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Medicines Q&As Q&A 420.2 Are there any complementary and alternative medicines that should be avoided in patients on cancer chemotherapy? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at https://www.sps.nhs.uk/articles/about-ukmi-medicinesqas/ Date prepared: 13 June 2016 Background The use of complementary therapies and alternative medicines (CAMs) has become increasingly popular in patients on cancer chemotherapy (1, 2, 3). They are used for many reasons which include relieving adverse effects of chemotherapy, relieving symptoms not addressed by conventional treatments or for presumed anti-tumour activity (1, 4). CAMs are often considered to be safe because they are natural (4). Many CAMs do not have to comply with medicine legislation and reach the market as unlicensed products. As a result, the content and relative safety of many CAMs is unpredictable, unless they are manufactured by an established company (2, 5). In addition, the lack of well-designed safety and efficacy studies means that there is limited awareness of adverse effects and interactions that may occur with conventional drugs (1, 2). This Q&A focuses on CAMs with pharmacological activity such as herbal medicines, vitamins and minerals. It summarises information from current literature regarding the common characteristics of CAMs that clinicians need to consider when using together with cancer chemotherapy and includes recommendations on commonly used CAMs. A review of all CAMs is beyond the scope of this Q&A, it is intended as a guide only and is not intended to be exhaustive. Answer There is currently limited evidence on the use of CAMs as adjuncts to conventional treatment (6, 7, 8). In most cases, the effect of CAMs on cancer chemotherapy is not known (2). Even for the most frequently used herbal drugs, dedicated interactions studies are sparse, making evidence-based decisions difficult. Moreover, where published evidence exists for a given herbal brand, generalisation to other brands may not be possible, due to the potential variability in the quality and quantity of active ingredients between brands (and even between batches). The absence of reports does not necessarily indicate the absence of an interaction (9). Clinical practice guidelines are being produced by the American Society for Integrative Oncology (SIO, http://www.integrativeonc.org/) to inform clinicians and patients about the evidence supporting or discouraging the use of specific CAMs during cancer treatment (3), but there are currently no UK guidelines available for CAMs used alongside prescribed cancer chemotherapy medicines. Understanding the common characteristics of CAMs can help patients and clinicians make informed decisions when safety and efficacy data are lacking. The following are some of the characteristics of CAMs that should be considered in patients on cancer chemotherapy. Antioxidants Many CAMs have antioxidant properties. These include the vitamins A, C and E, coenzyme Q10, garlic, gingko and green tea (7, 10). Several review articles (13-18) discuss the conflicting hypotheses on the potential benefits and potential adverse effects of using antioxidants in patients on cancer chemotherapy. There is currently limited evidence to support either argument (10). One hypothesis exists where antioxidants help to reduce toxicity and adverse effects by protecting normal cells against the effects of chemotherapy. This has been shown in vitro and in vivo (10, 15). Moreover, antioxidants have been claimed to increase the effectiveness of cytotoxic treatment and have direct cytotoxic effects at higher doses (15, 16, 17). However, others argue that antioxidants interfere with the mechanism of action of chemotherapy agents and may protect cancer cells from the effects cytotoxic therapy (6, 10, 13, 15, 17). Available through NICE Evidence Search at www.evidence.nhs.uk 1 Medicines Q&As Antioxidants help to neutralise reactive oxidative species (ROS), a type of free radical, which are constantly being produced in the body (14, 19). The presence of excessive amounts of ROS leads to oxidative stress, which can severely damage DNA, proteins and lipids and may lead to cell injury and cell death (10, 19). Many anticancer agents rely on the actions of ROS for antitumour activity. Examples of agents that rely on ROS are shown in table 1 (6, 10, 13). It is important to note that most chemotherapy agents have several mechanisms of action. The ability to generate free radicals not only depends on the dose, but also on the localisation and metabolism of the anticancer drug within specific tissues (13). Not all antioxidants can be anticipated to have the same effect on cancer chemotherapy. Moreover the same antioxidant cannot be viewed as having the same effect on different cancer chemotherapies. The effect of antioxidants will depend on characteristics such as strong nucleophilic properties, molecular weight, and, for some, the effect may also be dose-dependent (14, 17). More research is required before recommendations can be made for specific antioxidants to be used as adjuncts to chemotherapy (10, 14, 17). Therefore, it is best to discourage use of CAMs that have strong antioxidant properties unless there is strong evidence to suggest otherwise. Table 1. Examples of chemotherapy agents: the reliance on ROS for antitumour activity. Adapted from (6) and (13) Agents that may rely on ROS Alkylating agents (e.g. cyclophosphamide, melphalan, chlorambucil) Anthracyclines (e.g. doxorubicin, epirubicin) Epipodophyllotoxins (e.g. etoposide) Platinum compounds (e.g. cisplatin, carboplatin) Camptothecins (e.g. irinotecan) Agents that do not seem to rely on ROS Antimetabolites (e.g. methotrexate, fluorouracil, cytarabine) Vinca alkaloids (e.g. vincristine, vinblastine) Taxanes (e.g. paclitaxel, docetaxel) Hormonal agents (e.g. tamoxifen) Anticoagulant effects Many cancer patients are at an increased risk of bleeding or thromboembolism either from side effects of chemotherapy, treatment associated with the cancer (including surgery) or from the tumour itself (10). It is important to assess the anticoagulant effects of CAMs when used in cancer patients. CAMs known to have these effects include vitamin C, garlic, ginger, gingko and saw palmetto (6, 10, 11, 12). CAMs that affect the coagulation pathway should therefore be avoided in cancer patients (10). For information on when to stop herbal medicines in patients having surgery, see Q&A 368.2 How should herbal medicines be managed in patients undergoing surgery? https://www.sps.nhs.uk/articles/how-should-herbal-medicines-be-managed-in-patients-undergoingsurgery/ Hormonal effects of phytoestrogens Certain cancers of the breast, endometrium, ovaries and prostate are heavily influenced by the effects of hormones. The hormonal effects of CAMs should be taken into consideration in these patients as they may directly affect cancer cells, or may interact with conventional hormonal therapies (20). A review of all CAMs with hormonal effects is beyond the scope of this Q&A. For further information see Michaud et al (20). This Q&A will focus upon the use of phytoestrogens in breast cancer. Phytoestrogens are the largest group of CAMs taken by breast, endometrial and ovarian cancer patients as “natural” hormone replacement therapy and to help with relief of menopausal symptoms associated with chemotherapy/hormonal therapy (7, 20). Sources of phytoestrogen include flaxseed, alfalfa, clover and soy (7, 20). There are two main types of phytoestrogens: lignans and isoflavones. Flaxseeds are the greatest single dietary source of lignans. There is limited evidence on the role of lignans in patients with breast cancer (21). Genistein and daidzein are the two main isoflavones and are found in soy products (21). There are conflicting data on the use of isoflavones in breast cancer. Four randomised placebo controlled trials investigating the use of isoflavones in breast cancer survivors found no significant improvement for hot flash menopausal symptoms (21). Moreover, in vitro and in vivo animal studies suggest that low doses of genistein and daidzein may stimulate the growth of breast tumours and interfere with the Available through NICE Evidence Search at www.evidence.nhs.uk 2 Medicines Q&As antiproliferative activity of tamoxifen in oestrogen receptor positive breast cancer. In contrast, high doses of genistein may enhance the effects of tamoxifen and have inhibitory effects on breast tumour growth, possibly due to anti-cancer effects of phytoestrogens not related to hormonal activity (22). It should be noted that isoflavones also possess antioxidant properties and inhibit platelet aggregation (6). The use of phytoestrogens in cancer patients is controversial. The nature of the relationship between phytoestrogens and breast cancer depends on several factors, e.g. timing of exposure, source of phytoestrogen (food or supplement) and dose, oestrogen status of the patient (pre- or postmenopausal) (21, 27). There is agreement that high dose isoflavone supplements should be avoided in women at high risk or in breast cancer survivors (21). In addition, because genistein has been shown to decrease the efficacy of tamoxifen, soya products should not be used with tamoxifen in patients with ER-positive breast cancer (11, 23). There is currently insufficient evidence to make further definitive recommendations on the use of phytoestrogen supplementation in women with breast cancer, but some authors advise that it would be prudent to discourage the use of phytoestrogen supplements in these patients (6, 17, 21, 27). Pharmacokinetic interactions CAMs may have pharmacokinetic (PK) interactions, which affect the absorption, distribution, metabolism and elimination of anticancer drugs (20, 23). The most well-known example is the effects on CYP450 enzymes and P-gp (P-glycoprotein) of St John’s Wort, the only herbal supplement known to have clinically significant effects on the PK of anticancer drugs to date (1, 20, 24, 9). Information on pharmacokinetic interactions can be found in many databases and from primary literature (20, 9, 25). Commonly used CAMs Table 2 lists eight common CAMs that should be avoided or used with caution in patients on cancer chemotherapy. Most of the evidence available is based on in vitro and in vivo animal studies, as clinical data in humans are lacking. More research is needed before definitive positive or negative recommendations can be made. Further information regarding CAMs and chemotherapy interactions are available on the Memorial Sloan Kettering Cancer Center website (https://www.mskcc.org/cancer-care/treatments/symptommanagement/integrative-medicine/herbs/search?keys=&letter) and through the Lexi-interact tool accessible via http://www.uptodate.com (subscription needed). Summary The effects of many complementary and alternative medicines (CAMs) in patients on cancer chemotherapy are not well documented due a lack of well-designed safety and efficacy studies. Understanding the common characteristics of CAMs can help patients and clinicians make informed decisions. This includes looking at whether the CAM is an antioxidant, has anticoagulant or hormonal effects, or is likely to have pharmacokinetic interactions with cancer chemotherapy. This Q&A discusses the following: i) CAMs with antioxidant properties, e.g. vitamins A, C and E and their potential interactions with chemotherapy drugs. ii) The hormonal effects of phytoestrogens and their use in patients with gynaecological cancers. iii) Examples of CAMs with anticoagulant effects and those with pharmacokinetic interactions with chemotherapy drugs. More research is needed before definitive recommendations can be made. In the meantime, clinicians should discuss the (lack of) evidence and any theoretical concerns they have with patients before coming to a decision. Available through NICE Evidence Search at www.evidence.nhs.uk 3 Medicines Q&As Table 2. CAMs that should be avoided or used with caution in patients on cancer chemotherapy CAM Echinacea Main Properties Enzyme inhibitor / inducer (9) Immunomodulatory effects (20) Intended use (27) Protection against bacterial and viral infections (e.g. common cold, influenza) Evidence Garlic Enzyme inhibitor / inducer (9, 27) Antiplatelet activity (6, 10, 12, 27) Antioxidant (10) Treatment of respiratory tract infections Cardiovascular disease May possess anticancer properties Gingko Ginseng Enzyme inducer /inhibitor (9) Antioxidant (10, 26) Platelet activating factor (PAF) antagonist (11, 12) Phytoestrogen (26) Antiplatelet (12, 26); however research in humans suggests that ginseng does not affect platelet aggregation (12) CYP inhibitor /inducer (12, 9) Cerebrovascular disorders Peripheral vascular disease Tinnitus Asthma Improve mental and physical performance Enhance the body’s resistance to stress Insomnia Sexual dysfunction Improve healing Suggested Management Preliminary studies have shown that echinacea may have some beneficial effects in reducing the adverse effects of chemotherapy, but studies of Echinacea species for treating cancer-related illness are limited (2, 20) Studies have shown Echinacea purpurea weakly inhibits CYP1A2, 2C9 and 2C19 (9, 27). Studies have suggested inhibition or induction of CYP3A4 which are likely to affect drugs that are a substrate of this enzyme (11, 26, 27). Anticancer effects shown in human cell lines (1) Studies have shown inhibition / induction of CYP enzymes (2C9, 2C19, 2D6, 3A4) and induction of PGlycoprotein. This is unlikely to significantly affect anticancer drugs (26, 27). One human study suggested garlic inhibited CYP2E1 over a 4-week period, but further study is required (26, 27). Current knowledge suggests that garlic does not cause relevant PK changes (9) The antioxidants effects of gingko may interfere with the ROS action of chemotherapy agents (26). Different studies have shown both inhibition and induction of CYP3A4, 2C19, 2C9 (9). Current knowledge suggests that ginkgo do not cause relevant PK changes (9) Three common preparations include Panax ginseng (Chinese), Panax quinquefolius (American) and Eleutherococcus senticosus (Siberian) (27). Some preparations have shown to have phytoestrogen and antiplatelet activity (26). Studies have found weak inhibitory effects on CYP3A4 (26, 27) Available through NICE Evidence Search at www.evidence.nhs.uk Avoid with camptothecins, cyclophosphamide, epidermal growth factor receptor tyrosinekinase (EGFR-TK) inhibitors, epipodophyllotoxins, taxanes and vinca alkaloids (CYP3A4 induction) (11, 26). Potential clinical relevance for drug interactions seems to be limited to non-oral routes of administration or drugs with considerable firstpass metabolism (9) Prolonged use in cancer patients should be avoided (20) Avoid with dacarbazine and other substrates of CYP 2E1 Caution with other concurrent chemotherapy (1, 26) Caution with anticancer drugs that are substrates of CYP2C9, 2C19 and 3A4 including camptothecins, cyclophosphamide, EGFR-TK inhibitors, epipodophyllotoxins, taxanes and vinca alkaloids (1, 11, 26,). Discourage use with drugs that rely on the action of ROS (26) Discourage use of products in patients with oestrogen dependant breast and endometrial cancers due to phytoestrogen properties (11, 23, 26) Caution with anticancer drugs that are CYP3A4 substrates including: cyclophosphamide, EGFR-TK inhibitors, epipodophyllotoxins, taxanes, vinca alkaloids and imatinib (11) 4 Medicines Q&As CAM Main Properties Intended use (27) Evidence Suggested Management Soy In vitro and in vivo animal studies suggest that low doses of genistein (a isoflavone phytoestrogen) may stimulate the growth of breast tumours and interfere with the antiproliferative activity of tamoxifen in oestrogen receptor positive breast cancer (21) High doses of genistein may enhance the effects of tamoxifen and have inhibitory effects on breast tumour growth (21) Genistein (an isoflavone phytoestrogen) modestly increased the area under the curve for oral and IV paclitaxel, in animal studies (27). Studies have shown cytotoxic effects against tumour cells (23) St Johns Wort is known to induce CYP3A4, 2C9 isoenzymes and p-glycoprotein (1, 9, 26, 27). Avoid with all concurrent chemotherapy (1, 9, 26, 27) A constituent of valerian has shown to have weak inhibitory effects on CYP2C9 and 2C19 (26, 27) Other sources suggest CYP2C9 inhibition and CYP2C19 induction instead (11, 23) Caution when using with CYP2C9 substrates (tamoxifen) and CYP2C19 substrates (cyclophosphamide, etoposide, teniposide) (11, 23, 26) Studies have shown that cancer cells uptake more vitamin C than neighbouring cells suggesting vitamin C may protect cancer cells against oxidative damage from chemotherapy. Data exists showing that large amounts of vitamin C have pro-oxidant effects that may interfere with standard therapies (15, 17). Two randomised controlled trials failed to show any benefit with high dose vitamin C in cancer (6). To date, at least four phase I trials have been conducted to evaluate high dose IV vitamin C in patients with advanced cancer and no trial has adequately addressed antitumour efficacy (23) Leukaemia and lymphoma cell line studies suggest pretreatment with vitamin C reduces the cytotoxicity of doxorubicin, cisplatin, vincristine, methotrexate, and imatinib (28). Vitamin C may potentially affect antitumour activity of chemotherapy, including bortezomib (23). Discourage the use of vitamin C supplements in patients on chemotherapy that may interact with antioxidants. This is due to inconclusive safety data (10) Avoid vitamin C supplements in patients taking bortezomib (23) Discourage use of high dose vitamin C due to lack of evidence on efficacy (6) Phytoestrogen (26) Anticoagulant effects: Inhibits platelet aggregation (6) Antioxidant (6) Menopausal symptoms Hyperlipidaemia Osteoporosis Prevention of cancer (e.g. breast) St John’s Wort Enzyme inducer (9) Depression Valerian Vitamin C Enzyme inhibitor/inductor (11, 26, 27) Antioxidant (10) Anticoagulant effects: Inhibition of platelet aggregation, increased fibrinolytic activity Hysterical states and excitability Insomnia Used for its antioxidant properties to treat and prevent tumours (15) Available through NICE Evidence Search at www.evidence.nhs.uk Discourage the use of soy products in patients with oestrogen dependant breast and endometrial cancers, especially in patients on tamoxifen (5, 11, 17, 27) Use high doses with caution in patients on paclitaxel (27) 5 Medicines Q&As Limitations There is a lack of published evidence on the safety of CAMs in patients on cancer chemotherapy. The list of CAMs included in this review is not exhaustive. Absence from this Q&A does not imply that a CAM is safe to use in patients on cancer chemotherapy. References (1) Yap KY, See CS, Chan A. Clinically-relevant chemotherapy interactions with complementary and alternative medicines in patients with cancer. Recent Patents on Food, Nutrition and Agriculture 2010; 2: 12-55. (2) Barnes J, Anderson LA, Phillipson JD. Herbal medicines. Pharmaceutical Press: London. Accessed online at www.medicinescomplete.com on 12.05.16 (3) H Greenlee at al. Clinical Practice Guidelines on the use of integrative therapies as Supportive care in patients treated for breast cancer. Journal of the National Cancer Institute Monographs, 2014; 50 :346-58 (4) Tascilar M, Dejong FA, Verweij J et al. Complementary and alternative medicine during cancer treatment: beyond innocence. The Oncologist 2006; 11:732-741 (5) https://www.gov.uk/guidance/apply-for-a-traditional-herbal-registration-thr accessed on 27.05.16 (6) Weiger WA, Smith M, Boon H et al. Advising patients who seek complementary and alternative medical therapies for cancer. Ann Intern Med. 2002; 137:889-903 (7) Werneke U. A guide to using complementary alternative medicines in cancer. Nursing Times 2005; 5:32-35 (8) L Almog et al. Bridging cross-cultural gaps: monitoring herbal use during chemotherapy in patients referred to integrative medicine consultation in Israel. Support Care Cancer, 2014; 22: 2793-804 (9) Haefeli WE, Carls A. Drug interactions with phytotherapeutics in oncology. Expert Opinion on Drug Metabolism & Toxicology, 2014; 10:3, 359-77 (10) Michaud LB, Karpinski JP, Jones KL et al. Dietary supplements in patients with cancer: Risks and key concepts, part 1. Am J Health-Syst Pharm 2007; 64:369-381 (11) D Arslan, D Tural, E Akar. Herbal administration and interaction of cancer treatment. Journal of Palliative Medicine, 2013; Vol. 16, No 11: 1466-76 (12) E Ben-Arye et al. Potential risks associated with traditional herbal medicine use in cancer care: a study of middle eastern oncology health care professionals. Cancer, 2016; 122:598-610 (13) Block KI, Koch AC, Mead MN et al. Impact of antioxidant supplementation on chemotherapeutic efficacy: A systematic review of the evidence from randomized controlled trials. Cancer Treat Rev 2007; 33(5): 407-418 (14) Conklin KA. Cancer chemotherapy and antioxidants. J Nutr 2004; 134: 3201S-3204S (15) D’Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J Clin 2005; 55:319-321 (16) Whiteside MA, Heimburger DC, Johanning GL. Micronutrients and cancer therapy. Nutrition Rev. 2004; 62: 142-147 (17) Norman HA, Butrum RR, Feldman et al. The role of dietary supplements during cancer therapy. J Nutr 2003; 133:3794S-3799S (18) H Fritz et al. Green tea and lung cancer: a systematic review. 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A case of delayed methotrexate clearance following administration of a complementary medication containing chlorophyll. Journal of Oncology Pharmacy Practice, 2014; Vol 20(3): 225-8 (26) Sparreboom A, Cox MC, Acharya MR et al. Herbal remedies in the United States: Potential adverse interactions with anticancer agents. J Clin Oncol 2004; 22:2489-2503. (27) Williamson E, Driver S, Baxter K (Ed). Stockley's Herbal Medicines Interactions. London: Pharmaceutical Press. Accessed online at www.medicinescomplete.com on 26.05.16 (28) Heaney ML, Gardner JR, Karasavvas N et al. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res. 2008; 68(19):8031-8038 Quality Assurance Prepared by Simona Perano, South West Medicines information and Training, Bristol Date Prepared 13 June 2016 Checked by Julia Kuczynska, South West Medicines information and Training, Bristol Date of check 23rd August 2016 Search strategy Embase: [“exp DIET SUPPLEMENTATION” and “exp CANCER CHEMOTHERAPY”] or [“exp HERBAL MEDICINES” and “exp CANCER CHEMOTHERAPY”] and [“exp DRUG INTERACTION” or “exp DRUG SAFETY” or “exp TOXICITY” or “FOOD DRUG INTERACTION”] limit to “2013-2016”. Date of search 13/05/16 Medline: “exp ANTINEOPLASTIC AGENTS’’ and “exp COMPLEMENTARY THERAPIES’’ and “exp DRUG INTERACTIONS’’ limit to ‘’2013-2016’’Date of search 13/05/16 PubMed: ‘’exp ANTINEOPLASTIC AGENTS’’ and ‘’exp COMPLEMENTARY THERAPIES’’ and ‘’exp DRUG INTERACTIONS’’ and ‘’2013/01/01:2016/12/31’’. Date of search 11/02/16 NHS evidence: HERBAL MEDICINES and CANCER CHEMOTHERAPY, ANTIOXIDANTS and CANCER CHEMOTHERAPY. Date of search 01/12/15 Internet Search: (Google Search: HERBAL MEDICINES and CANCER CHEMOTHERAPY, ANTIOXIDANTS and CANCER CHEMOTHERAPY). Date of search 19/05/16 Cochrane Library: CANCER CHEMOTHERAPY and HERBAL MEDICINES, COMPLEMENTARY THERAPIES. Date of search 26/05/16 NICE and SIGN guidelines: CANCER CHEMOTHERAPY and HERBAL MEDICINES, COMPLEMENTARY THERAPIES. Date of search 26/05/16 Available through NICE Evidence Search at www.evidence.nhs.uk 7