Download Are there any complementary and alternative medicines that should

Medicines Q&As
Q&A 420.1
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 www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 19th July 2013
Background
The use of complementary therapies and alternative medicines (CAMs) has become increasingly
popular in patients on cancer chemotherapy (1, 2). 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, 3). CAMs are often considered to be safe because
they are natural (3). Many CAMs, such as herbal medicines, do not have to comply with medicine
legislation and reach the market as unlicensed products. As a result, the content and relative safety
of most CAMs is unpredictable, unless they are manufactured by an established company (2, 4). 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 (5, 6).
In most cases, the effect of CAMs on cancer chemotherapy is not known (2). There are also no
national guidelines available for CAMs used alongside prescribed medicines. Therefore,
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 (6, 7). Several review articles (8-12) 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 (7).
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 by in vitro and in vivo (7, 10).
Moreover, antioxidants have been claimed to increase the effectiveness of cytotoxic treatment and
have direct cytotoxic effects at higher doses (10,11,12). However, others argue that antioxidants
interfere with the mechanism of action of chemotherapy agents and may protect cancer cells from the
effects cytotoxic therapy (5, 7, 8,10,12).
Antioxidants help to neutralise reactive oxidative species (ROS), a type of free radical, which are
constantly being produced in the body (9, 13). 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 (7, 13). Many anticancer agents rely on the actions of ROS for antitumour activity.
Examples of agents that rely on ROS are shown in table 1 (5, 7, 8). 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 (8).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
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 (9,12). More
research is required before recommendations can be made for specific antioxidants to be used as
adjuncts to chemotherapy (7, 9, 12). Therefore, it is best to discourage use of CAMs that have strong
antioxidant properties unless there is strong evidence to suggest otherwise.
Table 1. Chemotherapy agents: The reliance on ROS for antitumour activity. Adapted from
“Advising patients who seek complementary and alternative medical therapies for cancer”
(5)






Agents that may rely on ROS
Alkylating agents (e.g. cyclophosphamide,
melphelan, chlorambucil)
Anthracyclines (e.g. doxorubicin, epirubicin)
Epipodophyllotoxins (e.g. etoposide)
Platinum analogues (e.g. cisplatin, carboplatin)
Antitumour antibiotics (e.g. mitomycin C,
bleomycin)
Camptothecins (e.g. irinotecan)
Agents that do not seem to rely on ROS

Antimetabolites (e.g. methotrexate,
fluorouracil, cytarabine)

Vinca alkaloids (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 or from the tumour itself (7). 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 (5,7). They should be
avoided in patients who have thrombocytopenia, are on medicines with anticoagulant effects or are in
the peri-operative period. For information on when to stop herbal medicines in patients having
surgery, see Q&A 368.1 How should herbal medicines be managed in patients undergoing surgery?
https://www.evidence.nhs.uk/search?q=how+should+herbal+medicines+be+managed+in+patients+un
dergoing++surgery
Hormonal effects
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 (14). A
review of all CAMs with hormonal effects is beyond the scope of this Q&A. For further information see
Michaud et al (14). 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 (6, 14). Sources of phytoestrogen include flaxseed,
alfalfa, clover and soy (6, 14). 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.
Genistein and daidzein are the two main isoflavones and are found in soy products (15).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 (15). 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
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 (16). It
should be noted that isoflavones also possess antioxidant properties and inhibit platelet aggregation
(5).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
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) (15). But there is agreement that high dose isoflavone
supplements should be avoided in women at high risk or in breast cancer survivors (15). There is
currently insufficient evidence to make definitive recommendations on the use of phytoestrogen
supplementation in women with breast cancer. It would be prudent to discourage the use of
phytoestrogen supplements in these patients (5,12,15).
Pharmacokinetic interactions
CAMs may have pharmacokinetic interactions which affect the absorption, distribution, metabolism
and elimination of anticancer drugs (14, 17). The most well-known example is the effects of St Johns
Wort on CYP450 enzymes (1, 14). Information on pharmacokinetic interactions can be found in many
databases and from primary literature (14).
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.
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, 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
Garlic
Main Properties (17,18)




Gingko



Ginseng



Enzyme inhibitor /
inducer
Common uses (19)

Enzyme inhibitor /
inducer
Anticoagulant effects:
Inhibit platelet
aggregation
Antioxidant

Enzyme inducer
/inhibitor
Free-radical
scavenging
(antioxidant)
Anticoagulant effects:
Inhibit platelet
aggregation

Phytoestrogen
Antiplatelet
CYP inhibitor










Protection against
bacterial and viral
infections (e.g.
common cold,
influenza)
Treatment of
respiratory tract
infections
Cardiovascular
disease
May possess
anticancer
properties
Cerebrovascular
disorders
Peripheral vascular
disease
Tinnitus
Asthma
Improve mental and
physical
performance
Enhance the body’s
resistance to stress
Insomnia
Sexual dysfunction
Improve healing
Evidence








Suggested Management
Shown to reduce adverse effects of cancer
chemotherapy (2)
Studies have shown echinacea purpurea weakly
inhibits CYP1A2, 2C9 and 2C19 (19).
Studies have suggested inhibition or induction of
CYP3A4 which are likely to affect drugs that are a
substrate of this enzyme (18,19).

Avoid with camptothecins,
cyclophosphamide, epidermal growth
factor receptor tyrosine-kinase (EGFR-TK)
inhibitors, epipodophyllotoxins, taxanes
and vinca alkaloids (CYP3A4 induction)
(18).
Anticancer effects shown in human cell lines (1)
Studies have shown inhibition / induction of CYP
enzymes (2C9, 2C19, 2D6, 3A4) and induction of
P-Glycoprotein. This is unlikely to significantly
affect anticancer drugs (18,19).
One human study suggested garlic inhibited
CYP2E1 over a 4 week period (18,19).

Avoid with dacarbazine and other
substrates of CYP 2E1
Caution with other concurrent
chemotherapy (1,18)
The antioxidants effects of gingko may interfere
with the ROS action of chemotherapy agents (18).
Studies have shown it inhibits CYP3A4 and
induces 2C19, 2C9 (1, 18, 19).






Three common preparations include panax
(Chinese), panax quynquefolius (American) and
eleutherococcus senticosus (Siberian) (19).
Some preparations have shown to have
phytoestrogen and antiplatelet activity (18).
Studies have found weak inhibitory effects on
CYP3A4 (18,19)
Available through NICE Evidence Search at www.evidence.nhs.uk


Caution with anticancer drugs that are
substrates of CYP2C9, 2C19 and 3A4
including camptothecins,
cyclophosphamide, EGFR-TK inhibitors,
epipodophyllotoxins, taxanes and vinca
alkaloids (1,18).
Discourage use with drugs that rely on the
action of ROS (18)
Discourage use of products in patients
with oestrogen dependant breast and
endometrial cancers due to phytoestrogen
properties (17,18)
Caution with anticancer drugs that are
CYP3A4 substrates including:
cyclophosphamide, EGFR-TK inhibitors,
epipodophyllotoxins, taxanes, vinca
alkaloids and imatinib
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Medicines Q&As
CAM
Main Properties (17,18)
Common uses (19)
Evidence
Suggested Management
Soy




In vivo and in vitro 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 (15)
High doses of genistein may enhance the effects
of tamoxifen and have inhibitory effects on breast
tumour growth (15)
Genistein (an isoflavone phytoestrogen) modestly
increased the area under the curve for oral and IV
paclitaxel, in animal studies (19).

Studies have shown cytotoxic effects against
tumour cells (17)
St Johns Wort is known to induce CYP3A4, 2C9
isoenzymes and p-glycoprotein (1, 18, 19).

Avoid with all concurrent chemotherapy
(1, 18, 19)

Phytoestrogen
Anticoagulant effects:
Inhibits platelet
aggregation (5)
Antioxidant (5)



Menopausal
symptoms
Hyperlipidaemia
osteoporosis
Prevention of cancer
(e.g. breast)


St Johns
Wort

Enzyme inducer

Depression



Discourage the use of soy products in
patients with oestrogen dependant breast
and endometrial cancers, especially in
patients on tamoxifen (5, 12, 19)
Use high doses with caution in patients
on paclitaxel (19)
Valerian

Enzyme inhibitor


Anxiety and stress
Insomnia

A constituent of valerian has shown to have weak
inhibitory effects on CYP2C9 and 2C19 (18, 19)

Caution when using with CYP2C9
substrates (tamoxifen) and CYP2C19
substrates (cyclophosphamide,
teniposide) (18)
Vitamin C


Antioxidant
Anticoagulant effects:
inhibits platelet
aggregation, increased
fibrinolytic activity

Used for its
antioxidant
properties to treat
and prevent tumours
(10)

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 (10, 12).
Two randomised controlled trial failed to show any
benefit with high dose vitamin C in cancer (5)
Leukaemia and lymphoma cell line studies suggest
pre-treatment with vitamin C reduces the
cytotoxicity of doxorubicin, cisplatin, vincristine,
methotrexate, and imatinib (20).
Vitamin C may potentially affect antitumour activity
of chemotherapy, including bortezomib (17).

Discourage the use of vitamin C
supplements in patients on chemotherapy
that may interact with antioxidants. This
is due to inconclusive safety data (7)
Avoid in patients on Bortezomib (17)
Discourage use of high dose vitamin C
due to lack of evidence on efficacy (5)



Available through NICE Evidence Search at www.evidence.nhs.uk


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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 12.05.13
(3) Tascilar M, Dejong FA, Verweij J et al. Complementary and alternative medicine during cancer
treatment: beyond innocence. The Oncologist 2006; 11:732-741
(4) http://www.mhra.gov.uk/Howweregulate/Medicines/Herbalmedicinesregulation/index.htm
and
http://www.mhra.gov.uk/Howweregulate/Medicines/Herbalmedicinesregulation/Licensedherbalmedicin
es/index.htm
and
http://www.mhra.gov.uk/Howweregulate/Medicines/Herbalmedicinesregulation/RegisteredTraditionalH
erbalMedicines/HowtoregisteryourproductundertheTraditionalHerbalMedicinesRegistrationScheme/Tr
aditionaluse/index.htm
accessed on 20.05.13
(5) 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
(6) Werneke U. A guide to using complementary alternative medicines in cancer. Nursing Times
2005; 5:32-35
(7) 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
(8) 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
(9) Conklin KA. Cancer chemotherapy and antioxidants. J Nutr 2004; 134: 3201S-3204S
(10) D’Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided.
CA Cancer J Clin 2005; 55:319-321
(11) Robinson NG. The Good, Bad and Uncertain: Combining Antioxidants and Chemotherapy.
2007. Accessed online
http://csuvets.colostate.edu/pain/Articlespdf/ChemotherapyandAntioxidantsTheGoodBadandUncertain
082106.pdf on 25.05.13
(12) Norman HA, Butrum RR, Feldman et al. The role of dietary supplements during cancer therapy.
J Nutr 2003; 133:3794S-3799S
(13) Mason P. Dietary supplements fourth edition. Pharmaceutical Press; 2012. p11-12
(14) 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
(15) Duffy C, Perez K, Patridge A. Implications of phytoestrogen intake for breast cancer. CA
Cancer J Clin 2007; 57:260-277
(16) Lemos ML. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann
Pharmacother 2001; 35:1118-1121
(17) Ernst E. Complementary and alternative therapies for cancer. 2013, UpToDate. Accessed on
26.04.13 via http://www.uptodateonline.com
(18)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.
(19) Williamson E, Driver S, Baxter K (Ed). Stockley's Herbal Medicines Interactions. London:
Pharmaceutical Press. Accessed online at www.medicinescomplete.com on 28.06.13
(20) Heaney ML, Gardner JR, Karasavvas N et al. Vitamin C antagonizes the cytotoxic effects of
antineoplastic drugs. Cancer Res. 2008; 68(19):8031-8038
Available through NICE Evidence Search at www.evidence.nhs.uk
6
Medicines Q&As
Quality Assurance
Prepared by
Richard Leung, South West Medicines information and Training, Bristol
Date Prepared
19th July 2013
Checked by
Julia Kuczynska, South West Medicines information and Training, Bristol
Date of check
24th July 2013
Search strategy
Embase: [exp DIET SUPPLEMENTATION] and [exp CANCER CHEMOTHERAPY], [exp HERBAL
MEDICINE] and [exp CANCER CHEMOTHERAPY]
Medline: [exp ANTINEOPLASTIC AGENTS] and [exp COMPLEMENTARY THERAPIES] and [exp
DRUG INTERACTIONS]
NHS evidence: HERBAL MEDICINES and CANCER CHEMOTHERAPY, ANTIOXIDANTS and
CANCER CHEMOTHERAPY
Internet Search: (Google Search: HERBAL MEDICINES and CANCER CHEMOTHERAPY,
ANTIOXIDANTS and CANCER CHEMOTHERAPY)
Cochrane Library: CANCER CHEMOTHERAPY and HERBAL MEDICINES, COMPLEMENTARY
THERAPIES
NICE and SIGN guidelines: CANCER CHEMOTHERAPY and HERBAL MEDICINES,
COMPLEMENTARY THERAPIES
Available through NICE Evidence Search at www.evidence.nhs.uk
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