Support Care Cancer (2004) 12:454462

DOI 10.1007/s00520-004-0598-1

Jeannine S. McCune
Amy J. Hatfield
Anne A. R. Blackburn
Patricia O. Leith
Robert B. Livingston
Georgiana K. Ellis

Received: 17 September 2003

Accepted: 18 December 2003
Published online: 27 February 2004

Springer-Verlag 2004

This work was supported by University of

Washington Undergraduate Research
Training and University of Washington
School of Pharmacy.
J. S. McCune A. J. Hatfield
A. A. R. Blackburn P. O. Leith
R. B. Livingston G. K. Ellis
University of Washington,
Seattle, WA, USA
J. S. McCune A. J. Hatfield
A. A. R. Blackburn P. O. Leith
R. B. Livingston G. K. Ellis
Seattle Cancer Care Alliance,
Seattle, WA, USA
J. S. McCune ())
University of Washington,
1959 NE Pacific Street, H361E, Box
357630, Seattle, WA 98195-7630, USA
e-mail: jmccune@u.washington.edu
Tel.: +1-206-5431412
Fax: +1-206-5433835

ORIGINAL ARTICLE

Potential of chemotherapyherb interactions

in adult cancer patients

Abstract Goals of work: The purpose of this study was to examine the
specific herbs or vitamins (HV) used
by patients receiving chemotherapy.
Specifically, the following aspects
were investigated: (1) HV use among
adult cancer patients receiving chemotherapy, (2) the frequency of potential chemotherapyHV interactions, (3) communication patterns
between oncologists and their cancer
patients taking HV, and (4) patients
reactions to two hypothetical scenarios of chemotherapyHV interactions. Patients and methods: Adult
cancer patients receiving chemotherapy at a university-based outpatient
clinic over a 1-month period were
sent a validated eight-page questionnaire regarding the use of complementary/alternative medicine, focusing on HV use. A total of 76 patients
participated; relevant medical information was obtained from study participants charts. The chemotherapy
received was compared with HV use
to assess for potentially detrimental

Introduction
Concern over adverse interactions between herbal supplements and vitamins (HV) and prescription medications
has substantially increased in parallel with the everincreasing use of complementary alternative medicine
(CAM) in the United States [8, 9, 11, 24]. The need to
identify patients at risk for adverse interactions between
HV and prescription medications is perhaps greatest for
patients receiving chemotherapy agents, which have a

chemotherapyHV interactions.
Results: HV use in patients receiving
chemotherapy was common (78%),
with 27% of the study participants
being at risk of a detrimental chemotherapyHV interaction. Most patients (>85%) would discontinue their
HV or ask their medical oncologist
for advice if a detrimental chemotherapyHV interaction was suspected. Although most patients discussed
HV use with their oncologist, the
majority also relied on their friends
and naturopathic physician for information regarding HV. Conclusions:
Considerable potential exists for
detrimental chemotherapyHV interactions. Methods to improve communication of HV use between cancer patients receiving chemotherapy
and health-care practitioners are necessary to identify and minimize the
risk of these interactions.
Keywords Interaction
Chemotherapy Herb Vitamin
Cancer

narrow therapeutic index. There is a paucity of clinical

data regarding the interactions between HV and chemotherapy. In vitro data suggest either beneficial or detrimental interactions through a variety of mechanisms (e.g.,
antioxidant, antineoplastic, immunomodulatory, estrogen,
and bleeding effects) [4, 7, 15, 16, 17, 33, 37]. In addition,
HV may affect chemotherapy metabolism, as shown by
the inductive effect of St. Johns wort upon irinotecan
metabolism [19]. It is imperative to ascertain the benefits
and adverse effects of HV in cancer patients and

455

interactions between HV and chemotherapy; particularly

as they are within two of the main focuses of the National
Center for Complementary and Alternative Medicine
(NCCAM), specifically to evaluate the safety and efficacy
of widely used natural products and to support pharmacologic studies evaluating drug interactions [30].
Cancer patients tend to use CAM more frequently than
the general population, with HV amongst the most
popular CAM [5, 10, 12, 23, 25, 30, 34, 36]. Usage of
HV in patients receiving chemotherapy is difficult to
discern from available data, as the cancer treatments and
timing of HV relative to chemotherapy are not precisely
reported. In a survey of 453 cancer patients, 76.6% of HV
users combined these with conventional treatment (i.e.,
chemotherapy, radiation or surgery) [30]. These data
suggest that concomitant administration of chemotherapy
with HV may be common, but the true prevalence is
unknown because the timing of HV use relative to
chemotherapy is rarely reported and the frequency and
doses of HV are also not known. This concern is
compounded by both the lack of communication between
cancer patients and their allopathic physicians concerning
CAM use, and that few Americans have seen a naturopathic physician [5, 8, 9, 23, 36]. Thus, it is difficult to
determine the risks of chemotherapyHV interactions
from a retrospective chart review. In addition, to our
knowledge, no-one has evaluated how cancer patients
would react if their allopathic physician alerted them to a
potentially detrimental chemotherapyHV interaction.
The purpose of this study was to examine the HV used
by patients receiving chemotherapy at a university-based
outpatient clinic. Specifically, this analysis evaluated: (1)
HV use among adult cancer patients receiving chemotherapy, (2) the frequency of potential chemotherapyHV
interactions based on the recommendations of Weiger et
al. [37], (3) communication patterns between oncologists
and their cancer patients who are taking HV, and (4)
patients reactions to hypothetical chemotherapyHV
interactions which could affect the efficacy or safety of
their chemotherapy.

Patients and methods

Patient population
Prior to initiation of study procedures, approval was obtained from
the Human Subjects Division at the University of Washington
(UW). Potential study participants were identified from pharmacy
records by searching for those who received chemotherapy in
November 2000 at the Outpatient Cancer Center at UW Medical
Center. This resulted in the identification of 195 patients, whose
medical records were subsequently reviewed to determine eligibility. Patients were asked to participate if they were diagnosed with
cancer and English-speaking. Of the 195 patients, 33 were not
eligible for study participation because they were not Englishspeaking (8 patients), not diagnosed with cancer (8) or deceased
(7), or the questionnaire was not deliverable (10).

An introductory letter explaining the study rationale and

requirements, along with a study questionnaire (eight-page) were
mailed to eligible patients in late February 2001. The questionnaire
was sent a second time only to those who did not respond to the
first mailing; eligible patients who did not respond within 1 month
of the second mailing were considered non-participants. All
questionnaires were coded with a unique identification number to
maintain confidentiality. Of the 162 eligible patients, 76 returned
their questionnaire (response rate 44%). Three patients declined
study participation by returning their mailed questionnaires to clinic
staff and 83 patients did not return their questionnaire after two
mailings. Patients responses on the questionnaire agreed with their
medical record with regard to age (100%), gender (100%), and
ethnicity (98%).
Questionnaire validation
A self-administered questionnaire was developed to assess a cancer
patients use of HV within the preceding 30 days. The questionnaire was first reviewed for content and face validity by six
allopathic health-care practitioners specializing in the care of
cancer patients. Subsequently, full questionnaire validation was
initiated after a separate approval by the UW Human Subjects
Division and written consent was obtained from all patients
participating in the questionnaire validation. During the Spring of
1999, the questionnaire was validated in two steps: (1) by
comparing the results of the questionnaire and a personal interview;
and (2) by evaluating the responses of cancer patients who
completed the questionnaire while awaiting an appointment in the
outpatient medical oncology waiting room. Testretest is usually
conducted by administering the same or a slightly altered questionnaire at two different time points. However, the method of
conducting an interview (i.e., the gold standard) and questionnaire completion were chosen because of the short (i.e., 30-day)
time period that the questionnaire referred to in the hope of
minimizing recall bias.
First, the principal investigator (J.S.M.) interviewed six patients
in the medical oncology clinic about their use of CAM, focusing on
herbs and vitamins used over the preceding 30 days; interviews
were usually 30 to 60 min in duration. Immediately following the
interview, the study participants were asked to complete the
questionnaire. The replies from the interview and the questionnaire
were compared to assess the reliability of the patients responses
regarding HV use. The verbal replies of six patients correlated well
with their questionnaire responses (76% match) which is above the
70% threshold for accepting testretest [18, 20]. The majority of the
differences between the interview and questionnaire responses were
that patients listed more HV in the questionnaire than they reported
during the interview. Further validation was conducted from the
responses of 50 additional cancer patients who completed the
questionnaire while awaiting an appointment in the outpatient
medical oncology waiting room.
The piloted questionnaire was modified based on these two
validation steps. Also, two hypothetical scenarios based on cytochrome P450 drugdrug and drugfood interactions were added to
the questionnaire and were reviewed for face validity by three
cancer patients and six allopathic health-care professionals. A final
copy of the questionnaire is available from the author.
Mailed questionnaire
The eight-page mailed, self-administered questionnaire asked
information regarding demographic characteristics associated with
HV use (i.e., age, ethnic background, educational background,
annual household income) [1], type of malignancy, and concomitant cancer treatments including chemotherapy. Additionally,

456

Table 1 HV listed in questionnaire (an Other category was

included for participants to write in HV they used which were not
included in this list)
Algae
Beta-carotene
Black cohosh
Calcium
Cascara
Cell forte/IP6
Chamomile
Chinese herbs
Chlorophyll
Cloves
CoEnzyme Q10
Cranberry
Dansen
DHEA
Dong Quai
Echinacea
Elderberry
Evening primrose
Feverfew

Folate
Garlic
Ginger
Ginkgo biloba
Ginseng
Glucosamine
Glutamine
Goldenseal
Grapeseed
Green tea extract
Hydrazine sulfate
Kava kava
Kelp
Lecithin
Magnesium
Melatonin
Milk thistle
Mistletoe/iscador
Multivitamin

Mushroom
PC-SPES
Pokeroot
Potassium
Psyllium seed
Pycogenol
Quercetin
Saw palmetto
Selenium
Shark cartilage
St. Johns wort
Valerian
Vitamin A
Vitamin B12
Vitamin B6
Vitamin C
Vitamin E
Wormwood
Zinc

several questions focused upon CAM use over the previous 30 days,
including the frequency of drinking teas (i.e., black, chapparal,
essiac, green, pau DArco, taheebo, willow), the use of CAM prior
to cancer diagnosis, and the rationale for CAM use. Subsequently,
57 selected HV therapies (Table 1) were listed and spaced to allow
the patient to describe the dose, frequency of administration, and
perceived benefit for each HV. Space was also allowed for
participants to write in HV that they used but were not included in
the list. The questionnaire also addressed patients resources for
information about HV, frequency of communication with their
oncology professionals, and potential barriers to communication
regarding HV use. Two hypothetical scenarios based on cyto-

Fig. 1 Participants responses to: Would you continue taking

Herbal or Juice? in hypothetical chemotherapyHV interactions.
The specific scenarios were as follows. Scenario 1: You are taking
a certain herbal therapy, which we will call Herbal #1. Herbal #1
decreases the time certain drugs stay in your body. Your chemotherapy is cleared from the body in the same way as these drugs and
less chemotherapy would be in contact with your cancer cells. This

chrome P450 drugdrug and drugfood interactions were described

and the participant was asked to state whether they would maintain
their HV if told their HV and chemotherapy interacted. The first
scenario was based on the known effects of St. Johns wort, referred
to as Herbal #1 in the questionnaire, increasing cytochrome P450
and p-glycoprotein activity [19, 26]. The second scenario was based
on data showing that grapefruit juice increases the absorption of
various medications that are substrates for cytochrome P450 3A4
and p-glycoprotein (e.g., etoposide) [2, 29]. The phrasing of the
hypothetical scenarios is shown in Figs. 1 and 2.
Upon receiving the completed questionnaires, the study participants medical records were reviewed for information regarding
chemotherapy and other medications used to assess potential
chemotherapyHV interactions. Relevant demographic information
(i.e., year of birth, gender, ethnic background), medical information
(i.e., cancer diagnosis, stage of disease, renal and hepatic function),
and treatment information (i.e., current cancer treatment including
chemotherapy, all concomitant medications including supportive
care medications such as growth factors and opioids) were also
collected. Potentially detrimental herbal interactions were assessed
based on the recommendations of Weiger et al. regarding the use of
CAM in cancer patients [37]. Because of the common use of CAM
by cancer patients, these authors summarized the evidence for the
efficacy and safety of selected CAM therapies commonly used by
cancer patients with the aim of developing evidence-based, patientcentered advice for health-care practitioners to offer to cancer
patients regarding CAM use [37]. These authors conducted a
comprehensive literature search to identify relevant preclinical and
clinical data, applied well-defined criteria for recommending or
discouraging CAM use, and also discuss the level of evidence for
their recommendations. A summary of the CAM therapy which the
authors deemed would be reasonable to discourage is presented in
Table 2.

means Herbal #1 could make your chemotherapy not work as well.

What would you do?. Scenario 2: You usually drink Juice #1 and
are also taking chemotherapy by mouth. Juice #1 increases the
amount of certain drugs in your body. Your chemotherapy is
absorbed into your body the same way as these certain drugs. This
could increase the amount of chemotherapy in your body and may
cause more side effects. What would you do?

457

Fig. 2 Participants responses

to the question If you decided
to keep taking Herbal or Juice,
would you want to receive more
(scenario 1) or less (scenario 2)
chemotherapy?

Table 2 Summary of CAM whose use would be reasonable to discourage

Therapy

Efficacy
a

Level

Direction of evidence

Vitamin A

Inconclusive

Vitamin C

Not effective

Soy for breast

cancer

III

Inconclusive

Level of risk

Reasonable advice

Documented major adverse effect (i.e., life-threatening

or permanently disabling) that occurred in association with
therapy in multiple instances with causal relationships
established
Theoretical possibility of minor adverse effect occurring as
a result of therapy but no clinical cases reported
to date
Theoretical possibility of major adverse effect occurring as
a result of therapy but no clinical cases reported to date

Discourage and
monitor
Discourage and
monitor
Discourage and
monitor

Adapted from Weiger et al. [37] Table 2, with permission. From criteria of the U.S. Preventive Task Force: I evidence obtained from at
least one properly designed randomized clinical trial, III opinions of respected authorities, based on clinical experience, descriptive studies
or reports of expert committees

Statistical analysis
Microsoft Excel was used for data entry and to calculate frequencies of participant responses; SPSS 9.0 was used for statistical
analysis. Differences between participants and non-participants
with respect to demographic characteristics (gender, race) were
assessed by chi-squared analysis and age was assessed using
Kruskal-Wallis. The demographic characteristics of users and nonusers of herbal and vitamin therapies were not compared because of
the low number of non-users accrued (n=13).

Results
The demographic characteristics, along with cancer diagnosis and treatment, for the 76 participants are presented
in detail in Table 3. The median age was 52 years (range
3083 years). Most of the participants were women (59)
and Caucasian (73). The demographic characteristics
between participants and non-participants were similar in
respect of age and gender, but not in respect of race. Most
of the study participants had normal liver and renal
function based on review of their medical records, with
one patient having a serum creatinine greater than 1.5 mg/
dl, and all patients liver function tests being less than two
times the upper limit of normal. Serum albumin was low
(<1.5 mg/dl, the lower limit of normal within the

treatment facility) in 20 patients. The cancer diagnoses

are listed in Table 3. The majority of patients (67) were
diagnosed with a solid tumor. Participants received the
following cancer treatments over the 30 days prior to the
questionnaire: chemotherapy (43), radiation (15), antibody therapy (11), hormonal therapy (10), and surgery
(6). Of the 76 participants, 35 (46%) were receiving
chemotherapy with a curative intent; the intent of chemotherapy was determined by the principal investigator
(J.S.M.) reviewing the primary tumor site, stage of
disease and previous cancer therapies (if any). The
median number of conventional medications (i.e., chemotherapy, supportive care and non-oncology-related
medications) used per patient was 6 (range 118).
The use of CAM, excluding HV, is shown in Table 4.
The question regarding the rationale for HV use was
answered by 52 participants, with the median number of
reasons chosen being 2 (range 08). Patients reported the
most common reasons for using HV were to improve
quality of life (20%) and to improve the immune system
(20%). Additional reasons included: to take an active role
in cancer therapy (12%), to prolong life (11%), to use a
more natural approach (10%), to slow cancer progression
(10%), to tolerate the chemotherapy or radiation better
(8%), and to relieve the symptoms of the disease (7%).

458

Table 5 Use of HV by study participants

Table 3 Demographics of participants

Number of participants
Total
Men
Women
Age (years)
Median
Range
Ethnic background
Caucasian
Hispanic
Others
Education
Did not finish high school
Finished high school
Finished college or trade school
Finished graduate school/professional education
Question not answered
Income (US $)
<34,999
35,00064,999
>65,000
Question not answered
Disease
Breast
Non-Hodgkins lymphoma
Lung
Cervical
Brain
Prostate
Sarcoma family of tumors
Hodgkins disease
Chronic lymphocytic leukemia
Unknown primary
Head and neck
Bladder
Stomach
Cancer therapies during the 30 days preceding the
questionnaire
Chemotherapy
Hormonal therapy
Antibodies
Radiotherapy
Surgery
Question not answered

76
17
59
52
3083
73
1
2
3
21
34
17
1
22
21
24
9
43
5
5
5
4
3
3
2
2
1
1
1
1
43
10
11
15
6
1

a
special
b

diet, juicing, exercise

Acupuncture, yoga, spirituality, therapeutic touch

56
25
23
5
2
36
14
0
4
20
2
0

2
126
53 (70%)
17 (22%)
34
25
16
15
15

(45%)
(33%)
(21%)
(20%)
(20%)

3 (4%)
14 (19%)
4 (6%)
26
16
15
11
7
5
2
6
3

(34%)
(21%)
(20%)
(14%)
(9%)
(7%)
(3%)
(8%)
(5%)

a
Described in Table 2
b
Garlic, feverfew, dong
c

quai, gingko
Reported use of garlic or St. Johns wort from among 56
participants receiving chemotherapy metabolized by cytochrome
P450 [19, 27]

(57%)
(13%)
(14%)
(20%)
( 8%)
(<1%)

Table 4 Use of CAM and rationale for CAM use by study

participants
Any CAM use
Lifestyle changesa
Complementary methodsb
Traditional Chinese medicine (Tai Chi, Qugoung)
Homeopathy
Tea
Black tea
Chapparal tea
Essiac tea
Green tea
Pau Darco tea
Taheebo tea

Number of HV used per patient

Median
Range
No. taking vitamins
No. taking herbals
Most commonly used HV
Multivitamin
Calcium
Vitamin C
Vitamin E
Vitamin B6
No. using HV reasonable to discouragea
Vitamin A
Vitamin C daily
HV with hormonal effects
No. using antioxidants
Any antioxidant
Vitamin C
Vitamin E
Selenium
Coenzyme Q10
Beta carotene
Glutamine
No. using HV with bleeding side effectsb
No. using HV that alter drug metabolism in vivoc

(73%)
(32%)
(30%)
(6%)
(3%)
(47%)

Patients were asked to rate the perceived benefit (extremely beneficial, somewhat beneficial, not beneficial at
all and dont know) of each specific HV therapy used:
61% reported that they did not know whether their HV
therapies were beneficial for them, 18% responded that
their HV use was extremely beneficial, whereas only one
participant (<1%) felt that there was no benefit.
To the question have you used herbal or vitamin
therapies during the 30 days prior to completing the
questionnaire?, 37 (49%) replied yes. However, 59
participants (78%) reported the use of at least one HV of
57 listed products. In addition, participants were allowed
to handwrite additional HV products they used that were
not included in the list. Table 5 is a detailed description of
the reported use of HV. The majority of participants (53)
used vitamins, while 17 used herbal therapies. Most
(91%) of the HV use was daily.
To estimate the number of potential interactions
between conventional medications (i.e., chemotherapy,
supportive care medications, and additional daily medications for medical conditions other than their malignancy) and HV, the equation n!/(nr)!r! was utilized [38]
(where n is the total number of conventional medications
and HV being used and r was arbitrarily set at a value of
two). This equation uses permutations to calculate the
number of potential combinations allowed between a
number of items (i.e., conventional medications and HV).

459

This calculation essentially estimates the minimal number

of interactions possible, by giving the total number of
two-agent combinations a patient is taking. For example,
a patient receiving four conventional medications (e.g.,
doxorubicin/cyclophosphamide with granisetron and
dexamethasone) and taking three HV (e.g., multivitamin,
calcium, vitamin C) would have 21 potential medication
HV interactions, i.e., 7!/(5!2!) [38]. The median number
of potential interactions in a patient was 45 (range 1496).
The challenge for allopathic and CAM practitioners is to
establish which of these high number of potential interactions are clinically relevant. We ascertained the potential for clinically relevant interactions using the recently
constructed recommendations for advising cancer patients
regarding CAM based on a comprehensive search of the
current scientific literature (summarized in Table 2) [37].
Three study participants reported using vitamin A on a
daily basis at doses of 10025,000 IU/day while 14 were
using vitamin C daily. Although soy itself was not
specifically listed as an HV, four participants were using
HV with hormonal effects (black cohosh, ginseng, dong
quai), including one breast cancer patient. Antioxidants
were being used by 26 patients: vitamin C (16), vitamin E
(15), selenium (11), coenzyme Q10 (7), beta carotene (5),
and glutamine (2). HV with bleeding side effects (garlic,
feverfew, dong quai, gingko) were being used by 6
patients. Additionally, HV that alter drug metabolism in
vivo (i.e., garlic, St. Johns wort) were being used by 3 of
the 56 participants receiving chemotherapy metabolized
by cytochrome P450 including cyclophosphamide, vincristine, vinorelbine, and paclitaxel [19, 27].
Participants were asked to decide their preference in
two scenarios based on known cytochrome P450 drug
HV and drugfood interactions. The results are summarized in Figs. 1 and 2. The first scenario was based on St.
Johns wort increasing indinavir clearance [26]. The
question was as follows: Herbal #1 decreases the time
certain drugs stay in your body. Your chemotherapy is
cleared from the body the same way as these drugs and
less chemotherapy would be in contact with your cancer
cells. This means Herbal #1 could make your chemotherapy not work as well. Participants chose one answer
from six choices; however, some participants chose more
than one answer. This question was answered by 62
participants for a total of 66 responses: 34 (55%) would
choose to discontinue HV use, and 26 (42%) would ask
their oncologist for advice. Other responses included:
depended on whether HV was beneficial (3), continuation
of HV at the same or different dose (2), and didnt know
(1). To the next question in this scenario (If you decided
to keep taking Herbal #1, would you want to receive more
chemotherapy?), 12 participants answered yes, 22 were
not decided, and 14 would not want to receive more
chemotherapy.
The second scenario was based on data showing that
grapefruit juice increases the absorption of oral medica-

tions which are cytochrome P450 or p-glycoprotein

substrates [2]. Participants were given the following
scenario: You usually drink juice #1 and are also taking
chemotherapy by mouth. Juice #1 increases the amount of
certain drugs in your body. Your chemotherapy is
absorbed into your body the same way as these certain
drugs. This could increase the amount of chemotherapy in
your body and may cause more side effects. What would
you do? In this scenario, 39 participants (58%) stated
that they would ask their oncologist for advice, 20 (30%)
would discontinue the juice, 3 would continue the juice at
the same or reduced dose, and 3 would determine the
benefit of the juice before making a decision. In response
to the follow-up question if you decided to keep drinking
juice #1, would you want to receive less chemotherapy?,
six participants said yes, 25 were not decided and 17
stated they would not want less chemotherapy.
The most frequent primary sources of HV information
were: a friend or family member (number of responses
19); naturopathic physician (17); physician (15); written
material including magazines, newspapers, and books
(14); health food/nutrition store (9); internet (8); nutritionist (6); nurse (5); pharmacist (4); primary physician
(3); television (2); and other sources (6). Additionally,
secondary sources included the patients naturopathic
physician (14), primary physician (11), nurse (10), nutritionist (7), and pharmacist (7). By participant self-report
in the questionnaire, 23 participants (31%) had not
reported their use to any health-care professional. HV
use had been discussed with their oncologist by 47
patients (62%). The most common reason for patients not
discussing HV use with their oncologist was that the
oncologist had not asked them about HV use (32%).
Other reasons included that the patients thought the
physician had no knowledge about HV, would not think it
was useful or that there was any scientific evidence to
support its use. However, only 14 participants (18%) had
mentioned HV use in the most recent visit to their medical
oncologist, as documented in their medical chart. Of these
patients, 10 were using a multivitamin, 4 vitamin E, 3
calcium, 2 vitamin C, 2 glucosamine, 1 valerian tincture,
1 melatonin, 1 primrose oil, and 1 chondroitin.

Discussion
The results of this survey show that: (1) concurrent HV
use in patients receiving chemotherapy was frequent; (2) a
considerable percentage (28%, Table 5) of patients were
at risk of a detrimental chemotherapyHV interaction
according to the meta-analysis by Weiger et al. [37],
although additional data are needed to ascertain the
specific risk of interactions; (3) most patients would
discontinue their HV or ask their medical oncologists for
advice if a detrimental chemotherapyHV interaction was
possible; (4) although most patients reported discussing

460

their HV use with their oncologist, HV use was infrequently documented in medical records and most patients
also relied on their friends and naturopathic physician for
information regarding HV.
The overall use of CAM in this population was 76%,
which is similar to the proportions previously reported in
larger cohorts of adult cancer patients [5, 23, 30]. The
demographic characteristics of this population were such
that the patients would be expected to have a high use of
CAM. Over half (56%) of the participants were women
with breast cancer, who tend to use CAM more frequently
than those with other malignancies [23, 39]. In addition,
the participants were younger and predominantly women,
both of which are associated with CAM use [6, 30, 31].
Herbals/vitamins were amongst the most commonly
used CAM, as has been found in other studies [3, 12, 30,
34, 39]; notably, some cohorts in which HV use is
common include cancer survivors who have completed
treatment and thus would not be at risk for chemotherapyHV interactions [3, 12, 30]. The majority (78%) of
our study participants reported using HV, with the most
commonly used HV being multivitamins, calcium, and
vitamin C (Table 5). Ganz et al. reported that, in a
population of 763 long-term, disease-free female breast
cancer survivors, Echinacea, gingko, and garlic are the
most frequently used herbals [12]. Green tea, Echinacea,
shark cartilage, grape seed extract and milk thistle were
the most common herbals in a cross-sectional study of
100 adult cancer patients, with multivitamin, vitamin C
and vitamin E being the most popular vitamins [3]. Most
of our study participants reported daily use of HV,
suggesting a high likelihood of an interaction.
Several approaches have been taken to evaluate the
frequency of detrimental chemotherapyHV interactions.
Weiger et al. recently summarized the current evidence of
the efficacy and safety of selected CAM therapies with
the aim of developing evidence-based, patient-centered
advice on CAM use for these patients [37]. Based upon
their review, it would be reasonable to discourage the use
of three HV, specifically daily vitamin C, vitamin A and
soy, as summarized in Table 2. Three of our patients
reported using vitamin A, 14 were using vitamin C daily
and four were using HV with hormonal effects (i.e., black
cohosh, ginseng, dong quai). We also evaluated the use of
HV with antioxidant effects (used by 26 patients) and
with potential bleeding effects (used by 6 patients).
A pharmacokinetic interaction between chemotherapy
and St. Johns wort or garlic could have occurred in 3 of
the 56 participants receiving chemotherapy metabolized
by cytochrome P450 (e.g., cyclophosphamide, vincristine,
vinblastine, vinorelbine, and paclitaxel) [19, 27]. Recent
data in healthy volunteers suggest that St. Johns wort
and garlic increase the clearance of indinavir [26] and
saquinavir [27], respectively, both of which are cytochrome P450 3A4 (CYP3A4) and p-glycoprotein substrates. Also, St. Johns wort influences the metabolism of

irinotecan, leading to lower concentrations of its active

metabolite SN-38 [19]. These data are of particular
concern to cancer patients, since many chemotherapeutic
agents (e.g., cyclophosphamide, ifosfamide, docetaxel,
paclitaxel, vincristine, vinblastine, vinorelbine, irinotecan, etoposide) are CYP3A4 and/or p-glycoprotein substrates. Similarly, several supportive care agents (e.g.,
granisetron, fentanyl, oxycodone) are CYP3A4 or pglycoprotein substrates; 18 participants were taking opioids in which altered pharmacokinetics could influence
pain relief.
Although only a few of our study participants reported
taking St. Johns wort or garlic, patient education regarding their interaction potential should be frequent, and the
risk versus benefit clearly explained, particularly when
the patient is using one of these herbs in the hope of
ameliorating the adverse effects of chemotherapy (e.g. St.
Johns wort relieving hot flashes) [22]. Notably, in vitro
data does not consistently predict in vivo interactions.
Grapefruit juice would be expected to lower intestinal
CYP3A content and hence increase the absorption of
CYP3A substrates such as etoposide. However, a recent
study in cancer patients has demonstrated the opposite
effect in that concomitant grapefruit juice administration
decreased etoposide absorption [28]. This example highlights the need for further studies evaluating how HV may
alter the pharmacokinetics and pharmacodynamics of
chemotherapy and supportive care medications.
The most common HV used, along with their frequency of use, could indicate what chemotherapyHV interactions are most concerning for immediate evaluation.
This is of imperative importance, as the participants
responses to the two hypothetical chemotherapyHV
interactions indicated that 3051% would discontinue
their use of a juice or herbal, respectively, if it influenced
the pharmacokinetics of their chemotherapy. The majority
of the remaining patients (3962%) indicated they would
ask their oncologist for advice regarding HV use in these
scenarios. The perceived benefit from HV may influence
continued HV use if an adverse interaction is realized.
Those who perceive a benefit from their HV may not
want to alter HV use due to a potential chemotherapyHV
interaction, although further work into the decision-making regarding discontinuing HV use if a potential harm is
recognized is needed. More data are also needed on effective education and communication strategies about the
adverse effects of HV [13, 32]. Based on a recent
assessment of the adequacy of herbal resources to answer
drug-herbal information questions, the Natural Medicines
Comprehensive Database is currently one of the most
reliable sources for information and may assist practitioners find relevant chemotherapyHV interactions [35].
The majority (62%) of study participants communicated HV use with their oncologists, although 31% failed
to discuss HV use to any health-care professional. In
addition, only 18% of the study participants had their HV

461

use documented in their medical record. The most

common reason for not discussing their HV use was that
their oncologist had not asked them about it (32%). The
use of a questionnaire regarding HV could allow the
oncologist to more efficiently assess HV use by a patient
and also initiate conversations regarding HV use, potentially allowing detrimental chemotherapyHV interactions to be identified. The most frequent primary sources
of HV information were: a friend or family member,
naturopathic physician, and physician. Nine patients
received information from a health food/nutrition store.
A recent report documented that health food store
employees commonly recommend HV to breast cancer
patients while rarely discussing the adverse effects and
potential chemotherapyHV interactions [21]. Richardson
et al. found that 74% of cancer patients desired more
information about CAM, preferably from books or pamphlets (90.4%) and from physicians (50%) [30]. Similarly,
in a survey by Swisher et al., over 75% of women
received CAM information from the media and the
internet, whereas only 25% of these same women
received information from their physicians or nurses
[34]. Thus, educational efforts regarding chemotherapy
HV interactions should be directed to several types of
health-care practitioners as well as the lay public,
particularly as recent data suggest that health-care professionals (i.e., physicians, pharmacists, nurses and dieticians) are generally deficient in their knowledge in the

adverse effects of herbals and other dietary supplements

[14].
There were limitations to this study. The frequency of
chemotherapyHV interactions is based upon a 44% rate
of study participation leading to a total of 76 study
participants. In addition, the participants self-reported HV
use. Ideally, a more objective method of estimating HV
use should be utilized, such as asking patients to bring in
all their medications and HV used at home and performing an in-depth interview. This method proved to be timeprohibitive, but the results from our questionnaire validation indicated that the questionnaire led to comparable
results. Unfortunately, HV use is rarely recorded in the
medical records (18%) and thus a retrospective chart
review could not be conducted. Estimation of adverse
chemotherapyHV interactions is challenging because of
a paucity of information regarding these interactions in
cancer patients and the numerous mechanisms of these
interactions. In addition, in vitro data do not consistently
predict in vivo findings in cancer patients. Thus, more
work is needed to establish which chemotherapyHV
interactions are of most concern, especially as these
results show that HV are commonly used by patients
receiving chemotherapy.
Acknowledgements The thoughtful comments of Danny D. Shen,
PhD, and Leanna Standish, ND, are greatly appreciated. We would
also like to thank Trey Powell and Geoff Chang for their data entry
support and the patients for their participation in this study.

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