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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
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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
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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
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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)
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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)
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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. Integrative Cancer Therapies,
2013; 12(1): 7-24.
(19) Mason P. Dietary supplements fourth edition. Pharmaceutical Press; 2012. p11-12
(20) Michaud LB, Karpinski JP, Jones KL et al. Dietary supplements in patients with cancer: Risks
and key concepts, part 2. Am J Health-Syst Pharm 2007; 64:467-480
(21) Duffy C, Perez K, Patridge A. Implications of phytoestrogen intake for breast cancer. CA
Cancer J Clin 2007; 57:260-277
(22) Lemos ML. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann
Pharmacother 2001; 35:1118-1121
(23) Ernst E. Complementary and alternative therapies for cancer. 2016, UpToDate. Accessed on
26.05.16 via http://www.uptodate.com
(24) AK Goey, JH Beijnen, JH Schellens. Herb-drug interactions in oncology. Clinical pharmacology
and therapeutics, 2014; Vol 95, no 4:354-5
Available through NICE Evidence Search at www.evidence.nhs.uk
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(25) SL Brooks et al. 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
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