33

Complementary and Alternative Medicine

Jeffrey D. White

SUMMARY

O F

K E Y

P O I N T S

Complementary and alternative

medicine encompasses various
approaches to all aspects of medical
assessment and management that
are not commonly or extensively
applied or recommended by
conventional western medical
practitioners.
Complementary and alternative
medicine approaches are frequently
used by patients, but patients often
do not discuss their use of these
approaches with their health care
team.
Some products purported to be
dietary supplements may be unsafe
for patients with cancer because of
adverse effects of the natural
components, adverse interactions
with medications, contamination with
toxic compounds, or adulteration
with drugs.
St. Johns wort and potentially
various other herbal products can
significantly alter the

pharmacokinetics of certain
chemotherapy drugs, such as
irinotecan.
High-dose alpha-tocopherol (i.e.,
400IU per day) should not be given
to patients with head and neck
cancer who are receiving radiation
therapy with curative intent.
Acupuncture can be useful for
managing cancer pain and
postsurgical pain.
Exercise can be an effective
intervention for preventing and
managing cancer-related fatigue.
Yoga may be effective in preventing
or managing fatigue and improving
sleep and quality of life in patients
with cancer.
Acupuncture, ginger, hypnosis,
relaxation therapy, and imagery can
provide additional relief from
chemotherapy-induced nausea and
vomiting in patients receiving
standard antiemetic regimens.

INTRODUCTION
Complementary and alternative medicine (CAM) is defined by the
National Center for Complementary and Alternative Medicine
(NCCAM), a component of the U.S. National Institutes of Health
(NIH), as a group of diverse medical and health care systems, practices, and products that are not generally considered part of conventional medicine, with conventional medicine defined as
medicine as practiced by holders of M.D. (medical doctor) and D.O.
(doctor of osteopathic medicine) degrees and by allied health professionals, such as physical therapists, psychologists, and registered
nurses.1 The World Health Organization defines CAM as a broad
set of health care practices that are not part of that countrys own
tradition and are not integrated into the dominant health care
system.2
It is generally accepted that complementary therapies are those
that are used along with conventional medical care for a given condition and alternative therapies are those that are used independent of
conventional care. Box 33-1 provides a categorization of CAM intervention and therapeutic systems using a modification of schema
developed by NCCAM.

High-dose oral glutamine and

intravenous glutathione may
decrease the frequency of
neuropathy from drugs containing
paclitaxel and platinum.
Preliminary evidence indicates that
acupuncture may effectively
decrease hot flash symptomatology
in women undergoing treatment for
breast cancer and in men receiving
androgen-deprivation therapy for
prostate cancer.
Aloe vera or honey taken orally and
intravenously administered glutamine
may decrease the incidence or
severity of chemotherapy-induced
oral mucositis.
Several interventions have been
found useful for stress reduction and
to increase the quality of life among
patients with cancer, including
music, meditation, relaxation
therapy, and imagery therapy.

A recent, large, national, population-based survey showed that

43.3% of U.S. patients with cancer had used at least one CAM
intervention in the preceding 12 months.3 Evidence suggests that the
use of such approaches, even those with the greatest theoretical potential for interaction with conventional therapy, is often not disclosed
to the treating oncologist.4,5
Integrative medicine is defined by the Consortium of Academic
Health Centers for Integrative Medicine as an approach to the practice of medicine that makes use of the best-available evidence taking
into account the whole person (body, mind, and spirit), including all
aspects of lifestyle. It emphasizes the therapeutic relationship and
makes use of both conventional and complementary/alternative
approaches.6
Although a broad definition of CAM could include diagnostic,
screening, and preventive approaches, the presentation in this chapter
will largely be focused on interventions used to improve quality of
life and prevent or manage cancer symptoms or adverse effects of
treatment, along with those used with the intent of improving survival or the response to standard medical treatment. In addition,
much of the research literature for certain CAM approaches,
for example, traditional Chinese medicine (TCM), is not readily

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Box 33-1. CATEGORIES OF COMPLEMENTARY THERAPIES*

Alternative Medical Systems (and Some
Specific Components)
Definition: Alternative medical systems incorporate complete systems
of theory and practice. Often, these systems have evolved apart
from and earlier than the conventional medical approach used in
the United States.
Examples: Traditional Chinese medicine, acupuncture, ayurveda,
homeopathy, naturopathy

Energy Therapies
Definition: Energy therapies involve the use of energy fields. They are
of two types:
Biofield therapies are intended to affect energy fields that
purportedly surround and penetrate the human body. The
existence of such fields has not yet been scientifically proved.
Examples: Qi gong, Reiki, therapeutic touch
Bioelectromagnetic-based therapies involve the unconventional use
of electromagnetic fields, such as pulsed fields, magnetic fields, or
alternating current or direct current fields.
Examples: Electromagnetic fields (pulsed fields, magnetic fields),
magnet therapy

Manipulative and Body-Based Methods

Definition: Manipulation and/or movement of one or more parts of
the body administered by a practitioner.
Examples: Chiropractic, therapeutic massage, osteopathy, reflexology

Mind-Body Interventions
Definition: Mind-body medicine uses a variety of techniques designed
to enhance the minds capacity to affect bodily function and
symptoms.
Examples: Aromatherapy, art therapy, biofeedback, cognitivebehavioral therapy, dance therapy, hypnosis, imagery, meditation,

music therapy, pet therapy, prayer, relaxation therapy, support

groups, yogic meditation, yogic breathing, biofeedback

Movement Therapies and Unconventional

Physical Therapies
Definition: Movement therapy is a process through which a person
learns to reeducate his or her bodys movement and improve on
patterns of movement that cause stress-related emotional
conditions.
Examples: Tai chi, hatha yoga, Feldenkrais, Alexander technique

Nutritional Therapeutics
Definition: An assortment of nutrients and nonnutrients, bioactive
food components that are used as chemopreventive agents, and
the use of specific foods or diets as cancer prevention or treatment
strategies.
Examples: Dietary regimens such as macrobiotics, Gerson diet, Kelley/
Gonzalez regimen, vitamins, dietary supplements, soy
phytoestrogens, antioxidants, glutamine, glutathione

Pharmacologic and Biologic Treatments

Definition: Drugs (including certain off-label uses of approved drugs),
complex natural products, certain vaccines, and other biological
interventions not yet accepted in mainstream medicine.
Examples: Antineoplastons, 714X, low-dose naltrexone, laetrile,
hydrazine sulfate

Subcategory: Multicomponent Natural Products

Definition: Whole-plant samples (botanicals), extracts of crude natural
substances, and unfractionated extracts from marine organisms
used for healing and treatment of disease.
Examples: Herbs and herbal extracts, mixtures of tea polyphenols,
shark cartilage

*Some modalities could be included under more than one category.

available in English. The presentation here is limited to findings

reported in the English language literature.

NUTRITIONAL THERAPEUTICS
Patients with cancer often have unmet needs for dietary advice.7,8
Various small studies have shown that nutritional counseling and
education improves outcomes (i.e., quality of life and/or survival) for
patients with head and neck,9 colorectal,10 and lung cancer.11

Dietary Supplements
The term dietary supplement refers to a product (other than
tobacco) intended to supplement the diet that bears or contains one
or more of the following dietary ingredients: a vitamin; a mineral; an
herb or other botanical; an amino acid; a dietary substance for use
by man to supplement the diet by increasing the total dietary intake.12

Legal and Regulatory Issues

Since the passage of the Dietary Supplement Health and Education
Act of 1994, companies seeking to market dietary supplements in the
United States do not need to obtain prior approval from the U.S.
Food and Drug Administration (FDA). By law, the advertisements
and labels for such products can only make structure and function
claims regarding a products effectiveness and cannot claim that the
product should be used to cure, mitigate, prevent, or treat a disease.

Contamination and Adulteration

The FDA and various state and local drug regulatory authorities and
academic researchers frequently find that dietary supplements that
are sold in U.S. stores or are available through the Internet are contaminated with heavy metals13 or adulterated with prescription medications.14 For example, PC-SPES was an herbal product manufactured
and distributed by a U.S.-based company and advertised as preserving
prostate health, but it was extensively used by patients with prostate
cancer. PC-SPES was also being investigated as a potential prostate
cancer therapy until the product was voluntarily withdrawn from the
market in 2005 after the California Department of Health Services
and the FDA published warnings indicating that several production
lots were found to contain various amounts of warfarin and
diethylstilbesterol.15

Adverse Effects
Adverse effects of a dietary supplement may be due to the labeled
contents in the supplement or a contaminant or adulterant. In
the case of herbal supplements, instances have occurred of the substitution of a different herb for one listed on the label, sometimes
because of misidentification of the plant. The Natural Medicine
Comprehensive Database16 and Micromedex17 contain referenced
information about the adverse effects of a large number of dietary
supplement components. The following sections provide examples of
some adverse effects that are relevant to patients with cancer.

Complementary and Alternative Medicine CHAPTER 33 521

Chaparral (Larrea divaricata Coville)

Licorice (Glycyrrhiza species)

The leaves of chaparral, a desert shrub also known as the creosote

bush, are reportedly used in Native American medicine.18 The plant
contains nordihydroguaiaretic acid, a compound that is under investigation as an anticancer agent.19 Renal and hepatic toxicity have been
associated with chronic use of products that contain chaparral.20-22

The root of the licorice plant has been used in TCM formulations
for centuries. The now-banned herbal product PC-SPES reportedly
contained Glycyrrhiza glabra,46 as do some herbal products currently
used by patients with prostate cancer. Glycyrrhizic acid, a component
of licorice, inhibits 11-hydroxysteroid dehydrogenase, thus resulting
in mineralocorticoid excess, which can cause hypertension and hypokalemia.47 Severe consequences of hypokalemia, including paralysis
and torsades de pointes ventricular arrhythmia, have been reported
in patients taking products that contain licorice.48,49

Kava (Piper methysticum)

Kava is an herbal remedy generally recommended for the treatment
of anxiety or to improve sleep.23 Two randomized, controlled trials
have confirmed evidence of its anxiolytic activity.24 However, several
cases of severe liver toxicity associated with the consumption of
products labeled as containing extracts of kava have been reported.
Consequently, kava is banned in several European countries,25 and
the U.S. FDA has issued a consumer advisory warning of the potential risk of hepatic toxicity from kava ingestion26; however, products
containing kava may still be legally sold in the United States as dietary
supplements.27

Laetrile
Laetrile, also known as amygdalin, is a cyanogenic glucoside found
in the pits of many fruits, in raw nuts, and in other plants such as
lima beans, clover, and sorghum.28,29 Although it is frequently called
vitamin B17 in the lay literature, amygdalin is not recognized as a
vitamin by the Committee on Nomenclature of the American Institute of Nutrition. Laetrile has been given orally and intravenously
with different pharmacokinetics and toxicity profiles. Laetrile became
a popular alternative cancer therapy in the 1950s and remained so
through the 1980s. Currently, its sale in the United States is banned
by the FDA; however, products labeled as containing laetrile can
easily be purchased via the Internet. When orally ingested, laetrile
can be hydrolyzed by intestinal beta-glucosidase to produce hydrogen
cyanide, benzaldehyde, and glucose. The enzymatic activity of betaglucosidase, and thus the rate of production of cyanide, can be
increased under various conditions, including the presence of vitamin
C.30 Signs and symptoms of cyanide poisoning have been reported
both from individual patients with cancer who ingested products
containing laetrile31,32 and from patients enrolled in clinical trials of
oral laetrile.33,34

Cesium Chloride
Cesium chloride has been promoted in books and on the Internet as
a cancer therapy. No clinical trials of the use of cesium chloride have
been published, but several case reports have described patients with
cancer in whom QT prolongation and torsades de pointes ventricular
tachycardia developed after they ingested products containing cesium
chloride.35-40 In some of these reported episodes of toxicity, the
patients also demonstrated hypokalemia and/or hypomagnesemia. In
one case, the patient was successfully treated with 4 weeks of oral
Prussian blue.35

Aloe Vera
Leaves from aloe vera, a fleshy, cactus-like plant, contain a clear gel
that is often used to soothe minor skin irritations, although a systematic review of the research failed to find firm evidence for a preventive
effect with regard to radiation-induced skin reactions.41 Aloe latex is
an extract of the inside of the outer lining of the leaves and is
approved by the German Commission E for treating constipation.42
The gel can also be made into a juice that has been promoted as a
cancer cure. In a male patient with HER2+ breast cancer who was
taking capecitabine, trastuzumab, and 1L a day of aloe vera juice for
2 weeks, severe hypokalemia developed that responded to potassium
supplementation after ingestion of the aloe juice was stopped.43 In
clinical trials of smaller doses of aloe juice (i.e., 10mL taken three
times a day), hypokalemia has not been found to be an associated
adverse effect.44,45

Herbs Containing Aristolochic Acid

Aristolochic acid, a nephrotoxin that also may induce urothelial
tumors, is found in herbs of the Aristolochiaceae family, as well as
some from Bragantia and Asarum genera.50 Some of these herbs are
used in TCM (e.g., guan mu tong [Caulis aristolochiae manshuriensis], which is used for dysmenorrhea and breast disorders), and they
are used in some weight-loss formulas found in Europe. Case reports
have been published of patients in the United States who have experienced toxicities (e.g., renal failure and urothelial cancer) after ingesting supplements derived from these plants.51 The FDA has found that
some botanical products labeled as containing Aristolochia, Bragantia, or Asarum contain aristolochic acid.52

Adverse Interactions between Dietary

Supplements and Drugs
Adverse effects resulting from interactions between a dietary supplement and a drug generally occur because of effects on the drugs
pharmacokinetic (PK) or pharmacodynamic (PD) properties. Many
of the PK-related interactions are due to induced alterations in
enzymes involved in drug metabolism or transport.

Cytochrome P450 Inducers and Inhibitors

The enzymes of the cytochrome P450 (CYP450) superfamily are
responsible for the activation or inactivation of the vast majority of
drugs currently in use.53 Drugs or other exogenous chemicals ingested
in the diet or via dietary supplements can affect the activity of
CYP450 enzymes to a sufficient degree to meaningfully change the
clinical effectiveness or toxicity of various chemotherapy drugs. Table
33-1 lists some herbs that have been shown to affect various CYP450
enzyme activities in humans and other herbs for which the effects on
CYP450 enzymes have been predominantly determined by in vitro
or animal studies, and thus are of uncertain clinical significance.
Other herbs interfere with drug PK via effects on the activity of
the P-glycoprotein multidrug transporter (e.g., curcumin) or other
adenosine triphosphatebinding cassette drug transporters (e.g.,
genistein).54
ST. JOHNS WORT

A classic example of an herb affecting drug PK is St. Johns wort.

Plasma levels of the active metabolite of irinotecan, SN-38, were
decreased by 42% in five patients receiving irinotecan and a commonly used dose of St. Johns wort (300mg three times daily), apparently because of induction of the CYP3A4 isoform.55 Imatinib is also
a CYP3A4 substrate, and a study using the same dosing schedule of
St. Johns wort found a 43% increase in the drugs clearance and a
30% decrease in the area under the curve of the plasma
concentration.56

Green Tea Extract and Epigallocatechin Gallate

Green tea and its polyphenols such as epigallocatechin gallate
(EGCG) can affect drug metabolism and effectiveness via actions on
either PK or PD. A PD-related dietary supplementdrug interaction
has been noted in preclinical studies of the combination of green tea

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and bortezomib. EGCG blocked bortezomibs anticancer effect on

human multiple myeloma and glioblastoma cell lines in vitro by
binding to the boronic acid component of the drug; this action
occurred at concentrations achievable in the blood of humans after
ingesting dietary supplements containing green tea.57 In addition, the
same research group reported that intragastric EGCG administration
(50mg/kg) completely abrogated bortezomib-induced apoptosis in
plasmacytoma xenografts in nude mice. Another animal study also
demonstrated that the antitumor activity of bortezomib on human
prostate cancer xenografts in severe combined immune deficiency
mice was completely eliminated with the very high plasma concentrations obtained after intravenous EGCG administration but not with
the lower concentrations resulting from subcutaneous administration.58 No human studies have been performed that directly address
the clinical significance of this interaction.
A published case report describes a Chinese patient with metastatic renal cell carcinoma who was being treated with sunitinib and

Table 33-1 Herb-Drug Interactions

noted aggravated symptoms from a retro-orbital ocular metastasis at

times when he increased the amount of green tea that he drank.59 An
animal study of the effects of coadministration of sunitinib and
EGCG revealed the formation of a precipitate in the stomach, resulting in lowered sunitinib absorption.
Table 33-2 lists several other herb-drug interactions of potential
relevance when advising and managing patients with cancer.

Antioxidants
Several different nutrients (e.g., vitamin C, vitamin E, and selenium)
and other bioactive food components (e.g., glutathione) can act as
electron donors in vivo and thus are considered antioxidants. Various
chemotherapy agents and radiation therapy induce the production of
chemically reactive free radicals (e.g., hydrogen peroxide, OH and
superoxide, O2) that can damage a variety of cellular components
(e.g., DNA and lipid membranes). Antioxidants can act as free radical
scavengers and thus could potentially alter both the therapeutic and
adverse effects of cancer therapies that produce free radicals. Consequently, the risk-benefit assessment for the concurrent use of highdose antioxidant supplements during chemotherapy or radiation
therapy remains controversial. Specific clinical trial results, however,
have generally failed to show a detrimental effect of antioxidants on
chemotherapy or radiation therapy effectiveness,60 although there is
at least one notable exception.

Herb

Drug

Affect

Source

St. Johns
wort

Irinotecan

Increases enzyme
activity and decreases
AUC of active
metabolite SN38

Clinical trial55

St. Johns
wort

Imatinib

Increases clearance
and decreases AUC of
drug

Clinical trial56

Green tea

Sunitinib

Decreases drug
absorption

Animal study and

case report59

Ginkgo
biloba

Teniposide

May decrease
circulating
concentration

Clinical trial
(theoretical
interaction based on
known effects of
herb on a similarly
metabolized drug)183

Black
cohosh

Substrates
of CYP2D6

Increases drug
metabolism

Clinical trial184

The term vitamin E can refer to any of eight compounds (four

tocopherols and four tocotrienols) with related chemical structures
and antioxidant properties, or a mixture of them. From among the
individual vitamin E compounds, only alpha-tocopherol has been
studied for its potential to prevent chemotherapy- or radiation
therapyinduced adverse effects in humans. Alpha-tocopherol at a
dose of 400IU per day has been found to decrease the acute
toxicity of radiation for patients receiving therapy for head and neck
cancer.61,62 However, in the largest randomized study thus far reported,
the patients who received the alpha-tocopherol supplements also
experienced a higher risk of recurrence of the tumor, more frequently
experienced the development of new primary tumors while receiving
the vitamin E, and had a poorer mean overall survival.63,64

Garlic

Saquinavir

Decreases serum levels

Clinical trial185

Anticoagulant Interactions

VITAMIN E

AUC, Area under the curve.

Various dietary supplements are suspected of having independent

anticoagulant activity, although the evidence is largely from case

Table 33-2 Adverse Interactions between Dietary Supplements and Cancer Therapies
Anticancer Agent

Herb/Dietary Supplement

Interaction

Source

Rituximab

Bilberry; bitter melon

Hypoglycemia

Theoretical interaction based on shared adverse

effects183

Radiation therapy

dl-alpha-tocopherol (vitamin E)

Increased tumor recurrence rate

Randomized clinical trial result64

Procarbazine

Ginseng

Mania

Theoretical interaction based on observed reaction

with another MAO inhibitor, phenelzine186,187

Imatinib

Ginseng

Transaminitis with biopsy evidence

of hepatic injury

Case report188

VEGF inhibitors

Licorice

Aggravated hypertension

Theoretical interaction based on shared adverse

effects

Bortezomib

EGCG, green tea extract

Decreased anticancer effect

In vitro57,58

Sunitinib

Green tea

Decreased anticancer effect

Preclinical research and a case report59

5-FU

Green tea

Increased 5-FU serum concentration

and AUC

Animal research189

AUC, Area under the curve; EGCG, epigallocatechin gallate; 5-FU, 5-fluorouracil; MAO, monoamine oxidase; VEGF, vascular endothelial growth factor.

Complementary and Alternative Medicine CHAPTER 33 523

Box 33-2. DIETARY SUPPLEMENTS WITH

PLATELET INHIBITOR ACTIVITY
Celadrin
Fish oil
Ginkgo biloba
Garlic

Ginseng
Glucosamine
Vitamin E

activity.67,68 Another notable difference between the two trials was

that women following the low-fat diet in the Womens Intervention
Nutrition Study trial lost weight, whereas women following the investigational diet on the Womens Healthy Eating and Living trial did
not lose weight.
SOY

Table 33-3 Supplements that May Interact

with Warfarin

Supplement

Action

Source

CoQ10

Decreased warfarin
effect

Animal studies and

in vitro human
microsomes studies

Dan shen (Salvia

miltiorrhiza)

Increased warfarin effect

Animal study

Dong quai
(Angelica sinensis)

Increased warfarin effect

Animal study

Fenugreek

Increased warfarin effect

Clinical case report

Green tea

Decreased warfarin
effect

Clinical case report

reports. Several dietary supplements have been found to inhibit platelet aggregation to varying degrees in vitro (see Box 33-2), and human
trials have demonstrated that vitamin E can augment aspirins antiplatelet affects.65 Table 33-3 provides some examples of supplements
reported to interact with warfarin.

CANCER TREATMENT
Breast Cancer
Nutrition and Physical Activity
LOW-FAT, HIGH-FRUIT, AND VEGETABLE DIET

Several observational studies have found that women who are overweight or obese at the time of breast cancer diagnosis have poorer
clinical outcomes, including survival. Additionally, similar studies
have shown better survival rates in women with breast cancer who
undertake greater amounts of physical activity; however, the potential
benefit of a healthy diet (i.e., low fat and high in fruit and vegetables) has been equivocal.
Two prospective studies have addressed the potential impact of
dietary modification, and to a lesser extent physical activity, on the
survival of women with early-stage breast cancer. The Womens Intervention Nutrition Study randomly assigned 2437 women with stage
I to III breast cancer and who had completed their adjuvant chemotherapy, when given, to either a diet low in fat (15% of calories) and
high in fruits and vegetables or a control group that received general
dietary advice from a dietician.66 After a median of 60 months of
follow-up, women following the low-fat diet experienced a statistically significant 24% reduced risk of relapse. The primary end
point of relapse-free survival, however, was not statistically different
(P = .07) for the entire study group, although women with estrogen
receptornegative tumors did have a significantly longer relapse-free
survival (P = .03). Another similarly designed and sized study, the
Womens Healthy Eating and Living trial, failed to find a significant
difference in recurrence rate for women on the low-fat diet, although
a better recurrence rate was seen in the subgroup of women who
adhered to the low-fat diet and undertook a greater degree of physical

Various foods such as legumes contain phytoestrogens; soy is particularly abundant in these compounds and has drawn the most attention
regarding its potential to produce estrogenic adverse effects. Much
speculation has occurred about the risk of soy intake by women with
breast cancers that express estrogen receptors and, largely because of
preclinical research findings about the effects of the phytoestrogens
in soy, such women frequently receive recommendations to avoid
eating soy products. However, an analysis of the pooled data from
two large U.S. trials and one trial from China, with a total of more
than 9500 women, found a nonsignificant reduced risk of breast
cancerspecific mortality and a statistically significant reduced risk of
breast cancer recurrence for women who consumed >10mg of soy
isoflavones per day after their cancer diagnosis. 69

Mind-Body Approaches
Studies in which animals bearing implanted tumors are exposed to
stressful conditions thought to mimic psychological stress in humans
often result in increased tumor growth and metastases rates and
diminished responsiveness of the tumor to chemotherapy. However,
the potential for a mind-body intervention to affect the course of
cancer progression or treatment response in humans has been very
controversial, and few relevant experimental data are available. Several
studies of support group interventions that included assessments of
patient survival have been performed in patients who have cancer
with conflicting results. Specifically regarding metastatic breast
cancer, at least six randomized trials have been reported,70-74 although
only the first study yielded positive results for survival.70 This first
study found that patients who received the combined support group
and hypnosis interventions experienced a longer median survival than
did those in the control group.70 However, three subsequent studies
utilizing a very similar intervention failed to confirm this finding,
showing no benefit in survival for the patients receiving the expressivesupport therapy.71,73,74
Only two studies have specifically explored the effects of psychosocial support or stress-reduction approaches on recurrence or survival in women with early-stage breast cancer. The studies utilized
different support interventions, and the study that used a stressreduction intervention (26 sessions over 12 months) found a statistically significant benefit both for risk of recurrence and survival,
although the number of both events was very small.75 The other study
utilized cognitive-existential group therapy weekly (20 weekly sessions) and found no effect on recurrence or survival.76

Pancreatic Cancer
Curcumin
In addition to many chemotherapy agents, a few dietary compounds
have been paired with gemcitabine in pancreatic cancer treatment
trials. Oral curcumin at a dose of 8g a day showed signs of singleagent activity in a phase 2 trial; however, the same dose was not as
well tolerated when given with gemcitabine.81,82 A nanoparticle formulation of curcumin for intravenous administration has been produced and may prove to be better tolerated.83,84

Kelley-Gonzalez Regimen
Dr. William D. Kelley, a dentist from Texas, developed a complex
regimen based on the treatment approach of an earlier alternative
medicine physician, Dr. Max Gerson, and promoted it as a cancer
therapy. A main component of this approach is the use of oral

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pancreatic enzymes, but the regimen also includes (1) vitamin and
mineral supplementation, (2) concentrates of raw beef organs and
glands in pill form, (3) other digestive aids, including hydrochloric
acid and bile salts, and (4) a detoxification regimen including frequent coffee enemas.85 An initial uncontrolled study of this regimen
yielded promising survival results for the subset of patients with
unresectable pancreatic cancer who had the best compliance with the
regimen.86 However, a subsequent prospective, nonrandomized
cohort study of patients with unresectable pancreatic cancer found
an inferior survival for patients who self-selected to receive the KellyGonzalez therapy compared with patients treated with various chemotherapy regimens containing gemcitabine.87

Colorectal Cancer
Exercise
As with breast cancer, observational studies have demonstrated a
strong association between the degree of physical activity and outcomes of patients with early-stage colorectal cancer. Two such studies,
one in women with stage I to III colorectal cancer and the other of
men and women with stage III colorectal cancer, both showed statistically significant improvements with moderate to strenuous physical
activity for both risk of recurrence and survival.88,89 Several relatively
small trials are underway that are designed primarily to assess the
potential benefit of increased physical activity on quality of life,
functional measures, or biological end points, but none yet focusing
on survival.

Prostate Cancer
Lifestyle Modification during Active Surveillance
The Prostate Cancer Lifestyle Trial was a 1-year randomized controlled trial of 93 patients with early-stage prostate cancer (Gleason
score <7; prostate-specific antigen, 4-10ng/mL) who were undergoing active surveillance. The experimental group received a low-fat,
plant-based (vegan) diet supplemented with soy, fish oil, vitamin E,
selenium, and vitamin C, along with a regimen of moderate aerobic
exercise (walking 30 minutes, 6 days weekly) and stress management
(gentle yoga-based stretching, breathing, meditation, imagery, and
progressive relaxation for 60 minutes daily) and 1-hour weekly group
support sessions to enhance adherence to the program. Control
patients received usual care. At the end of the 1-year program,
patients in the experimental group had had a significant reduction in
prostate-specific antigen level and fewer prostate cancerrelated clinical events compared with control patients.90 After 2 years of follow-up,
fewer patients in the experimental group experienced signs of progression that required medical or surgical management (2 of 43 [5%] vs.
13 of 49 [27%], P = .05).91

SYMPTOM/ADVERSE-EFFECT MANAGEMENT
AND QUALITY OF LIFE
Complementary therapies have gained greatest acceptance, both in
research and practice, for the management of cancer symptoms and
treatment adverse effects and for their potential to improve overall
quality of life. This section presents some approaches that are available and in use to varying degrees in North America. Many of these
approaches may affect multiple complaints simultaneously, so-called
symptom clusters, and thus present the potential for efficient, welltolerated management.92,93 However, various factors limit the interpretation of the research findings, lessening the utility of the evidence
base for each of these practices. Many of these interventions are
poorly standardized, if at all, and thus variables that are carefully
controlled in a good-quality clinical trial (e.g., product quality) may
not be so carefully controlled in general practice. For some dietary
supplements, particularly herbs, the active ingredient(s) may not be
known.

Consequently, it may be very difficult to select a product with the

appropriate biological activity. Also, the need still exists for consistent
and validated ways to assess the clinical competence of certain types
of practitioners who administer and advise about the use of these
approaches. Some complex complementary interventions (e.g., alternative medical systems) are intentionally simplified when studied in
clinical trials to facilitate the conduct and interpretation of the
studies. This process has led to criticism from practitioners about the
integrity of the approach under study and therefore the practical
significance of the research findings. Finally, although many of these
interventions have a significant research literature, most of them have
been studied in only a limited number of clinical cancer settings, and
it may be inappropriate to generalize the findings to other settings.

Pain
Acupuncture
Acupuncture has demonstrated analgesic activity in animal models
of cancer pain through studies in at least two independent
laboratories.94,95 These studies have also identified effects on various
mediators of pain sensation, including substance P, endorphins, and
interleukin 1beta. Other work has supported a role for effects of
vasopressin secretion.94,96
Acupuncture, acupressure, and acustimulation (i.e., electrical
stimulation of acupuncture points) have been used and studied for
their effects in relieving various types of pain. However, very few
well-designed clinical trials of these modalities have been conducted
in patients with cancer-related pain. One randomized, controlled
clinical trial of auricular acupuncture was performed in patients
whose pain was not adequately controlled with analgesic medications.
In this study, patients who received electroacupuncture applied to the
proposed active points had significantly less pain than did patients in
the placebo treatment groups.97
POSTSURGICAL PAIN

One small, nonrandomized study reported greater pain relief and an

increased range of motion in patients treated with acupuncture after
breast cancer surgery and axillary lymph node dissection.98 A randomized trial comparing weekly acupuncture versus usual care in
patients after surgical resection for head and neck cancer found significant improvements in pain and dysfunction among patients
receiving acupuncture.99

Imagery
The exploration of guided imagery as a potential therapeutic modality in the management of cancer pain has been very limited; only a
few small studies have been conducted, with no two exploring the
same clinical situation. A pilot study of progressive muscle relaxation
and analgesic imagery showed some positive effects for each among
hospitalized patients with pain related to cancer.100 A randomized,
controlled trial using relaxation, imagery, and cognitive-behavior
training found lower mucositis pain scores in patients undergoing
bone marrow transplantation.101 Another study in patients with pain
due to metastatic breast cancer failed to demonstrate an effect of the
combination of relaxation, visualization, and cognitive coping skills
training on pain intensity or its psychological effect.102

Reiki
Reiki is a healing system based on Tibetan scriptures but developed
in Japan. The therapy is provided by practitioners called Reiki masters
and is a form of energy therapy that involves placing ones hands near
or on portions of the patients body while maintaining a specific
therapeutic intention. This intervention has been studied in only a
few clinical trials. A randomized phase 2 study demonstrated
improved pain control in patients with advanced cancer who received
Reiki therapy compared with a resting control.103

Complementary and Alternative Medicine CHAPTER 33 525

Aromatase InhibitorInduced Arthralgia

Acupuncture
A small randomized, blinded study of acupuncture for aromataserelated joint symptoms found that true acupuncture given for 30
minutes twice weekly for 6 weeks was significantly more effective
than sham acupuncture.104 The research base for the Southwest
Oncology Group Community Clinical Oncology Program has
recently initiated a follow-up study using the same acupuncture
approach.105 However, another multicenter trial was stopped early for
futility based on interim results.106

unsupervised, home-based exercise; however, even home-based exercise produced a significant benefit versus usual care or a placebo
stretching program.119 A prospective clinical trial assessing the potential benefits of enhanced physical activity during cancer treatment on
fatigue and quality of life of patients with breast and colon cancer is
underway.120

Yoga

Although low serum levels of vitamin D have not consistently been

associated with the risk of developing aromatase inhibitorinduced
musculoskeletal symptoms, recent studies have shown promising
results from vitamin D supplementation.107 A randomized, placebocontrolled trial in woman with anastrozole-induced musculoskeletal
symptoms demonstrated a significant benefit with high-dose oral
vitamin D2 supplementation (i.e., 50,000IU weekly for varying
periods), while simultaneously contributing to diminished bone
loss.108 A similar but less intense strategy was employed in a study
using high-dose vitamin D3 supplementation to attempt to prevent
musculoskeletal symptoms in women about to start taking letrozole.
Beneficial effects were seen in the women having the greatest improvement in 25-hydroxyvitamin D levels.109

Yoga may be most accurately defined as a system of physical, mental,

and spiritual development that originated in ancient India, but in the
modern international context, the term includes many variations on
the traditional practices (e.g., restorative yoga), as well as practices,
both ancient and recent, that developed in other countries (e.g.,
Tibetan yoga). The major components of the many systems of yoga
include physical postures, breath control, and meditation. A metaanalysis of yogas effects on cancer-related fatigue has synthesized the
results of several trials.121 The type of yoga intervention and the
length and frequency was different in each trial. The pooled results
of all studies (n = 362) found that yoga compared with control was
associated with a significantly greater improvement in fatigue.
Another recent large multicenter randomized study (n = 410) assessed
the effect of the University of Rochesters Yoga for Cancer Survivors
program on cancer survivors without metastatic disease who also had
fatigue and moderate or greater sleep disruption. On average, the
patients in the yoga intervention group experienced improved sleep
quality, fatigue, and quality of life.122

Cachexia

Energy Therapies

Vitamin D

Nutritional Therapeutics
The ingestion of high doses of fish oil, or the omega-3 fatty acids
derived from it, has been proposed to produce salutary effects in
patients with various conditions. Results from one randomized controlled trial demonstrated improvement in appetite and lean body
mass in patients with advanced pancreatic cancer.110 Another trial,
however, failed to demonstrate any improvement in appetite, nutritional status, caloric intake, or other related symptoms in patients
with other types of advanced cancer.111 Fish oil generally is well
tolerated at doses up to 3 g per day. Higher doses can cause eructation, halitosis, heartburn, gastrointestinal upset, nausea, and loose
stools.112

Fatigue
Cancer-related fatigue is the perception of unusual tiredness that
varies in pattern of severity and has a negative impact on the ability
to function in patients who have or have had cancer.113 Its etiology
is likely multifactorial, but recent work has found an association with
inflammation.114

Acupuncture
Three randomized controlled trials have been reported, all of which
used some acupuncture points in common, but no two of the studies
used exactly the same protocol; all three trials used sham acupuncture
controls. One study116 attempted to prevent fatigue in patients receiving external radiation therapy and failed to show a statistically significant advantage of the true acupuncture intervention. The other
two trials117,118 attempted to ameliorate chronic fatigue after completion of chemotherapy, but only one trial117 showed an advantage for
the true acupuncture intervention.

Various energy therapy approaches have been prospectively studied

as potential fatigue therapies with somewhat mixed results. Two
randomized controlled trials in patients with cancer have demonstrated the potential of healing touch to improve fatigue and
other physical and psychological adverse effects of chemotherapy.123,124 A study of therapeutic touch found significant improvement over relaxation or usual care both for fatigue and quality of
life, and a recent study of an approach known as energy chelation
therapy showed improvement in patients fatigue for both the
active and sham treatment groups compared with an untreated
control group.125

Herbs and Other Dietary Supplements

GINSENG

Both Asian ginseng (Panax ginseng) and American ginseng (Panax

quinquefolius) have been studied for their potential effects on cancerrelated fatigue, yielding positive results in small single-arm and randomized trials. These plants are classified by herbalists as adaptogens
because of the belief, supported by some research results, that their
use can help improve a persons ability to better adapt to physical
stress. Both types of ginseng contain several bioactive compounds,
including polysaccharides and triterpene saponins, known as ginsenosides. The North Central Cancer Treatment Group recently completed a multicenter, randomized, placebo-controlled trial in which
American ginseng, standardized to contain 5% ginsenoside, at a dose
of 2000mg per day in two divided doses, significantly improved a
validated measure of cancer-related fatigue in patients with cancer
who were undergoing, or had completed, treatment with curative
intent.126 A randomized, placebo-controlled trial of Asian ginseng in
patients undergoing chemotherapy or radiation therapy is underway
at MD Anderson Cancer Center.

Exercise

GUARANA

Various exercise approaches have been studied in several different

patient populations at different points in the continuum of care. A
meta-analysis of 18 randomized controlled trials of patients with
various cancer types, although mostly breast cancer and prostate
cancer, has shown that supervised exercise is more effective than

The caffeine-containing herb guarana was tested against placebo in a

small study of patients with breast cancer who were experiencing
fatigue while undergoing chemotherapy and was found to be effective.127 Apparently, no randomized controlled trials of caffeine alone
for cancer-related fatigue have been reported.

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L-CARNITINE

Preliminary evidence indicated that correction of carnitine deficiency

in adult patients with cancer who experienced fatigue led to improvement of the symptom.128 However, a larger multicenter trial failed to
find a significant improvement in a more heterogeneous group of
patients with a diagnosis of invasive cancer and fatigue but who were
not required to have carnitine deficiency prior to study entry.129

Hypnosis

Sleep

Hypnosis, including self-hypnosis, has been studied in clinical trials

of both pediatric and adult patients with cancer for a variety of indications. At least one small pilot study137 and three small randomized
controlled trials101,138,139 have demonstrated efficacy for hypnosis as a
treatment of anticipatory or chemotherapy-induced nausea and vomiting in patients with cancer. Other less-studied mind-body
approaches, such as cognitive distraction approaches, have also shown
positive effects in randomized controlled trials.140

Yoga

Relaxation and Imagery

A randomized trial of Tibetan yoga versus wait-list control in

patients with lymphoma showed improvements in sleep quality,
sleep latency, sleep duration, and use of sleep medications.130 More
recently, a multicenter, randomized, controlled trial demonstrated
that a program utilizing yoga postures (asanas), breathing exercises
(pranayama), and meditation could decrease the use of sleep medications among patients with cancer who experienced moderate or
greater sleep disruption.122

Relaxation and or imagery interventions have been studied in at least

seven randomized clinical trials against a control, with anticipatory
or chemotherapy-induced nausea and vomiting as a predetermined
study end point.141-147 In all of these trials the relaxation/imagery
group fared significantly better than the control group for at least one
relevant outcome measure.

Herbs

Acupuncture

Valerian (Valeriana officinalis) at a dose of 450mg at bedtime did

not show a significant benefit over placebo in patients undergoing
treatment for cancer and with a baseline moderate to severe sleep
disturbance.131

Acupuncture has been studied as a potential treatment for various

forms of neuropathy. Several case reports and small case series have
reported clinically significant improvements in patients neuropathic
symptoms after various different acupuncture interventions. However,
thus far no randomized controlled trials addressing chemotherapyinduced neuropathy have been reported in the English language
medical literature.

Nausea and Vomiting

Acupuncture and Acupressure
After a systematic review of the literature, the NIH Consensus Development Panel on Acupuncture in 1997 found promising results had
emerged suggesting efficacy in managing chemotherapy-induced
nausea.132 Among the studies reviewed by the panel were three randomized controlled trials, all of which evaluated the effects of electrical stimulation at the P6 (Neiguan) acupuncture point on the volar
surface of the wrist with or without costimulation at other acupuncture sites, and all of which included only adult patients with cancer
as subjects, with control groups receiving antiemetic regimens that
did not include a 5-hydroxytryptamine (5-HT) receptor antagonist.
Several subsequent studies have continued to demonstrate the effectiveness of acupuncture for the prevention of chemotherapy-induced
nausea in patients already receiving a 5-HT receptor antagonist, in
children, and using other acupuncture points (e.g., ST35, known as
Zusanli).
Most studies thus far indicate that acupuncture is primarily
effective for the prevention of acute chemotherapy-induced vomiting and less effective against acute nausea or delayed nausea. For
example, a multicenter, randomized controlled trial of acustimulation wrist bands applied to the P6 point did not show a significant
effect on delayed nausea of women receiving chemotherapy for
breast cancer.133
Only one randomized controlled trial of acupuncture for the
prevention of radiation-induced nausea and vomiting has been
reported in full article form, and it showed decreased nausea and
vomiting in both the true and sham acupuncture groups.134

Ginger
A large randomized, double-blind, placebo-controlled trial has demonstrated an additive antiemetic effect of ginger extract (either 0.5 or
1.0g taken orally twice daily) to a 5HT receptor antagonist for the
prevention of acute chemotherapy-induced nausea.135
A small randomized, double-blind, placebo-controlled trial found
improved measures of nausea and vomiting in children and young
adults receiving a weight-adjusted dose of oral encapsulated ginger
powder (up to 2g per day) while undergoing cisplatin and doxorubicin therapy for bone sarcomas. Both acute and delayed nausea and
vomiting were improved with this regimen.136

Neuropathy

Herbs and Dietary Compounds

GLUTAMINE

Oral glutamine, at doses of 10g three times a day and 15g twice a
day, has been shown to be effective at decreasing the frequency of
paclitaxel-induced and oxaliplatin-induced peripheral neurop
athy,148,149 although a trial of 500mg, three times a day, was not
effective.150
GLUTATHIONE

Glutathione is an abundant tripeptide that acts as the primary endogenous, intracellular antioxidant for mammalian cells. Exogenously
administered glutathione has been reproducibly shown to protect
against certain chemotherapy-related toxicities. Several small randomized controlled trials have demonstrated that intravenous glutathione given in doses of 1.5 to 3g/m2 over 15 to 20 minutes prior
to cisplatin or oxaliplatin administration resulted in lower rates of
clinically significant neuropathy without compromising the anticancer effect of the chemotherapy agent.60
VITAMIN E

Doses of either 300mg daily or twice a day of dl-alpha-tocopherol

have been found to be effective in decreasing the frequency of development of neuropathic symptoms in patients being treated with
chemotherapy regimens containing cisplatin.151,152 However, the
largest randomized, placebo-controlled clinical trial conducted thus
far failed to show a benefit of alpha-tocopherol on the development
of neuropathy in a mixed group of patients, some receiving taxanes
and others receiving various platinum-based chemotherapeutic
agents.153

Hot Flashes
Acupuncture
Acupuncture given twice a week for 30 minutes per session has been
shown to decrease hot flash symptomatology, both in women with
breast cancer and men with prostate cancer who were receiving

Complementary and Alternative Medicine CHAPTER 33 527

androgen-deprivation therapy.154,155 The degree of effectiveness

appears to be at least equivalent to that of venlafaxine.155 Multiple
acupuncture points (e.g., 9 to 20 points) are generally needled simultaneously in each treatment session.

demonstrate improved symptoms during the course of treatment.

However, in one study in which patients were undergoing radiotherapy, a statistically significant advantage was actually found for the
control group over the aromatherapy group.174

Hypnosis

Music

Very little research has been reported on the use of hypnosis for the
treatment or prevention of hot flashes. A pilot study in which hypnosis was compared with a no-treatment control suggested a beneficial effect for hypnosis,156 and a larger randomized trial with an
attention control is underway.157

Music may be used with therapeutic intent either to create a distraction from the stress-inducing cancer treatment experience or as a
means to promote a positive, adaptive response. The term music
therapy has generally been applied to the use of a music intervention
by a trained music therapist and incorporating an individualized
musical experience. A metaanalysis of randomized controlled trials of
music interventions used with patients with cancer found significantly lower anxiety levels and improved quality of life in patients
receiving the music intervention.176

Vitamin E
Vitamin E supplementation at the dose of 400mg twice a day has
been found to have a marginal effect on hot flashes in women with
a history of breast cancer.158,159

Phytoestrogens
No significant effect was noted in a small randomized, placebocontrolled trial of 20g of soy protein containing 160mg total isoflavones on vasomotor symptoms in men with prostate cancer who
were undergoing androgen deprivation.160 In three randomized,
placebo-controlled trials of women with early-stage breast cancer,
various soy isoflavone supplements in doses ranging from 70 to
150mg per day failed to demonstrate a significant benefit on menopausal symptoms.161-163 A systematic review in 2007 found five trials
with data suitable for pooling for metaanalysis.164 No significant difference was detected in the frequency of hot flashes between a red
clover extract and placebo.

Black Cohosh
Despite some promising data from a single-arm pilot study, the two
randomized, placebo-controlled trials of black cohosh supplements
(20mg twice a day in one and dose not given in the other) have
failed to demonstrate that the black cohosh supplement provided any
greater relief from hot flashes than did placebo.165-167

Expressive Writing
Two randomized trials have failed to demonstrate a beneficial effect
of expressive writing on psychological well-being, fatigue, or sleep
quality.177,178

Meditation
Meditation is a component of several so-called mind-body
approaches, as well as some exercise therapies, including yoga, tai chi,
and mindfulness-based stress reduction (MBSR). MBSR is a structured program that combines yoga exercises, educational sessions on
lifestyle modification, and a sequence of meditation exercises. Randomized controlled trials of MBSR have consistently found that this
approach can improve quality of life and mood and reduce distress
in patients with cancer.179

Relaxation and Imagery

Various CAM approaches have been studied in randomized controlled trials for their potential preventive or therapeutic effects on
chemotherapy- or radiation-induced mucositis in patients with
cancer. At least three of these (aloe vera, intravenous glutamine, and
honey) have had more than one trial with statistically significant
findings demonstrating a benefit compared with either placebo or no
treatment.168 Aloe vera gel (not the latex component) has also been
demonstrated in at least one randomized controlled trial to improve
symptomatology of ulcerative colitis169 and has been proposed by
some herbalists as a therapy for radiation-induced rectal mucositis.

Relaxation training, often accompanied by imagery, is frequently

advocated to assist patients with cancer in managing the stress of
receiving a cancer diagnosis, as well as stress in the treatment and
follow-up periods. Various forms of this therapy have been utilized
in several randomized controlled trials with indicators of stress,
coping, and quality of life as outcomes, with mixed results.180 Most
studies have utilized a type of progressive muscle relaxation that the
patient learns through a series of guided experiential sessions and then
practices independently. Two of the larger trials have studied women
with localized breast cancer. The trials showed significant benefits of
relaxation with or without imagery over standard care181 or a semi
structured one-on-one encounter session.182 At least one study showed
some advantage of adding imagery to relaxation for relieving anxiety.182
Most of the studies of the effect of relaxation and imagery on stress
reduction and quality of life have enrolled patients who were early in
their diagnosis with limited stage disease. Studies are needed to assess
the utility of these interventions in other clinical settings.

Homeopathy

Massage

Traumeel S is a multicomponent, over-the-counter product containing a mixture of low-concentration botanical extracts. It is produced
following homeopathic principles and has been traditionally recommended to treat inflammatory conditions. Traumeel S was studied in
a small pilot trial to attempt to prevent and treat oral mucositis in
pediatric patients undergoing bone marrow transplantation, yielding
positive results.170 However, a follow-up multicenter, randomized
controlled study by the Childrens Oncology Group failed to show a
significant benefit for Traumeel S in the same patient population.171

A systematic review of the effects of massage on symptom relief in

patients with cancer found 10 trials that met the criteria, and results
suggested that massage might decrease anxiety in the short term.178

Mucositis

Stress Reduction and Quality of Life

Aromatherapy
Aromatherapy, with and without massage, has been studied in several
randomized controlled trials of patients with cancer.172-175 In these
trials, a weekly aromatherapy massage intervention often did

Xerostomia
Acupuncture
Small single-arm and randomized studies have indicated that acupuncture and acupuncture-like transcutaneous nerve stimulation179
can improve saliva flow and quality of life among patients with head
and neck cancer who have severe xerostomia. A systematic review in
2010180 found three eligible trials, all with significant risks of bias,
and concluded that evidence was insufficient to recommend acupuncture for the management of this adverse effect. Subsequently, the
results of three more randomized trials have been reported. One trial
comparing weekly acupuncture versus usual care found significant

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improvements in xerostomia among patients receiving acupuncture.99

The other two studies explored whether acupuncture might be able
to prevent xerostomia if given simultaneously with a course of radiation for head and neck cancer and both found improved outcomes
in the acupuncture-treated groups.181,182

INFORMATION RESOURCES
Databases
The National Cancer Institutes Physicians Data Query (http://
www.cancer.gov/cancertopics/pdq/cam) provides summaries of the
literature for several types of CAM approaches. Most topics have
separately designed summaries for health care practitioners and
patients.
MedlinePlus, a service of the U.S. National Library of Medicine,
provides an easily searched format with useful information on CAM
topics, including a page providing links to several summaries of the
literature on herbs and supplements from the NIH, Natural Medicines Comprehensive Database, and the National Toxicology Program
(http://www.nlm.nih.gov/medlineplus/druginfo/herb_All.html).

MD Anderson Cancer Center (http://www.mdanderson.org/

education-and-research/resources-for-professionals/clinical-toolsand-resources/cimer/index.html) provides complementary/integrative
medicine education resources.
Memorial Sloan Kettering Cancer Center (http://www.mskcc.org/
cancer-care/integrative-medicine/about-herbs-botanicals-otherproducts) provides information about herbs, botanicals, and other
products.
The American Cancer Societys Web site provides an herbs, vitamins, and minerals page with links to summaries on various related
topics (http://www.cancer.org/treatment/treatmentsandsideeffects/
complementaryandalternativemedicine/herbsvitaminsandminerals/
index).

The complete reference list is available online at

www.expertconsult.com.

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