REVIEW ARTICLE

EVIDENCE-BASED MANAGEMENT OF HERB-DRUG INTERACTION

IN CANCER CHEMOTHERAPY
Chung-Wah Cheng, Mphil,1 Wing Fan, Mphil,1 Seong-Gyu Ko, MD, PhD, MPH,2 Lisa Song, MSc, MLib,3 and
Zhao-Xiang Bian, PhD1#

The fact that many cancer patients take herbal medicine,

including Chinese herbal medicine, together with chemotherapy is well known. The potential for side effects resulting
from concurrent use of these two different treatment modalities requires physicians to be aware of the potential risks and
benefits that might arise. This study searched available evidence for herb-drug interaction in cancer therapy and identified 168 articles. Little direct evidence for such interaction
could be found, whereas there is some indirect evidence for
benefit. Hence, most of the concern about herb-drug interaction in chemotherapy appears to be theoretical. To resolve
this discrepancy, evidence-based studies should be under-

taken to document the positive and/or negative effects of the

concomitant use of herbs with anticancer chemotherapeutic
drugs. As evidence accumulates, it would be helpful to set up
an internationally accessible database to document the use of
Chinese medicine herbs with anticancer drugs. Once this
information is collected, efforts should be made to educate
health care professionals and patients about the use of Chinese herbal medicine together with Western drugs in treating
cancer.

INTRODUCTION
An increasing tendency for the use of herbal remedies as one
kind of complementary and alternative medicine (CAM) is documented in the population,1-4 and it is especially strong among
cancer patients.5,6 A study describing the prevalence of CAM
use in patients enrolled in early-phase chemotherapy trials
showed that more than 80% of patients simultaneously used
CAM with their experimental chemotherapeutic agents.7 In another survey, 77% of 453 cancer patients took herbs and vitamins together with conventional treatment, that is, chemotherapy, radiation, or surgery.8 A recent survey showed 37% and
38% concurrent use of herbal remedies among patients also
taking palliative chemotherapy and curative chemotherapy, respectively.9 Our research team conducted a survey in cancer
patients in Hong Kong and found that 53.9% of 786 (424/786)
took Chinese herbal medicine.10 These reports show that many
cancer patients take herbal medicines together with chemotherapeutic agents.
Drug-drug interaction occurs when drugs used in combination produce a clinical or pharmacologic response that is different from the effects that are expected when the drugs are admin-

istered individually. The greater the number of drugs involved,

the greater the potential for drug-drug interaction. These interactions can be categorized as pharmaceutical, pharmacokinetic,
or pharmacodynamic.11 Although drug interaction has been
shown to provide clinical benefit as well, the term drug-drug
interaction usually has a negative connotation arising from an
often reported increase in toxicity or loss of therapeutic activity.12-14 Because of frequent use of herbal medicine, especially
among cancer patients, the concern for potential herb-drug interaction has arisen and is receiving increasing attention.15-20
Herbs are usually complex mixtures of many molecular entities.
These entities, which may be active or inactive, can interact with
chemotherapy drugs, with positive or negative effects. For example, Saint-Johns-wort, a well-known cytochrome P450 inducer,
may affect systemic bioavailability of many conventional
drugs.20 But the discussions around this topic have not resolved
the controversy as to whether or not herbal medicines should be
taken or can be recommended to be taken during conventional cancer treatment, especially chemotherapy.
This article reviewed available evidence on herb-drug interactions and evaluated research data to offer guidance for both
doctors and patients in the concomitant use of herbs with chemotherapy in the treatment of cancer. Herb was defined in this
review as follows: (1) raw medicinal herbal plants that could be
used in humans in single or mixed formulation, and (2) natural
products original from medical herbal plants.

1 School of Chinese Medicine, Hong Kong Baptist University, Kowloon

Tong, Hong Kong, China
2 Department of Preventive Medicine, College of Korean Medicine,
Kyunghee University, Seoul, Korea
3 Chinese Medicine Library, Hong Kong Baptist University, Kowloon
Tong, Hong Kong, China
# Corresponding Author. Address:
School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong,
Hong Kong, China
E-mail: bzxiang@hkbu.edu.hk

324

2010 Elsevier Inc. All rights reserved.

ISSN 1550-8307/$36.00

Key words: Chinese herbal medicine, cancer, chemotherapy,

interaction
(Explore 2010; 6:324-329. 2010 Elsevier Inc. All rights reserved.)

METHODS
Literature Search
All reports that describe (or might describe) herb-drug interactions were obtained by searching the following electronic data-

EXPLORE September/October 2010, Vol. 6, No. 5

doi:10.1016/j.explore.2010.06.004

bases in November 2009: Ovid OLDMEDLINE, Ovid MEDLINE, Excerpta Medica Database (EMBASE), Cochrane
Database of Systematic Reviews (CDSR), ACP Journal Club,
Database of Abstracts of Reviews of Effects (DARE), Cochrane
Central Register of Controlled Trials (CCTR), Health Technology Assessment (CLHTA), NHS Economic Evaluation Database (CLEED). The search strategy, using the following terms,
resulted in 168 articles after 15 duplicates were removed: herbdrug interactions, food-drug interactions, drug-plant interactions, neoplasms or cancer, or tumor or carcinoma, and chemotherapy. Titles and abstracts were screened to identify those
eligible for review. Of the 168 articles, only 26 were found to be
related to herb-drug interaction in cancer chemotherapy, and
142 articles were unrelated. Of those 26 articles, one involved
clinical practice guidelines, two were editorials, one was a research letter, one was a research article on cell lines, six were
epidemiological studies about herb-drug use, and 15 were review
articles. The major contents of these articles are summarized
below.

Clinical practice guidelines. The single paper on herb-drug interactions in clinical practice guidelines was from the American
College of Chest Physicians.21 Their comments about herb-drug
interactions were general, not specific, and in some sense, theoretical. These guidelines advise physicians to evaluate evidence
in terms of risk-to-benefit ratio. The guidelines suggested that
potential interactions of herbal medicines with chemotherapy
and other medications should be evaluated, and those likely to
cause negative side effects should not be used during chemotherapy. The potential for therapeutic enhancement, that is, positive
side effects, was not expressly mentioned.
Editorial/review papers. One editorial paper was published in
Oncology22 and the other one in MedGenMed: Medscape General
Medicine.23 The paper published in Oncology pointed out that
integrative oncology is the synthesis of mainstream care and
nonpharmacologic evidence-based complementary therapies for
the control of cancer-related physical and emotional symptoms,
but stated that because of over-the-counter herbal products, patients should be advised to use caution and consult with their
physicians before taking those herbs. The second editorial article
pointed out that integrative medicine is part of a rapidly evolving era, and that integrative medicine will benefit both patients
and practitioners.23 In general, the messages from both editorial
papers were positive, but there was no strategy as to how to
manage the concomitant use, especially how to guide the Western medicine doctor to make judgments when patients seek their
advice about herbal medicine use in conjunction with
chemotherapy.
The focus of the 15 review papers differed, and the papers
covered topics including potential interactions (both positive
and negative), the mechanism of potential interaction, especially
with regard to induction, and knowledge of herbal medicine.16,24-38 Almost all articles reviewed pointed out the potential for negative herb-drug interaction; only one review paper
pointed out the potential synergism of natural products in the
treatment of cancers.31 One review, published in 2002, observed

Management of Herb-Drug Interaction in Chemotherapy

that no herb-drug interactions had, thus far, actually been reported clinically in cancer treatment, so the potential for such
interaction must still be regarded as theoretical.36 In fact, most
concerns about the potential of negative interactions were based
on preclinical data. Further, these reviews pointed out the following: (1) more communication between patients and physicians about the use of herbal medicine is needed,26 (2) physicians should be aware of herb-drug interactions and encourage
patients to discuss herbal medicine use,28 (3) more preclinical
and clinical studies should be conducted about herb-drug interactions,16,29,30 (4) physicians should question patients on their
use of herbal medicines and urge patients to avoid herbs that
could confound their cancer care,35 and (5) government regulatory authority should put more efforts in to herbal medicine
regulation.38 The herbs commonly reviewed include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), Saint-Johns-wort (Hypericum perforatum), black cohosh (Actaea racemosa), and kava (Piper
methysticum).16,28,31,34-36. Based on these reviews, neither patients nor physicians could conclude whether herbal medicine
should or should not be used among cancer patients.

Epidemiological surveys about herb-drug interaction among

cancer patients. The search strategy identified six epidemiological survey studies concerning herb-drug interactions. Each
study had a different focus. Engdal and colleagues39 reported
that among 42 cancer patients using herbal remedies concurrently with chemotherapy, 136 two-agent herb-drug combinations were registered, and 47 different potential herb-drug interactions were identified on the level of cytochrome P450
metabolizing enzymes metabolism and P-glycoprotein transport
in vitro. Garlic, ginger, green tea, and noni juice were the herbal
remedies most frequently used in such combinations. They concluded that the large number of in vitro potential herb-drug
interactions supported the need for more clinical pharmacokinetic interaction studies in humans. Also, his research group
reported that it is very common for cancer patients undergoing
chemotherapy to use herbal medicine.9 Similar results were reported from Taiwan,40 Sweden,41 and the United States.42,43
Unrelated studies. Of the 142 studies we found to be unrelated
to herb-drug interaction, most were animal studies and drugdrug interaction studies, as our understanding of drug-drug interactions comes primarily from laboratory studies. Although
laboratory experiments provide powerful evidence of potential
interactions,44,45 this preclinical evidence cannot be extrapolated to the clinic without confirmation from human studies,19,44-47 and these data do not consistently predict in vivo
interactions.48,49 Therefore, knowledge regarding pharmacokinetic interactions, especially as found in some reviews about
herb-drug interaction, is mostly theoretical; it does not come
directly from clinical trials. With regard to food-drug interaction
studies, 29 articles were identified, with seven review articles and
some clinical trials. Based on the articles identified in this review
of the literature, it seems that clinical evidence about food-drug
interaction is stronger than that of herb-drug interaction.

EXPLORE September/October 2010, Vol. 6, No. 5 325

DISCUSSION AND RECOMMENDATION

Theoretically, herb-drug interactions could be positive, negative,
or neutral. Our study found that there is little direct evidence
from clinical research or clinical practice about such interactions. However, some indirect evidence for both positive and
negative effects of concomitant use of herbs and chemotherapeutic agents is available. On the one hand, preclinical studies
have shown that a number of herbal medicines can increase the
sensitivity of cancer cells to chemotherapeutic drugs, improve
survival rates, enhance tumor response to chemotherapeutic
drugs, and reduce the toxicity of cancer chemotherapy.40-54 On
the opposite end of the spectrum, some herbs such as SaintJohns-wort, garlic, ginkgo, echinacea (Asteraceae), ginseng, and
kava have been reported to cause potential negative pharmacokinetic interactions with anticancer drugs.16,35 But most of the
available information, both positive and negative, came from
basic experiments or trials testing the use of a single herb along
with chemotherapy drugs. Such information cannot effectively
guide clinical practice, because in actual clinical practice, herbs
are usually used in mixtures, especially in Traditional Chinese
Medicine. Thus, there is a large and critical gap between research
methodology and actual clinical practice. Given these factors,
even the limited data currently available about herb-drug interaction offers little guidance for clinical practice.
Management of Potential Herb-Drug Interactions
As discussed above, the current knowledge base of basic and
clinical data is insufficient to draw conclusions on whether or
not to condone coadministration of herbal remedies and cancer
chemotherapy agents. Even so, the evidence we do have suggests
that herbs can do more good than harm. To solve this dilemma,
an evidence-based approach should be advocated. Currently, it
appears that herbal medicine may be particularly valuable in
helping the body cope with the side effects of chemotherapy
agents;52,54 however, which herbs in what dosages and how the
concurrent administration should be handled are questions
largely unanswered. Relevant, high-quality studies must be performed and the results of these studies disseminated to frontline
healthcare providers and their patients.
Evidence for the Concurrent Administration of
Chemotherapy And Herbal Medicine
Given the many concerns about the concomitant use of herbal
medicine with chemotherapy drugs, the most important question behind issues of safety of herb-drug interaction is whether
herbs should be given at all. The common purposes of concurrent administration of an herb with chemotherapy are to enhance the efficacy and/or to reduce the side effects of chemotherapy. Our review of the evidence showed that, although there
is in fact some evidence to support the concomitant use of
herbal medicine and chemotherapy drugs, much of this evidence is not reliable due to methodological problems with the
studies.53,54 For example, one review showed that decoctions of
Huang qi compounds may stimulate the activity of immunocompetent cells and decrease side effects in colorectal cancer
patients treated with chemotherapy; however, due to methodological limitations, the studies provide no robust demonstration of benefit.54 Therefore, high-quality randomized controlled

326 EXPLORE September/October 2010, Vol. 6, No. 5

studies investigating the effects of herbal medicines on chemotherapy-related side effects are highly recommended to generate
reliable evidence to guide clinical practice.54 At this point, serious ethical considerations arise. For example, should cancer patients have to wait for high-quality evidence? Is it ethical to let
patients wait for high-quality evidence condoning the use of
herbs, while there is equally no evidence of harm?
A second question might arise as to what constitutes concomitant use. If dosages can be administered such that the
herbs and drugs are not in the body at the same time, then
interaction is effectively prevented. A previous study pointed
out that five half-lives are needed for a drug to reach steady state
and five half-lives to be virtually eliminated from the body.55
Knowing the half-lives of both herbal medicine and chemotherapy can allow for a dosing regimen to be designed that will
theoretically ensure that both agents are not present in the blood
stream at the same time.55 But it is not easy to identify the active
compounds related to efficacy and to investigate the half life of
a herbal medicine or a formula.
In this dilemma, it is not reasonable to discard the potential
usefulness of the traditional wisdom of herbal medicine, which
has the backing of thousands of years of clinical experience.
Concomitant treatment of herbs and drugs could be guided
based on Chinese medicine theories. In other words, the Western chemotherapeutic agent could be treated as an influence on
the body, and the appropriate herbs prescribed to restore balance to the system. When a cancer patient is taking chemotherapy drugs, the herbal medicine practitioner is treating not just
the patient with cancer, but a cancer patient under the influence
of a chemotherapy drug one whose Yin, Yang, Qi, and Blood
are affected accordingly. This scenario would require a platform,
or vocabulary, by which Western physicians and herbal medicine practitioners can discuss and manage the concomitant use
of herbal medicine and chemotherapy agents. At the moment,
most concomitant use of herbal medicine and chemotherapy
agents is initiated and regulated by patients themselves, with
little communication with their physicians about such use.10
This is perhaps the most dangerous situation of all. Hence, the
need to evaluate and understand potential interactions, to share
knowledge among Western physicians and herbal medicine
practitioners, and to disseminate findings is increasingly urgent.
Evidence for the Effectiveness of Herbal Medicine
Botanicals and other herbal products are a valuable source for
the development of therapeutic agents. Approximately one
fourth of prescription drugs contain active ingredients derived
from plants, including several chemotherapeutic agents (paclitaxel, docetaxel), camptothecin (irinotecan, topotecan), and
vinca alkaloids (vincristine, vinorelbine).42 Despite the long history of using herbal medicines, only a few have been evaluated
with a strict scientific research approach. Evidence is needed
about the effectiveness of herbal medicine for specific cancers,
including dosage, efficacy, and safety; and concomitant use with
chemotherapy for cancer patients. At present, many herbal medicine formulas are prescribed daily for cancer patients by herbal
medicine practitioners, even concomitantly with chemotherapy,
but daily use has not automatically generated powerful evidence
to support their efficacy and safety. Clinical studies should be

Management of Herb-Drug Interaction in Chemotherapy

carried out to assess their safety and efficacy. One point that
should be mentioned is that it is not necessary to rely solely on
randomized controlled trials for evidence. Although randomized controlled trials can provide the highest ranking evidence
among all trial categories, sometimes a single case report can
provide valuable evidence. If possible, determination of the
pharmacologically active components of formulas will benefit
the study about potential herb-drug interactions. In order to do
this, sufficiently sensitive analytical methods to determine the
bioavailability and pharmacokinetics of herbal medicines are
required as well.
Evidence for the Safety of Herbal Medicine
Safety issues of herbal medicine should be taken into consideration when dealing with coadministration of herbal medicine
and chemotherapy agents. Negative effects from the concomitant use of herbs and chemotherapy drugs may come from the
herbal medicine directly. A big problem in scientifically evaluating herbal preparations is the lack of consistency in their quality. Herbal medications are rarely produced with the same standards of conventional medicines; product inconsistency and
contamination have frequently been reported.56,57 First, the
safety of herbal medicines depends on proper identification of
raw materials and strict control of adulterants, contaminants (eg,
heavy metals or pesticides), manufacturing techniques, and storage methods.57 Secondly, safe use of Chinese herbs depends on
following the dicta prescribed by the ancient canon. There are
caveats about the use of specific herbs in Chinese medicine
practice. For example, the 18 incompatible herbs and the 19
antagonistic herbs, when used in combination, will produce
toxic reactions, harmful side effects, or a diminished therapeutic
effect. The ancient wisdom about herb-herb interaction provides
an alert that inappropriate combinations of herbs will bring out
negative results; it also suggests that mixing herbs with chemotherapy drugs could also generate negative effects. Therefore, the
negative effects from using herbal medicines could come from
quality issues of herbal medicine or incompatible combinations
of herbal medicine with other herbs or with new chemotherapeutic agents. Because cancer patients are already in a state of
weakened health, safety issues about the use of herbal medicine
in clinical practice need close attention.
Evidence-Based Database for the Management
of Herb-Drug Interaction
Reliable sources of evidence are important for all involved in the
care of cancer patients to justify the concurrent use of herbal
medicines and chemotherapy in practice. The concomitant use
of Chinese herbal medicine and chemotherapy drugs in mainland China has been occurring for many years. Although there is
no presentable documented evidence showing the benefit or
harm of such use, the continued practice is itself circumstantial
evidence that the practice is effective. From this point of view, it
is necessary not only to conduct clinical research, but also to
collect and summarize the data from the existing clinical practice, especially with regard to concomitant use of herbal medicine and chemotherapy drugs.
An internationally accessible database would be ideal. In this
database, any findings of synergistic or antagonistic effects, and

Management of Herb-Drug Interaction in Chemotherapy

reducing or enhancing side effects due to herb-drug interaction,

should be clearly stated. The database could serve as an open
platform for peers to share personal experience during such practice and elaborate discussion in this area. Such a setup could be
a way to bring the traditional herbal medicine wisdom to the
new integrative medicine in the 21st century. With the database
on the Internet, doctors everywhere could instantly share experiences, and patients or their relatives could get related information accordingly.
The key issue to successfully establishing such a database is to
set up the form for requesting information. How the information is recorded will greatly influence how it can be analyzed. All
relevant information, including the patients, herbal medicine
interventions, chemotherapy agents, treatment process, outcome assessment, etc, should be clearly requested by a standard
form. Currently, a large body of traditional knowledge exists
regarding herbal medicines role in the treatment of cancer, especially throughout Asia.58-60 Much of this information is recorded in the form of unproven case reports. Although such
anecdotal evidence cannot automatically be extrapolated to generic recommendations, it does represent valid information that
should not be discounted. If enough such evidence can be collected and analyzed, trends will emerge that can then direct
controlled research to examine and test the key points with
greater efficiency in terms of useful outcomes. Such a database
would also help doctors and practitioners share their expertise
and knowledge, ultimately benefiting patients all over the world.
Education
Given the increasing tendency for patients to use herbal medicine together with chemotherapy, evidence is needed as to potential interactions, and the conclusions need to be disseminated. For frontline healthcare professionals, an open mind is
crucial to providing clinical recommendations on concurrent
treatments of conventional medicine and complementary and
alternative medicine. Reading research publications is one way
to get up-to-date findings. Reporting and discussing any suspicious herb-drug interaction cases with peers would also be a big
contribution for the development of research studies on herbdrug interaction. For patients, professional advice should be
sought first before undertaking any concurrent treatment. Good
communication between patients and doctors is of the utmost
importance for developing an optimal treatment strategy.

CONCLUSION
Current studies on herb-drug interaction among cancer patients
undergoing chemotherapy are insufficient to make definite recommendations. Evidence-based research is needed, as well as
efforts to consolidate knowledge gleaned from experience apparent in existing clinical practices. Evidence-based approaches
should be implemented to document the positive and/or negative effects of the concomitant use of herbs and anticancer chemotherapeutic drugs. At the same time, it would be helpful to set
up an internationally accessible database to document the use of
herbal medicines and anticancer drugs. Finally, efforts should be
made to educate both healthcare professionals and patients
about the use of herbal medicine for cancer patients.

EXPLORE September/October 2010, Vol. 6, No. 5 327

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