome is a clinical objective.
The published literature regarding concurrent chemotherapy or radiation with antioxidants reach a wide variety of conclusions, some showing improved survival and status and others, a reduction in survival. A convenient list was published by Ladas et al.4 When viewed in light of the governing pharmacology, however, these apparently contradictory results are understandable. Some combinations interacted, and others did not.
Unfortunately, the generalizations about all antioxidant–reactive oxygen species interactions based on these single combinations tested are misleading. In fact, it may not even be accurate to predict the interaction of a specific combination that’s been tested when applied to a different patient or condition until we have a greater knowledge of the independent variables that can affect outcome.
Explaining Potential Risks to Patients
When the patient comes in with antioxidant recommendations based on data that appear to be too good to be true, consider that there may be other factors at play. The most obvious explanation is that an inadvertent dose reduction from an antioxidant–reactive oxygen species interaction will likely reduce adverse effects, no different from administering a reduced dose. Also, supplements with anti-inflammatory activity may improve patient status and give the appearance of tumor response in the short term even with reduced effective dosage.
Trial data from short-term or salvage therapy, where a reduced tumor response resulting from an interaction may not be noticeable, should be viewed with caution. This is especially important in patients where long-term disease-free survival is a clinical objective, as the same interference may dramatically interfere with survival if the net effect of treatment falls below the therapeutic index.
In the sole long-term, randomized, placebo-controlled prospective trial to have addressed this topic, Bairati et al administered antioxidants with radiotherapy for 540 stage I and II squamous cell head and neck patients and found a significant increase in relapse rate for the antioxidant arm.5 The same authors published again, this time adjusting for patients who continued to smoke after treatment,6 and suggested that the differences could be resolved by removing smokers from the randomization. However, this adjustment has been controversial, and the authors concede that antioxidants do, in fact, interact with radiotherapy.
Minimizing and Managing Interactions
In terms of patient management and safety, the evidence is clear that chemotherapy agents that rely on reactive oxygen species mechanisms for their cytotoxicity, including alkylators, antitumor antibiotics, and others, should be considered potentially vulnerable to interference from antioxidant supplementation greater than dietary levels. If antioxidants are to be used with these patients, interaction can be minimized by separating dosage by at least 4 half-lives for the drug and a return to normal dietary serum levels for the antioxidant. Both the antioxidant and the drug multicompartment pharmacokinetics should be considered. The same principles apply to radiotherapy.
The pharmacokinetics of the vulnerable chemotherapy treatments and antioxidants, including strategies for managing these interactions, has been reviewed in greater detail and can be helpful.7 When looking for supplement information, unfortunately not all Internet websites and database services are accurate, but one reliable source is the evidence-based Memorial Sloan Kettering Cancer Center Integrative Medicine website.8 Broader, patient-friendly explanations of the many oncology-nutrient interactions including antioxidants are also available.9,10
Frequently Asked Questions
Chemotherapy and radiation therapy are powerful treatments. How is it that a few vitamins or other relatively benign substances can interfere?
Cytotoxic treatments are indeed powerful, but their efficacy is governed by a relatively narrow therapeutic index, which means that dosage is already close to the upper or lower limit. The trial by Bairati et al5 used a modest 400 IU of vitamin E and 30 mg of beta-carotene. Patients frequently self-treat with much higher dosages.
Can the risk for an unwanted interaction be avoided by instructing the patient to avoid antioxidants within 24 hours of chemotherapy or radiation?
The answer depends on the treatments and the patient. The rule of thumb is to separate interacting agents by at least 4 terminal half-lives of the cancer treatment and, for the supplemental antioxidant, return to normal serum levels. For example, it is unlikely that the cytotoxicity of busulfan (Busulfex, Myleran), with a terminal half-life of approximately 3 hours, would have a meaningful interaction after 24 hours, whereas oxaliplatin, whose terminal half-life is more than 50 hours, would be vulnerable to interference the next day and longer.
When the route of administration is other than intravenous, the appropriate compartment pharmacokinetics is also important. You would not use first-compartment kinetics with intrathecal methotrexate.
The pharmacokinetics of the antioxidant is important as well. The half-life of vitamin E, for example, is approximately 48 hours, which puts it well beyond 24 hours for even modest dosages.
What are the most common sources of antioxidants?
Vitamins A (including beta-carotene), B6, C, and E are powerful antioxidants. Minerals zinc and selenium also have significant antioxidant activity. Since these are life-sustaining nutrients that cannot be manufactured by the body, they must still be available at reasonable levels in the diet and/or with supplementation.
There are also many plant-based antioxidant sources including some fruits, vegetables, and herbal medicines.
Is it safe for patients to take just a multiple vitamin during treatment?
Not all multiple vitamin products are appropriate. Many have 2,000% or more of the daily value of some ingredients. It is best to find a multiple vitamin that has approximately 100% of daily values for all ingredients.
Are herbal medicines a potential source of antioxidant interference?
Some botanicals have more than 50 pharmacologically active alkaloids, many of which have antioxidant activity. Those that have been scientifically tested, standardized for their active ingredients, and manufactured with good quality control will behave predictably. For others, we simply don’t yet have enough data to know all of their actions. When uncertain, the safest course is to assume the agent has antioxidant activity and separate it from treatment.
Can diet be a potential source of interference?
A normal, varied diet should not be a problem. It is useful, however, to caution patients to avoid practices that can concentrate antioxidants such as severe “mono-diets” and juicing vegetables. Also, some sports drinks and protein supplements are fortified with levels of nutrients that may interfere with treatment. Consult the label.
Many other complementary and alternative medicine products such as homeopathic treatments and traditional Chinese medicine herbs are promoted for use with cancer treatment. Are these a potential source for antioxidant interference?
Traditional homeopathics are very dilute and unlikely to interact. Some products labelled as homeopathic, however, have other ingredients that are not dilute and may pose a risk.
The botanicals associated with traditional Chinese medicine and other Asian healing arts face the same challenges as Western herbs, namely that we do not always know how much antioxidant activity they contain. The same cautions are recommended.
Are there any other concerns when combining supplements with cancer treatments that are vulnerable to antioxidant interference?
There are many evidence-based complementary and alternative medicine therapies with demonstrated benefit11 when delivered in a disciplined, integrative care setting, but there are also risks for interference with treatment efficacy, increasing adverse effects, and creating new problems when administered incorrectly. Providers of these treatments frequently do not understand the technology of modern cancer care and, as a result, do not recognize potentially negative interactions.
Patients are also confused when the interactions produce results that are not intuitive. In cases where a supplement treatment reduces side effects, it can be difficult for the patient to understand that this may not be a wholly positive event in relationship to outcome. Patients who are anxious to do something on their own to improve the cancer journey are frequently baffled when normally healthful strategies such as juicing vegetables and fruits are described as risky.
It is recommended that patient supplement treatments be limited to those whose actions and interactions are understood; when there is doubt, one should err on the side of caution. The potential benefits of reduced side effects frequently do not outweigh the potential risk of a poor outcome. It is important to note that antioxidants represent just one of many complementary and alternative medicine treatments with the potential to interact with oncology care.
Patient compliance and satisfaction are improved if these interactions can be explained rather than “just saying no.” Compliance will be even better if a safe substitute can be prescribed in place of a supplement that is risky, especially for patients who are seriously committed to using these products during treatment. Patients appreciate receiving knowledgeable guidance from their oncology team, especially when they have been receiving conflicting information.
Initial patient screening for possible interactions can be accomplished by a midlevel provider with appropriate training. For patients who want a treatment plan using complementary and alternative medicine therapies, a competent integrative oncology service is strongly recommended.
For the future, as we advance our knowledge with new research, it is possible that dietary and botanical antioxidants will find a place in conventional oncology care. ■
Dr. Labriola is Director, Northwest Natural Health Specialty Care Clinic, and Medical Director, Naturopathic Services, Swedish Cancer Institute, Swedish Medical Center, Seattle. Dr. Livingston is Professor of Medicine and Hematology, University of Arizona Cancer Center, Tucson.
Disclosure: Drs. Livingston and Labriola reported no potential conflicts of interest.
1. Lariviere D: Nutritional supplements flexing muscles as growth industry. Forbes, April 2013. Available at www.forbes.com. Accessed June 30, 2014.
2. Erhola M, Kellokumpu-Lehtinen P, Metsa-Ketela T, et al: Effect of anthracycline-based chemotherapy on total plasma antioxidant capacity in small-cell lung cancer patients. Free Radic Biol Med 21:383-390, 1996.
3. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst 90:1205-1211, 1998.
4. Ladas EJ, Jacobson JS, Kennedy DD, et al: Antioxidants and cancer therapy: A systematic review. J Clin Oncol 22:517-528, 2004.
5. Bairati I, Meyer F, Gélinas M, et al: Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J Clin Oncol 23:5805-5813, 2005.
6. Meyer F, Bairati I, Fortin A, et al: Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: A randomized trial among head and neck cancer patients. Int J Cancer 122:1679-1683, 2008.
7. Labriola D, Livingston R: Possible interactions between dietary antioxidants and chemotherapy. Oncology (Williston Park) 13:1003-1008, 1999.
8. Memorial Sloan Kettering Cancer Center: Integrative Medicine. Available at www.mskcc.org/cancer-care/integrative-medicine. Accessed June 30, 2014.
9. Cassileth B: Survivorship: Living Well During and After Cancer. Ann Arbor, Michigan, Spry Publishing, 2014.
10. Labriola D: Complementary Cancer Therapies. New York, Three Rivers Press, 2000.
11. Integrating conventional and naturopathic medicine. Swedish Medical Center Update, March 2011. Available at www.nwnaturalhealth.com/holmstrom-article.pdf. Accessed June 30, 2014.
Integrative Oncology is guest edited by 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.
The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 269 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.
In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http://itunes.apple.com/us/app/about-herbs/id554267162?mt=8.