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CAACancerJClinicians-2017-Greenlee-ClinicalpracticeguidelinesontheevidenceE28090baseduseofintegrative.pdf

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ARTICLE TITLE: Clinical Practice Guidelines on the Evidence-Based Use of Integrative Therapies During and After Breast Cancer Treatment

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SPONSORED BY THE AMERICAN CANCER SOCIETY, INC.194 VOLUME 67 | NUMBER 3 | MAY/JUNE 2017

1. Highlight current practice guidelines on the use of integrative therapies during and after breast cancer treatment. 2. Apply evidence-based gradings of the efficacy of integrative treatment modalities that balance potential benefits and harms in formulating treatment decisions and referrals for addressing the symptoms and side effects of breast cancer therapy. 3. Acknowledge the strengths and limitations of integrative therapies for treating breast cancer-related symptoms and side effects and future research needs in this area.

Clinical Practice Guidelines on the Evidence-Based Use of Integrative Therapies During and After Breast Cancer

Treatment

Heather Greenlee, ND, PhD, MPH 1,2

; Melissa J. DuPont-Reyes, MPH, MPhil 3 ; Lynda G. Balneaves, RN, PhD

4 ;

Linda E. Carlson, PhD 5 ; Misha R. Cohen, OMD, LAc

6,7 ; Gary Deng, MD, PhD

8 ; Jillian A. Johnson, PhD

9 ; Matthew Mumber, MD

10 ;

Dugald Seely, ND, MSc 11,12

; Suzanna M. Zick, ND, MPH 13,14

; Lindsay M. Boyce, MLIS 15

; Debu Tripathy, MD 16

Abstract: Patients with breast cancer commonly use complementary and integrative thera- pies as supportive care during cancer treatment and to manage treatment-related side effects. However, evidence supporting the use of such therapies in the oncology setting is limited. This report provides updated clinical practice guidelines from the Society for Integra- tive Oncology on the use of integrative therapies for specific clinical indications during and after breast cancer treatment, including anxiety/stress, depression/mood disorders, fatigue, quality of life/physical functioning, chemotherapy-induced nausea and vomiting, lymphede- ma, chemotherapy-induced peripheral neuropathy, pain, and sleep disturbance. Clinical prac- tice guidelines are based on a systematic literature review from 1990 through 2015. Music therapy, meditation, stress management, and yoga are recommended for anxiety/stress reduction. Meditation, relaxation, yoga, massage, and music therapy are recommended for depression/mood disorders. Meditation and yoga are recommended to improve quality of life. Acupressure and acupuncture are recommended for reducing chemotherapy-induced nausea and vomiting. Acetyl-L-carnitine is not recommended to prevent chemotherapy- induced peripheral neuropathy due to a possibility of harm. No strong evidence supports the use of ingested dietary supplements to manage breast cancer treatment-related side effects. In summary, there is a growing body of evidence supporting the use of integrative therapies, especially mind-body therapies, as effective supportive care strategies during breast cancer treatment. Many integrative practices, however, remain understudied, with insufficient evi- dence to be definitively recommended or avoided. CA Cancer J Clin 2017;67:194-232. VC 2017 American Cancer Society.

Keywords: acupressure, acupuncture, breast cancer, complementary therapies, integrative medicine, integrative oncology, massage, meditation, music therapy, stress management, yoga

Practical Implications for Continuing Education

> To make informed decisions on the use of integrative therapies in the oncology setting, clinicians and patients should understand the level of evidence of associated benefits and harms for each therapy.

> Based on a systematic review of the literature, the Society for Integrative Oncology makes the following recommendations:

– Use of music therapy, meditation, stress management and yoga for anxiety/ stress reduction.

– Use of meditation, relaxation, yoga, massage and music therapy for depression/mood disorders.

– Use of meditation and yoga to improve quality of life.

– Use of acupressure and acupuncture for reducing CINV.

– There is a lack of strong evidence supporting the use of ingested dietary supplements or botanical agents as supportive care and/or to manage breast cancer treatment-related side effects.

> Implementing integrative therapies in a clinical setting requires a coordinated team approach with well-trained providers. Training and credentialing for many integrative providers varies by jurisdictions. Best practices suggest that providers be trained to the highest standard of their profession and educated in other relevant disciplines.

1 Assistant Professor, Department of

Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; 2 Member, Herbert Irving Comprehensive

Cancer Center, Columbia University, New York, NY;

3 Doctoral Fellow, Department of

Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; 4 Associate Professor, College of Nursing,

Rady Faculty of Health Sciences, Winnipeg, MB, Canada;

5 Professor, Department of

Oncology, University of Calgary, Calgary, AB, Canada;

6 Adjunct Professor, American

College of Traditional Chinese Medicine at California Institute of Integral Studies, San Francisco, CA;

7 Clinic Director, Chicken Soup

Chinese Medicine, San Francisco, CA; 8 Medical Director, Integrative Oncology,

Memorial Sloan Kettering Cancer Center, New York, NY;

9 Post-Doctoral Scholar,

Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA;

10 Radiation Oncologist, Harbin

Clinic, Rome, GA; 11

Executive Director, Ottawa Integrative Cancer Center, Ottawa, ON, Canada;

12 Executive Director of

Research, Canadian College of Naturopathic Medicine, Toronto, ON, Canada;

13 Research

Associate Professor, Department of Family Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI;

14 Research

Associate Professor, Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI; 15

Research Informationist, Memorial Sloan Kettering Library, Memorial Sloan Kettering Cancer Center, New York, NY;

16 Professor,

Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Additional supporting information may be found in the online version of this article.

Corresponding author: Heather Greenlee, ND, PhD, MPH, Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 West 168th St, Seventh Fl, New York, NY 10032; [email protected]

DISCLOSURES: Linda E. Carlson reports book royalties from New Harbinger and the American Psychological Association. Misha R. Cohen reports royalties from Health Concerns Inc., outside the submitted work. Matthew Mumber owns stock in I Thrive. All remaining authors report no conflicts of interest.

doi: 10.3322/caac.21397. Available online at cacancerjournal.com

VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 195

CA CANCER J CLIN 2017;67:194–232

Introduction

Patients with breast cancer and breast cancer survivors are

frequent users of complementary and integrative therapies,

and there are growing numbers of formal, integrative oncol-

ogy programs within cancer centers. 1-6

Various terms are

used to describe such therapies, and it is helpful at the outset

to define terms. Complementary and alternative therapies are

generally defined as any medical system, practice, or product

that is not part of conventional medical care.7,8 Other rele-

vant terminology includes complementary medicine, which

comprises therapies used as a complement alongside

conventional medicine; alternative medicine, which com-

prises therapies used in place of conventional medicine; and

integrative medicine, which is the coordinated use of

evidence-based complementary practices and conventional

care. Integrative oncology refers to the use of complementary

and integrative therapies in collaboration with conventional

oncology care. In oncology, individuals use complementary

and integrative therapies with the intent of enhancing

wellness, improving quality of life (QOL), and relieving

symptoms of disease and side effects of conventional treat-

ments. However, the evidence supporting the use of

complementary and integrative therapies in the oncology

setting is limited.

In November 2014, the Society for Integrative Oncology

(SIO) published clinical practice guidelines to inform both

clinicians and patients on the use of integrative therapies

during breast cancer treatment and to treat breast cancer

treatment-related symptoms.9 The SIO adapted methods

established by the US Preventive Services Task Force10 to

develop graded recommendations on the use of specific inte-

grative therapies for defined clinical indications based on

the strength of available evidence concerning associated

benefits and harms. The 2014 clinical practice guidelines

were derived from a systematic review of randomized clini-

cal trials published between 1990 and 2013 and organized

by specific clinical conditions (eg, anxiety/stress, fatigue).

This review provides an updated set of clinical practice

guidelines based on a current, systematic literature review of

randomized controlled trials (RCTs) published through

December 2015 along with detailed definitions of integra-

tive therapies and clinical outcomes of interest, a detailed

summary of the literature upon which the clinical practice

guidelines are based, and suggestions for how appropriate

therapies may be integrated into clinical practice.

Of note, it is important to define the use of the term rec-

ommendation in these clinical practice guidelines. In many

settings, a clinical guideline recommendation suggests that it

should be used as the standard of care and is favorable or

equal compared with all other options based on best clinical

evidence for benefit/risk ratio. Here, in the setting of inte-

grative oncology, we use the term recommendation to

conclude that the therapy should be considered as a viable

but not singular option for the management of a specific

symptom or side effect. Few studies have conducted a head-

to-head comparison of a given integrative therapy against a

conventional treatment, and most integrative therapies are

used in conjunction with standard therapy and have been

studied in this manner. Moreover, combination-based

approaches and the interactions of the numerous permuta-

tions of integrative and conventional treatments have not

been formally investigated, such that recommendations must

account for this limitation of our knowledge. Despite these

limitations to evaluating the use of integrative therapies in

the oncology setting, there is a body of well conducted trials

of specific therapies for specific conditions that provides suf-

ficient evidence to warrant recommendations on the thera-

pies as viable options for treating specific conditions.

In this review, we provide clinicians and patients with

updated SIO clinical practice guidelines on the use of inte-

grative therapies to manage symptoms and side effects during

and after breast cancer treatment. The clinical practice guide-

lines do not address breast cancer recurrence or survival end-

points, because very few adequately powered RCTs have

examined the effect of integrative therapies on these out-

comes. We also provide a definition for each integrative ther-

apy that had a sufficiently large body of evidence to formulate

a specific recommendation. Information is also provided on

how to implement the recommendations into the clinical set-

ting, with caveats for specific clinical situations. In addition,

this review summarizes pertinent meta-analyses and identifies

promising areas for future investigation. The information

that arose from other published reviews and meta-analyses

did not change the interpretation of the findings or the quali-

ty of specific trials, but the information was used to influence

the establishment of specific recommendation grades based

on consistency, reproducibility, and assessment of potential

harms and benefits. The goal of this current review is to pro-

vide clinicians and patients with practical information and

tools to evaluate whether there is an evidence base to support

the use of a defined integrative therapy for a specific clinical

application in the context of breast cancer.

Methods

Systematic Review Methodology

To update the previously published clinical practice guide-

lines, which were based on a systematic review of the litera-

ture from January 1, 1990 through December 31, 2013, 9

we

conducted a systematic review of published RCTs from Jan-

uary 1, 2014 through December 31, 2015, using the same

search criteria and process. The process followed the meth-

ods set forth by the Institute of Medicine on clinical guide-

line development. 11

The following databases were searched:

Embase, MEDLINE, PsychINFO, and CINAHL.

Integrative Therapies During and After Breast Cancer Treatment

196 CA: A Cancer Journal for Clinicians

As previously reported,9 trials were selected for inclusion in

the systematic review if they met the following criteria:

1) peer-reviewed, published RCT; 2) available in English;

3) included �50% patients with breast cancer and/or reported results separately for patients with breast cancer;

4) used an integrative therapy as an intervention during stan-

dard treatment with surgery, chemotherapy, radiation thera-

py, and/or hormonal therapy or addressed symptoms and

side effects resulting from diagnosis and/or treatment; and

5) addressed an endpoint of clinical relevance to patients

with breast cancer and breast cancer survivors (see Support-

ing Information Table 1).9 Several lifestyle and psychological

interventions were excluded from current as well as previous

guidelines, because they have already been well summarized

by other groups (eg, diet 12,13

and physical activity 12-14

rec-

ommendations for cancer survivors) and/or because they

have a strong evidence base and are often considered to be

mainstream rather than integrative or complementary (eg,

cognitive-behavioral therapy, 15

psychoeducation, 16

counsel-

ing, 17

and support groups 16

). Other interventions that were

excluded were in early or pilot stages of research (eg,

attention-restoration therapy) or were not considered to be

an integrative oncology therapy for the purposes of the SIO

guidelines (eg, prayer, spirituality). Each article was scored

according to the quality of design and reporting based on the

Jadad scoring scale and a modified scale adapted from the

Delphi scoring system.18,19 Finally, grades of evidence were

determined for each therapy as applied to a specific clinical

outcome using a modified version of the US Preventive Serv-

ices Task Force grading system. 10

Grades were based on

strength of evidence, determined by the number of trials,

quality of trials, magnitude of effect, statistical significance,

sample size, consistency of results across studies, and whether

the outcomes were primary or secondary. The highest grades

(A and B) indicate that a specific therapy is recommended for

a particular clinical indication. Grade A indicates there is

high certainty that the net benefit is substantial, while grade

B indicates there is high certainty that the net benefit is mod-

erate or there is moderate certainty that the net benefit is

moderate to substantial. Grade C indicates that the evidence

is equivocal or that there is at least moderate certainty that

the net benefit is small. The lowest grades (D, H, and I) indi-

cate no demonstrated effect, suggest harm, or indicate that

the current evidence is inconclusive, respectively.

According to the clinical guideline development process

outlined by the Institute of Medicine,11 drafts prepared by

the SIO Guideline Working Group were distributed to an

interdisciplinary group of SIO internal and external reviewers.

Reviewer comments, suggestions, and critiques were incorpo-

rated into the final version of these guidelines.

It is important to note that, as we reviewed the literature,

we recognized the difference between statistical and

clinical significance. The graded recommendations reflect

our assessment of the clinical significance based on our

assessment of the body of literature, including the impor-

tance of statistical significance with respect to the primary

endpoint. We did not report on specific magnitudes of

effect because of the range of outcome measures and statisti-

cal methods used across the trials, which made it difficult to

describe detailed data on effect sizes across all trials.

Although some of the trials with small sample sizes (n <

100) may have been methodologically sound, we down-

played their contribution to the graded recommendation,

because larger trials provided more information on general-

izability of results to larger populations. Because of space

limitations, P values are reported and citations are provided

to reference the primary reports for additional details.

Definitions of Complementary and Integrative Therapies

Below are definitions listed alphabetically for each of the

complementary and integrative therapies that received

a grade of A, B, C, D, or H in the updated clinical

practice guidelines.20,21 Table 1 displays the graded rec-

ommendations. 10,22-151

Table 2 provides background

information on the specific training, licensure, and profes-

sional organizations associated with each therapy.152 If a

therapy is known to have a specific contraindication or

caution, it is noted in the description. The descriptions

include statements on how the therapies are often used by

patients with cancer and by survivors but do not indicate

the level of evidence supporting such use. The guideline

recommendations provide a summary of the evidence on

the use for specific conditions. In addition to the informa-

tion provided below, there are continuously updated, well

referenced websites that can provide additional details on

the range of therapies, including Natural Medicines (nat-

uralmedicines.therapeuticresearch.com), Memorial Sloan

Kettering Cancer Center’s About Herbs website (mskcc.org/

cancer-care/treatments/symptom-management/integrative-

medicine/herbs), and the National Cancer Institute (NCI)

Office of Cancer Complementary and Alternative Medicine

Therapies: A-Z website (cam.cancer.gov/health_informa-

tion/cam_therapies_a-z.htm).

Acetyl-L-carnitine

Acetyl-L-carnitine is a dietary supplement that some

patients use to treat cancer-related fatigue by enhancing

energy and lowering inflammation in the body. 153

It has

demonstrated effectiveness in preventing and treating dia-

betic neuropathy and thus was of interest to examine in the

context of chemotherapy-induced peripheral neuropathy

(CIPN). It is a substance made in muscle and liver tissue

and is found in foods, including meats, poultry, fish, and

some dairy products.

CA CANCER J CLIN 2017;67:194–232

VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 197

TABLE 1. Graded Integrative Therapies for Use in Patients With Breast Cancer According to Clinical Outcomes a

CLINICAL OUTCOMES RECOMMENDED THERAPY

STRENGTH OF EVIDENCE GRADEb

Acute radiation skin reaction

Aloe vera22,23 and hyaluronic acid cream24,25 should not be recommended for improving acute radiation skin reaction.

D

Anxiety/stress reduction Meditation is recommended for reducing anxiety.26-30 A

Music therapy is recommended for reducing anxiety.31-35 B

Stress management is recommended for reducing anxiety during treatment, but longer group programs are likely better than self-administered home programs or shorter programs.36-39

B

Yoga is recommended for reducing anxiety.40-48 B

Acupuncture,49-51 massage,52-55 and relaxation56-60 can be considered for reducing anxiety. C

Chemotherapy-induced nausea and vomiting

Acupressure can be considered as an addition to antiemetics drugs to control nausea and vomiting during chemotherapy.61-63

B

Electroacupuncture can be considered as an addition to antiemetics drugs to control vomiting during chemotherapy.64,65

B

Ginger66-68 and relaxation59,69 can be considered as additions to antiemetic drugs to control nausea and vomiting during chemotherapy.

C

Glutamine70,71 should not be recommended for improving nausea and vomiting during chemotherapy.

D

Depression/mood disturbance

Meditation, particularly MBSR, is recommended for treating mood disturbance and depressive symptoms.26-30,72-76

A

Relaxation is recommended for improving mood disturbance and depressive symptoms.56,59,60,69,77,78

A

Yoga is recommended for improving mood and depressive symptoms.40-43,45-48,79-85 B

Massage is recommended for improving mood disturbance.53-55,86-88 B

Music therapy is recommended for improving mood.33,35,89,90 B

Acupuncture,49-51,91,92 healing touch,93,94 and stress management36-38,95,96 can be considered for improving mood disturbance and depressive symptoms.

C

Fatigue Hypnosis97,98 and ginseng99,100 can be considered for improving fatigue during treatment. C

Acupuncture51,101-103 and yoga45,80,84,104-106 can be considered for improving post-treatment fatigue.

C

Acetyl-L-carnitine107 and guarana108,109 should not be recommended for improving fatigue during treatment.

D

Lymphedema Low-level laser therapy,110,111 manual lymphatic drainage,112-118 and compression bandag- ing114-116 can be considered for improving lymphedema.

C

Neuropathy Acetyl-L-carnitine is not recommended for the prevention of chemotherapy-induced peripheral neuropathy in patients with BC due to potential harm.107

H

Pain Acupuncture,119-124 healing touch,93 hypnosis,125,126 and music therapy31,34 can be considered for the management of pain.

C

Quality of life Meditation is recommended for improving quality of life.27-29,73-75,127 A

Yoga is recommended for improving quality of life.43,46-48,82-85,104-106,128 B

Acupuncture,49,51,102,129,130 mistletoe,131-134 qigong,135,136 reflexology,137-139 and stress management36-38,95,96,140,141 can be considered for improving quality of life.

C

Sleep disturbance Gentle yoga45,48,79,84,142 can be considered for improving sleep. C

Vasomotor/hot flashes Acupuncture49,91,92,143-148 can be considered for improving hot flashes. C

Soy149-151 is not recommended for hot flashes in patients with BC due to lack of effect. D

Abbreviations: BC, breast cancer; MBSR, mindfulness-based stress reduction. a The clinical population is patients with BC during treatment, including surgery,

chemotherapy, hormonal/biological therapy, and radiation therapy. The clinical question is “What integrative therapies can be used to prevent, treat and man- age symptoms and side effects encountered during breast cancer treatment?”

b Definitions of the grade of recommendations are as follows

10 : Grade A recom-

mends the modality (there is high certainty that the net benefit is substantial: offer/provide this modality). Grade B recommends the modality (there is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial: offer/provide this modality). Grade C recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences (there is at least mod- erate certainty that the net benefit is small: offer/provide this modality for selected patients, depending on individual circumstances). Grade D recommends against the service (there is moderate or high certainty that the modality has no net benefit: discourage the use of this modality). Grade H recommends against the service (there is moderate or high certainty that the harms outweigh the benefits: discourage the use of this modality).

Integrative Therapies During and After Breast Cancer Treatment

198 CA: A Cancer Journal for Clinicians

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U N

IT ED

ST A

TE S:

A cu

pu nc

tu re

, C

hi ne

se he

rb o lo

gy ,

an d

O ri

en ta

l m

ed ic

in e

ar e

re gu

la te

d vi

a st

at e

lic en

si ng

bo di

es .

Th e

N at

io na

l C

er ti

fi ca

ti o n

C o m

m is

si o n

fo r

A cu

pu nc

tu re

an d

O ri

en ta

l M

ed ic

in e

(N C

C A

O M

) re

po rt

s th

at 4

4 st

at es

pl us

th e

D is

tr ic

t o f

C o lu

m bi

a ha

ve ac

up un

ct ur

e pr

ac ti

ce ac

ts .

Fo rt

y- th

re e

st at

es cu

rr en

tl y

re qu

ir e

pa ss

ag e

o f

N C

C A

O M

na ti

o na

l ex

am in

at io

ns fo

r in

it ia

l lic

en su

re .

Th e

N C

C A

O M

ce rt

if ie

s ac

up un

ct ur

e, C

hi ne

se he

rb o lo

gy ,

an d

O ri

en ta

l m

ed ic

in e.

C ur

re nt

ly ,

C al

if o rn

ia re

qu ir

es pa

ss ag

e o f

it s

o w

n st

at e

ex am

in at

io ns

fo r

lic en

su re

an d

do es

no t

ac ce

pt th

e N

C C

A O

M ce

rt if ic

at io

n. A

su bs

et o f

st at

es re

gu la

te s

ac up

re ss

ur e

un de

r ac

up un

ct ur

e o r

m as

sa ge

re gu

la ti

o ns

.

C A

N A

D A

: A

cu pu

nc tu

re is

re gu

la te

d vi

a pr

o vi

nc ia

l lic

en si

ng bo

di es

in th

e pr

o vi

nc es

o f

B ri

ti sh

C o lu

m bi

a, A

lb er

ta ,

O nt

ar io

, Q

ue be

c, an

d N

ew fo

un dl

an d.

C hi

ne se

m ed

ic in

e is

cu rr

en t-

ly o nl

y re

gu la

te d

in B

ri ti

sh C

o lu

m bi

a an

d O

nt ar

io .

A C

A O

M ,

ac ao

m .o

rg ;

N C

C A

O M

, m

x. nc

ca o m

.o rg

C ol

le ge

of Tr

ad iti

on al

C hi

ne se

M ed

ic in

e Pr

ac tit

io ne

rs an

d A

cu -

pu nc

tu ris

ts of

B rit

is h

C ol

um bi

a (C

TC M

A ),

ct cm

a. bc

.c a;

C ol

le ge

of Tr

ad it io

na l

C hi

ne se

M ed

ic in

e Pr

ac tit

io ne

rs an

d A

cu pu

nc tu

ri st

s of

O nt

ar io

(C TC

M PA

O ),

ct cm

pa o.

on .c

a/ ;

C ol

le ge

an d

A ss

oc ia

ti on

of A

cu pu

nc tu

ris ts

of A

lb er

ta (C

A A

A ),

ac up

un ct

ur ea

lb er

ta .c

a/ ;

A ss

oc ia

tio n

of A

cu pu

nc tu

ris ts

of Q

ue be

c (A

A Q

), ac

up un

ct ur

e- qu

eb ec

. co

m /e

n/ ho

m e.

ht m

l; N

ew fo

un dl

an d

an d

La br

ad or

C ou

nc il

of H

ea lth

Pr of

es si

on al

s (N

LC H

P) ,

nl ch

p. ca

/

H yp

no si

s M

en ta

l he

al th

an d

m ed

ic al

pr o fe

ss io

na ls

ty pi

ca lly

pr ac

ti ce

hy pn

o si

s as

a sp

ec ia

lt y

o r

su bs

pe ci

al ty

. C

er ti

fi ed

hy pn

o -

th er

ap is

ts ,

in ge

ne ra

l, ho

ld a

gr ad

ua te

-l ev

el o r

ba ch

el o r’

s- le

ve l

de gr

ee in

a br

o ad

ra ng

e o f

sp ec

ia lt

ie s,

in cl

ud in

g M

D ,

re gi

st er

ed nu

rs e,

de nt

is t,

so ci

al w

o rk

er ,

lic en

se d

co un

se lo

r o r

ps yc

ho lo

gi st

. pa

st o ra

l co

un se

lo r,

o rd

ai ne

d m

in is

te r,

an d

ch ir

o pr

ac to

r, am

o ng

m an

y o th

er s,

pr io

r to

o bt

ai ni

ng tr

ai ni

ng in

hy pn

o si

s.

C ur

re nt

ly ,

th er

e ar

e no

ac cr

ed it

ed sc

ho o ls

o ff

er in

g st

an da

rd co

lle ge

o r

un iv

er si

ty de

gr ee

s in

hy pn

o si

s; th

er ef

o re

, tr

ai ni

ng in

o ne

o f

th e

ab o ve

pr o fe

ss io

ns is

ty pi

ca lly

re qu

ir ed

be fo

re ac

ce pt

an ce

in to

o ne

o f

m an

y tr

ai ni

ng o r

ce rt

if ic

at io

n pr

o gr

am s.

Th es

e pr

o gr

am s

ha ve

a w

id e

ra ng

e o f

tr ai

ni ng

re qu

ir em

en ts

bu t

in ge

ne ra

l re

qu ir

e an

yw he

re fr

o m

5 0

to 2

0 0

h o f

cl as

sr o o m

an d

cl in

ic al

tr ai

ni ng

be fo

re ce

rt if ic

at io

n.

U N

IT ED

ST A

TE S:

To be

ce rt

if ie

d as

a cl

in ic

al hy

pn o th

er ap

is t,

ap pl

ic an

ts ty

pi ca

lly re

qu ir

e an

yw he

re fr

o m

5 0

to 2

0 0

h o f

tr ai

ni ng

an d

o ft

en y

o f

ex pe

ri en

ce .

Th er

e ar

e a

nu m

be r

o f

ce rt

if ic

at io

n pr

o gr

am s

w it

h a

ra ng

e o f

re qu

ir em

en ts

(s ee

lin ks

). R

eg ul

at io

ns fo

r th

e pr

ac ti

ce o f

hy pn

o si

s va

ry o n

a st

at e-

by -s

ta te

ba si

s (a

ih cp

.o rg

/h yp

no si

s- re

gu la

ti o n.

ht m

). Ty

pi ca

lly ,

cl in

ic al

hy pn

o th

er ap

is ts

m us

t re

ne w

th ei

r ce

rt if ic

at io

n ev

er y

2 to

4 y

an d

m us

t ha

ve co

m pl

et ed

2 0 1

h o f

ap pr

o ve

d tr

ai ni

ng du

ri ng

th at

ti m

e.

C A

N A

D A

: C

er ti

fi ca

ti o n

is si

m ila

r to

th e

U ni

te d

St at

es ;

ho w

ev er

, re

qu ir

em en

ts ar

e m

uc h

hi gh

er ,

be tw

ee n

2 2

5 an

d 1

1 0

0 h

(a rc

hc a-

na da

.c a/

).

Th e

C o un

ci l

o f

Pr o fe

ss io

na l

H yp

no si

s en

co m

pa ss

es m

an y

pr o fe

s- si

o na

l so

ci et

ie s

an d

o rg

an iz

at io

ns lis

te d

(c o ph

o .c

o m

/o rg

.h tm

).

A ss

o ci

at io

n o f

R eg

is te

re d

C lin

ic al

H yp

no th

er ap

is ts

(A R

C H

), ar

ch -

ca na

da .c

a/ ;

A m

er ic

an C

o lle

ge o f

H yp

no th

er ap

y at

th e

A m

er ic

an In

st itu

te of

H ea

lth C

ar e

Pr of

es si

on al

s, ai

hc p.

ne t/

am er

ic an

-c ol

le ge

-o f-

hy pn

ot he

ra py

/; A

m er

ic an

So ci

et y

of C

lin ic

al H

yp no

si s

(A SC

H ),

as ch

. ne

t/ ;

H yp

no si

s M

ot iv

at io

n In

st it ut

e (H

M I),

hy pn

os is

.e du

; N

at io

na l

B oa

rd fo

r C

er tif

ie d

C lin

ic al

H yp

no th

er ap

is ts

(N B

C C

H ),

na tb

oa rd

. co

m ;

Th e

In te

rn at

io na

l So

ci et

y of

H yp

no si

s (IS

H ),

is hh

yp no

si s.

or g/

; So

ci et

y fo

r C

lin ic

al an

d Ex

pe rim

en ta

l H

yp no

si s

(S C

EH ),

sc eh

.u s/

; Th

e M

ilt on

H .

Er ic

ks on

Fo un

da tio

n, er

ic ks

on -f

ou nd

at io

n. or

g/

M as

sa ge

A ss

o ci

at ed

B o dy

w o rk

an d

M as

sa ge

Pr o fe

ss io

na l

(A B

M P)

m em

be rs

at th

e ce

rt if ie

d o r

pr o fe

ss io

na l

le ve

ls m

us t

po ss

es s

a va

lid m

as -

sa ge

lic en

se fr

o m

a re

gu la

te d

st at

e/ pr

o vi

nc e/

te rr

it o ry

, m

us t

ha ve

co m

pl et

ed 5

0 0

ap pr

o ve

d ed

uc at

io na

l h

o r

be ce

rt if ie

d th

ro ug

h th

e N

at io

na l

C er

ti fi ca

ti o n

B o ar

d fo

r Th

er ap

eu ti

c M

as sa

ge an

d B

o dy

w o rk

(N C

TM B

). Li

ce ns

ed nu

rs e

an d

ph ys

ic al

th er

ap is

ts m

ay qu

al if y

fo r

m em

be rs

hi p

at ei

th er

th e

ce rt

if ie

d o r

pr o fe

ss io

na l

le ve

l w

it h

a m

in im

um o f

5 0

h o f

ad di

ti o na

l m

as sa

ge th

er ap

y tr

ai ni

ng .

B o ar

d ce

rt if ic

at io

n is

th e

hi gh

es t

vo lu

nt ar

y cr

ed en

ti al

at ta

in ab

le to

m as

sa ge

th er

ap is

ts an

d bo

dy w

or ke

rs in

th e

pr o fe

ss io

n to

da y

(f o r

th e

re qu

ir em

en ts

o f

bo ar

d ce

rt if ic

at io

n, se

e nc

bt m

b. o rg

/ bo

ar d-

ce rt

if ic

at io

n) .

U N

IT ED

ST A

TE S:

M as

sa ge

th er

ap y

is re

gu la

te d

by so

m e

U S

st at

es .

Se e

lin k

fo r

st at

e- by

-s ta

te m

as sa

ge lic

en su

re in

fo rm

at io

n (m

as sa

ge th

er ap

y. co

m /c

ar ee

rs /s

ta te

bo ar

ds .p

hp ).

C A

N A

D A

: M

as sa

ge th

er ap

is ts

ca n

o nl

y be

re gi

st er

ed ,

no t

lic en

se d,

in C

an ad

a. C

ur re

nt ly

, o nl

y 4

pr o vi

nc es

re gu

la te

m as

sa ge

th er

ap is

ts :

O nt

ar io

, B

ri ti

sh C

o lu

m bi

a, N

ew B

ru ns

w ic

k, an

d N

ew fo

un dl

an d.

Th e

W eb

si te

fo r

th e

O nt

ar io

M as

sa ge

Th er

ap is

ts ha

s lin

ks to

th e

4 pr

o vi

nc es

’ re

gi st

ra ti

o n

pr o ce

du re

s an

d lin

ks to

o th

er pr

o vi

nc ia

l m

as sa

ge o rg

an iz

at io

ns .

A m

er ic

an M

as sa

ge Th

er ap

y A

ss o ci

at io

n, am

ta m

as sa

ge .o

rg ;

A B

M P,

ab m

p. co

m ;

N C

TM B

, nc

bt m

b. o rg

/; So

ci et

y fo

r O

nc o lo

gy M

as sa

ge ,

s4 o m

.o rg

/

M as

sa ge

Th er

ap is

ts ’

A ss

o ci

at io

n o f

O nt

ar io

, se

cu re

.r m

ta o .c

o m

/ m

as sa

ge _

th er

ap y/

re gu

la tio

n_ of

_ m

t/ m

as sa

ge _

th er

ap y_

in _

ca na

da .

ht m

CA CANCER J CLIN 2017;67:194–232

VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 199

T A

B L E

2 .

C o

n ti

n u

e d

M O

D A

LI T Y

O R

T H

E R

A P Y

T R

A IN

IN G

LI C

E N

S U

R E

A N

D R

E G

U LA

T IO

N P R

O FE

S S IO

N A

L S O

C IE

T IE

S A

N D

O R

G A

N IZ

A T IO

N S

M ed

it at

io n

M in

df ul

ne ss

-B as

ed St

re ss

R ed

uc ti

o n:

Th e

C en

te r

fo r

M in

df ul

ne ss

in M

as sa

ch us

et ts

pr o vi

de s

m ed

it at

io n

sp ec

ia lis

t tr

ai ni

ng (u

m as

sm ed

.e du

/c fm

/t ra

in in

g/ de

ta ile

d- tr

ai ni

ng -i

nf o rm

at io

n/ te

ac he

r- ce

rt if ic

at io

n- re

vi ew

/) .

In bo

th th

e U

ni te

d St

at es

an d

C an

ad a,

bo ar

d ce

rt if ic

at io

n is

th e

hi gh

es t

cr ed

en ti

al at

ta in

ab le

fo r

m ed

it at

io n

te ac

he rs

in th

e he

al th

ca re

pr o fe

ss io

n to

da y.

Th er

e is

no re

gi st

ra ti

o n

o r

lic en

su re

cu rr

en tl

y av

ai la

bl e.

A m

er ic

an M

in df

ul ne

ss R

es ea

rc h

A ss

o ci

at io

n, go

am ra

.o rg

/

Th e

U ni

ve rs

it y

o f

C al

if o rn

ia at

Sa n

D ie

go C

en te

r fo

r M

in df

ul ne

ss pr

o vi

de s

ex te

ns iv

e tr

ai ni

ng (m

bp ti

.o rg

/) .

Th e

U ni

ve rs

it y

o f

B an

go r

in W

al es

aw ar

ds a

M as

te rs

in M

in df

ul -

ne ss

an d

al so

ha s

a ra

ng e

o f

te ac

he r

tr ai

ni ng

pr o gr

am s

(b an

go r.

ac .u

k/ m

in df

ul ne

ss /c

o ur

se s.

ph p.

en )

Th e

C en

tr e

fo r

M in

df ul

ne ss

St ud

ie s

in To

ro nt

o ,

O nt

ar io

, C

an ad

a, o ff

er s

1 -d

w o rk

sh o ps

as w

el l

as in

te ns

iv e

pr o fe

ss io

na l

tr ai

ni ng

in M

in df

ul ne

ss -B

as ed

C o gn

it iv

e Th

er ap

y (m

in df

ul ne

ss st

ud ie

s. co

m /)

.

C o m

pl et

in g

m in

df ul

ne ss

te ac

he r

tr ai

ni ng

co ur

se s

at o ne

o f

th e

re co

gn iz

ed tr

ai ni

ng pr

o gr

am s,

in ad

di ti

o n

to pr

o fe

ss io

na l

ce rt

if ic

at io

n, w

o ul

d be

th e

o pt

im al

le ve

l o f

tr ai

ni ng

fo r

pr o vi

di ng

th es

e in

te rv

en ti

o ns

.

M us

ic th

er ap

y A

pr o fe

ss io

na l

m us

ic th

er ap

is t

ho ld

s a

ba ch

el o r’

s de

gr ee

o r

hi gh

er in

m us

ic th

er ap

y fr

o m

o ne

o f

o ve

r 7

0 A

m er

ic an

M us

ic Th

er ap

y A

ss o ci

at io

n- ap

pr o ve

d co

lle ge

an d

un iv

er si

ty pr

o gr

am s.

M us

ic th

er ap

is ts

w ho

cu rr

en tl

y ho

ld pr

o fe

ss io

na l

de si

gn at

io n

ar e

lis te

d o n

th e

N at

io na

l M

us ic

Th er

ap y

R eg

is tr

y an

d ar

e qu

al if ie

d to

pr ac

ti ce

m us

ic th

er ap

y.

M us

ic th

er ap

is ts

ar e

re gu

la te

d by

so m

e U

S st

at es

(e g,

N o rt

h D

ak o ta

, N

ev ad

a; fo

r st

at e-

by -s

ta te

m as

sa ge

lic en

su re

in fo

rm at

io n,

se e

cb m

t. o rg

/e xa

m in

at io

n/ st

at e-

lic en

su re

/) .

C ur

re nt

ly no

C an

ad ia

n pr

o vi

nc es

/t er

ri to

ri es

lic en

se o r

re gu

la te

m us

ic th

er ap

is ts

.

Th e

C er

ti fi ca

ti o n

B o ar

d fo

r M

us ic

Th er

ap is

ts (C

B M

T) ,

cb m

t. o rg

/; C

an ad

ia n

A ss

o ci

at io

n fo

r M

us ic

Th er

ap y

(C A

M T)

, m

us ic

th er

ap y.

ca /

R el

ax at

io n

an d

st re

ss m

an ag

em en

t R

el ax

at io

n an

d st

re ss

m an

ag em

en t

ar e

us ua

lly pr

o vi

de d

by tr

ai ne

d m

en ta

l he

al th

pr o fe

ss io

na ls

, su

ch as

re gi

st er

ed /c

ha rt

er ed

/ co

un se

lin g

ps yc

ho lo

gi st

s, ps

yc hi

at ri

st s,

m ar

it al

an d

fa m

ily co

un se

lo rs

, cl

in ic

al so

ci al

w o rk

er s,

an d

nu rs

es .

A ny

o f

th es

e pr

o fe

ss io

ns co

ul d

ha ve

sp ec

if ic

tr ai

ni ng

in th

es e

2 m

o da

lit ie

s.

Ty pi

ca lly

, th

e af

o re

m en

ti o ne

d pr

o fe

ss io

na ls

w o ul

d ta

ke co

ur se

s in

re la

xa ti

o n

tr ai

ni ng

o r

st re

ss m

an ag

em en

t as

pa rt

o f

th ei

r tr

ai ni

ng .

Ev er

y ju

ri sd

ic ti

o n

ha s

a co

lle ge

o f

ps yc

ho lo

gi st

s an

d so

ci al

w o rk

er s.

A m

er ic

an Ps

yc ho

lo gi

ca l

A ss

o ci

at io

n (A

PA ),

ap a.

o rg

/; C

an ad

ia n

Ps yc

ho lo

gi ca

l A

ss o ci

at io

n (C

PA ),

cp a.

ca

Y o ga

Th er

e ar

e ve

ry st

ri ng

en t

cr it

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Integrative Therapies During and After Breast Cancer Treatment

200 CA: A Cancer Journal for Clinicians

Acupuncture

Acupuncture involves the stimulation of specific points, (ie,

acupoints) by penetrating the skin with thin, solid, metallic

needles.154,155 A variation of acupuncture includes electro-

acupuncture, in which a small electric current is passed

along acupuncture needles to provide a stronger stimulus

than acupuncture alone, with distinct effects suggested by

functional magnetic resonance imaging.156,157 Acupuncture

has been practiced in Asia for thousands of years as a com-

ponent of traditional medicine systems (eg, traditional forms

of Chinese, Japanese, and Korean medicine) and is thought

to stimulate the flow of a form of energy called qi (chee)

throughout the body. Traditional Chinese acupuncture,

which is commonly used in North America, requires needle

manipulation to produce a de qi sensation (a soreness, full-

ness, heaviness, or local area distension157,158), along with a

period of rest with the needles in place. 159

It is posited that

this removes energetic blockages, thus reestablishing

homeostasis. The mechanisms for acupuncture’s effects are

not well understood but are thought to function in part

through modulation of specific neuronal/cortical path-

ways. 160

Acupuncture practice typically requires formal edu-

cation through schools, training programs, and certifications

(Table 2). Acupuncture is often used in the oncology setting

for chemotherapy-induced nausea/vomiting (CINV), pain

management, musculoskeletal complaints, hot flashes,

fatigue, stress, anxiety, and sleep disorders. The practice of

acupuncture in North America is regulated by some US

states and Canadian provinces and territories (Table 2).

Acupressure

Acupressure draws on the same knowledge and philosophi-

cal system as acupuncture. A trained therapist or the patient

uses his/her hands and fingers, or possibly a device, to apply

pressure to specific points on the body (acupoints), in con-

trast to metallic needles.161 Practices can range from stimu-

lating a single point or a combination of points to achieve

the intended outcome. In the oncology setting, acupressure

is often used for CINV pain, stress management, and

fatigue.

Aloe vera

Aloe vera gel is derived from the leaves of the perennial suc-

culent plant, Aloe vera (Liliaceae). Typically, it is applied

topically or ingested in the form of a clear, thick gel.153

Aloe vera gel is found in multiple skin products, such as

lotions, creams, and sunblock, and is used as a topical oint-

ment to heal wounds, sunburn, insect bites, and skin condi-

tions, including psoriasis and frostbite.162 In oncology, it is

typically used with the goal of healing surgical wounds or

preventing or treating radiation-induced dermatitis.

Ginger

Ginger (Zingiber officianale) comes from the rhizome or

root of a tropical plant with green-purple flowers and an

aromatic stem.153,163 Ginger can be used as a food in cook-

ing and for medicinal purposes. In Asian medicine, ginger is

used to treat stomach aches, nausea, and diarrhea. For

patients with cancer, it has been studied for the treatment

of CINV. Ginger is available in capsule form, fresh as a

root, as a tea, as a candy, or at highly diluted quantities in

ginger ale. Ginger supplementation should not be used in

perioperative settings or in patients with bleeding disorders

due to a potential risk of increased bleeding. 162

Ginseng

Ginseng is derived from a plant root and has been used to

treat certain medical problems. 153

Two common types of

ginseng are used: Asian ginseng (Panax ginseng) and Ameri-

can ginseng (Panax quinquefolius). Another herb called

Siberian ginseng or eleuthero is not a true ginseng.162 Asian

and American ginsengs are used to boost the immune sys-

tem and promote well being and stamina. Ginseng comes in

capsule form made of ground ginseng, extracts, and teas and

in creams and other products for topical use. Taken as an

herbal supplement, ginseng is often used to treat cancer-

related fatigue.162 Side effects of taking ginseng may include

headaches, breast tenderness and menstrual irregularities,

sleep problems, restlessness, rapid heart rate, low blood sug-

ar, allergic reactions, and gastrointestinal problems.162

Glutamine

Glutamine is a nonessential amino acid used in the biosyn-

thesis of proteins and is primarily synthesized in skeletal

muscle.162 Most of the glutamine synthesized in the body is

used by the intestinal tract. Glutamine has numerous bio-

logic functions, including protein and lipid synthesis and

the regulation of acid-base balance in the kidney, and it is

an important mitochondrial cellular energy source. Normal-

ly, the body can synthesize its own glutamine; however, dur-

ing a critical illness like cancer, not enough glutamine is

made, leading to problems such as fatigue and muscle wast-

ing. Glutamine has been used as an oral supplement in

patients with cancer to reverse cachexia in those who have

advanced disease. It has also been used for CINV in patients

with cancer. Glutamine can be obtained from food or sup-

plements, and important food sources include beef, pork,

chicken, fish, eggs, milk, dairy products, wheat, cabbage,

beets, beans, spinach, and parsley. 162

Guarana

Guarana is an herbal supplement from the guarana plant

(Paullinia cupana), which is native to the Amazon basin.162

Guarana supplements contain various phytochemicals,

including caffeine, theobromine, theophylline, tannins, sap-

onins, catechins, epicatechins, proanthocyanidols, and other

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compounds, in minor concentrations. Guarana has been

used as a stimulant since pre-Columbian times. 162

In the

oncology setting, guarana is often used to decrease fatigue.

Healing touch

Healing touch (also known as therapeutic touch) is based on

the belief that vital energy flows through and around the

human body and may be transferred or modified. 93,94

A

healing touch practitioner (often a nurse trained in the prac-

tice) passes his/her hands over, or gently touches, a patient’s

body to balance or increase their energy. Healing touch is

often used in patients with cancer to improve QOL, pain,

fatigue, and depression.

Hyaluronic acid cream

Hyaluronic acid cream is a topical cream containing hyalur-

onic acid that is used to heal wounds through repair-

promoting, skin-moisturizing, and potential radioprotective

properties.153 When the cream is applied, the hyaluronic

acid adheres to injured tissue, provides hydration to the

skin, and protects against dehydration and chemical and

mechanical irritation. Hyaluronic acid cream is often used

by patients with cancer to prevent and treat radiation-

induced dermatitis.

Hypnosis

Hypnosis is facilitated by a specially trained therapist or is

practiced on one’s own (self-hypnosis). It is characterized by

a trance-like state, which allows a patient to be more aware,

focused, and open to suggestion. A person in a hypnotic

state can concentrate more clearly on specific feelings,

thoughts, images, sensations, or behaviors without distrac-

tion.164 The hypnotic state is obtained by first relaxing the

body and then shifting attention toward a narrow range of

objects or ideas given by the hypnotist or hypnotherapist. A

person under hypnosis may feel more calm and relaxed. In

patients with cancer, hypnosis is often used to help relieve

stress, anxiety, and pain.

Laser therapy

Low-level laser therapy has been cleared by the FDA to

treat lymphedema after breast cancer surgery 165

and should

be administered by trained users. It is believed that low-level

laser therapy stimulates macrophages and the immune sys-

tem and breaks down scar tissue, thus improving lymphatic

flow.166

Manual lymphatic drainage and compression bandaging

Manual lymphatic drainage and compression bandaging are

used individually and in combination for the treatment of

lymphedema after breast cancer surgery.166 Manual lymph

drainage is a specific type of therapeutic massage that ideally

is delivered by a health professional who is certified in the

technique. Manual lymph drainage can decrease lymphede-

ma when administered early, before symptoms advance. 166

Compression bandages or garments, including sleeves,

stockings, bras, compression shorts, gloves, bandages, or

neck compression wraps, are also used to treat lymphedema

and can be worn during the day or night, depending on the

garment and the individual.166

Massage

There are many different forms of this type of physical ther-

apy, which involves a therapist stroking, kneading, applying

friction, and stretching specific muscles and other connec-

tive tissues at an even tempo with various levels of pres-

sure. 167

In patients with cancer, the goal of massage is to

promote relaxation, address muscle stiffness and pain, and

resolve musculoskeletal complaints. There are multiple

forms of massage, including, but not limited to, Swedish,

Shiatsu, and deep-tissue massage. Massage therapists should

take precautions with all patients who have cancer and to

avoid massaging specific vulnerable areas of the body,

including open wounds, bruises, skin breakdown, a blood

clot in a vein, a tumor site, areas near a medical device (eg,

drain), or sensitive skin after radiation therapy. 168

In addi-

tion, certain patients with multiple bone metastases may be

at risk for fracture during deep massage. The practice of

massage therapy in North America is regulated by some US

states and Canadian provinces and territories (Table 2).

Meditation

Meditation is a group of self-regulation practices focused on

training attention and awareness to bring mental processes

under greater voluntary control.169 In patients with cancer,

these practices are intended to foster general mental well

being, calmness, clarity, and concentration. The ultimate

goal of meditation varies, depending on the type of practice,

its history, and its application. Most meditation practices

have 4 elements in common: a quiet location with few dis-

tractions; a specific, comfortable posture achieved by sitting

or lying down; a focus of attention; and an open attitude of

letting thoughts come and go naturally without judg-

ment.170 The focus of attention may be on a specific target,

such as the breath or a repeated sound or mantra (known as

concentration meditation); on all experiences that enter the

field of awareness (called open awareness or mindfulness medi-

tation); or a combination of both. There has been growing

interest in cancer care on the practice of a secular form of

mindfulness meditation called mindfulness-based stress reduc-

tion (MBSR), which is based on the work of Jon Kabat-

Zinn. 171

MBSR is typically delivered in an 8-week, struc-

tured group program consisting of a range of meditation

practices, including a sensate focus body scan, sitting medi-

tation, walking meditation, loving-kindness practice, and

gentle Hatha yoga postures. All formal practices are

designed to cultivate increasing levels of mindfulness in

day-to-day life. Participants engage in home practice daily

Integrative Therapies During and After Breast Cancer Treatment

202 CA: A Cancer Journal for Clinicians

throughout the program, and each session involves teaching

relevant concepts, discussions of progress and barriers to

practice, and introduction and practice of new meditation

modalities. Several recent articles and meta-analyses have

reviewed the literature on the use of MBSR in the oncology

setting, and some are specific to breast cancer.172-175

Mistletoe

The use of mistletoe in cancer care is based on the premise

that injections of specially prepared extracts of the plant

during chemotherapy and radiation therapy can create a

host response that is immune-stimulatory, preferentially

cytotoxic to cancer cells, and protective of host cells. 176

Mis-

tletoe is a parasitic plant from the Santalacea family that

attaches to and penetrates the branches of a tree or shrub to

absorb water and nutrients from the host plant. The use of

mistletoe as a medicine extends back centuries, whereas its

modern use for cancer care was promoted in Europe, and

particularly in Germany, in the early part of the 20th centu-

ry. 177

There are 3 main types of mistletoe: European mistle-

toe (Viscum album), Korean mistletoe (Viscum album var.

coloratum), and American mistletoe (Phoradendron leucar-

pum), but multiple methods of preparation and formulation

exist. Preparations from European mistletoe are some of the

most common internationally prescribed substances in out-

patient clinics for cancer, where they are delivered most

often as a subcutaneous injection or occasionally as an intra-

venous infusion. 178

While this therapy is often used clinical-

ly for its antineoplastic potential, clinical trial evidence on

the use of mistletoe is based on trials in which it is coadmi-

nistered with conventional treatments to improve QOL. 178

Music therapy

Music therapy is the clinical use of music to accomplish

individualized goals within a therapeutic relationship by a

credentialed professional.179 In cancer care, music therapy is

used to address various physical, emotional, cognitive, and

social needs. Qualified music therapists assess patients’

strengths and needs and provide indicated treatment, such

as creating, singing, moving to, and listening to music.

Music therapy interventions can be described as either pas-

sive (eg, listening to music before a medical intervention) or

active (eg, a therapist instructing a patient to engage in the

creation of live music), depending on the level of engage-

ment required. Although the exact mechanisms by which

music therapy works are not well understood, the most

commonly accepted theories are through neurologic, psy-

chological, behavioral, and physiologic pathways.180,181 The

practice of music therapy in North American is regulated by

some US states (Table 2).

Reflexology

In reflexology, a trained practitioner applies pressure to the

feet, hands, ears, and face using specific thumb, finger, and

hand techniques with the goal of stimulating the reflex areas

to promote physiologic changes in the body. The theory

behind reflexology states that specific areas on the feet and

hands correspond to specific glands, organs, and other parts

of the body, which are stimulated to help numerous health

problems.182 Reflexology is used to cause relaxation and

healing in those specific stimulated parts of the body. In

oncology, reflexology is often used to promote relaxation

and improve QOL.

Relaxation techniques

Various techniques are used to promote relaxation in

patients with cancer. The NCI defines relaxation techniques

as including progressive muscle relaxation (PMR), guided

imagery, autogenic training, biofeedback, self-hypnosis, and

deep breathing exercises. 183

PMR focuses on the tightening

and relaxation of specific, successive muscle groups and is

usually combined with breathing and imagery exercises. 183

Guided imagery can be self-directed or led by a practitioner

or a recording and often involves focusing on pleasant imag-

ery to replace negative or stressful feelings. 183

Autogenic

training involves concentrating on physical sensations of

warmth, heaviness, and relaxation in different parts of the

body. 183

Biofeedback uses electronic devices to monitor and

teach control of certain bodily functions, such as breathing

or heart rate, to facilitate relaxation. 183

Self-hypnosis refers

to training patients to induce a hypnotic state, which is a

natural state of aroused, attentive, focal concentration along

with a relative suspension of peripheral awareness, either on

their own or when prompted by a phrase or a cue. 183

Deep

breathing exercises involve the use of slow, deep, and even

breaths, sometimes called diaphragmatic or belly breathing. 183

Qigong

The word qigong consists of 2 Chinese words: qi (chee),

meaning life force or vital energy that flows through all

things in the universe, and gong (gung), meaning accom-

plishment or skill that is cultivated through steady prac-

tice.184 Qigong is a form of ancient and traditional Chinese

medicine that integrates movement (physical postures),

meditation (focused attention), and controlled breathing.

Qigong aims to enhance vital energy or life force that balan-

ces a patient’s spiritual, emotional, mental, and physical

health. Qigong practices are used to increase the qi, circulate

it, use it to cleanse and heal the body, store it, or emit qi to

help heal others. Practices range in intensity from the gentle

movements of tai chi to the more vigorous practice of kung

fu.184 In patients with cancer, qigong is often used to reduce

anxiety, fatigue, and pain; to support the immune system;

and to improve physical and emotional balance.

Stress management

Acute stress is a normal physical and emotional reaction

that people experience as they encounter changes in life,185

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VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 203

including after a cancer diagnosis, during cancer treatment,

and throughout cancer survivorship. Long-term chronic stress

may contribute to or worsen a range of health problems,

including digestive disorders, headaches, sleep disorders,

depression, anxiety, and other mental health problems.185 To

address stress and induce the relaxation response, stress-

management programs teach techniques like PMR, guided

imagery, and breathing exercises. Stress management also

typically incorporates elements of cognitive-behavioral thera-

py, such as understanding the effects of appraisal and percep-

tion on the experience of subjective stress.186,187 Participants

are taught coping skills and practice various techniques for

cognitive reappraisal. One common structured group stress-

reduction program studied in oncology is called cognitive-

behavioral stress management.140,188 There are overlaps in

some techniques used in stress management, relaxation, and

meditation therapies. For example, meditation, guided imag-

ery, and yoga may be practiced as techniques in isolation or

combined. In this review, we distinguish between stress-

management, relaxation, and meditation interventions.

Stress-management interventions include psychoeducation on

stress and coping and emphasize cognitive-behavioral therapy

and coping skills training; relaxation interventions typically

consist of PMR and guided imagery; and meditation inter-

ventions use some form of meditation practice as the focal

point of the training.

Soy

Soy is a plant in the pea family that has been common in

Asian diets for thousands of year and more recently in the

American diet. 162

Soybeans are the seeds of the soy plant

and contain isoflavones and soy protein. Soy is available as a

dietary supplement in tablet or capsule form and contains

isoflavones and/or soy protein. Soybeans can be cooked or

eaten or may be used to make tofu, soy milk, and other food

products. Soy is also used as an additive to other processed

foods, such as baked goods. Soy is used to treat menopausal

symptoms, osteoporosis, memory problems, high blood

pressure, and high cholesterol levels.162 In patients with

cancer, soy is often used to treat hot flashes.

Yoga

Yoga is a mind-body practice with origins in ancient South

Asian philosophy and practice. 189

The term yoga is derived

from the Sanskrit word yug, meaning “yoke” or “union.”190

This, according to traditional yoga philosophy, is the ulti-

mate intent of a yoga practice—to unite the individual with

the totality of the universe. The techniques of yoga include

ethical daily living (yamas and niyamas), physical postures

(asanas), breathing techniques (pranayama), and meditation

training (dhyana). There is a wide range of yoga forms and

styles. The most commonly practiced form of yoga in the

United States and Canada is Hatha yoga, which emphasizes

postures (asanas) and often breathing exercises (pranayama).

In patients with cancer, yoga is used for a variety of condi-

tions, including stress, anxiety, depression, and fatigue, and

as a method to increase physical activity.

Literature Review on the Use of Complementary and Integrative Therapies for Clinical Outcomes in Patients With Breast Cancer

The clinical outcomes addressed here are common symp-

toms and side effects experienced by patients with breast

cancer during treatment or as sequelae of treatment. The

outcomes of interest include: anxiety/stress, pain, depres-

sion/mood, fatigue, sleep disturbances, QOL and physical

functioning, CINV, radiation dermatitis, vasomotor out-

comes, lymphedema, CIPN, pain, and sleep disturbance.

Guidelines outlining conventional approaches to managing

these symptoms and outcomes have been issued by national

organizations like the National Comprehensive Cancer

Network and the American Society of Clinical Oncology,

but many of the prior guidelines and reviews did not include

thorough reviews of complementary and integrative medi-

cine approaches.191-197 This review fills that gap for patients

with breast cancer.

Below, for each therapy and clinical outcome of interest

that received a grade of A or B, we summarize the trials that

contributed to the graded recommendation to give the reader

an understanding of the specific interventions that were test-

ed. To provide additional context, there is a brief review of

the literature on the use of each integrative therapy for condi-

tions other than breast cancer. We also provide a risk/benefit

assessment of each therapy as well as suggestions for future

research. For therapies and clinical outcomes of interest that

received grades of C, D, or H, we provide a brief overview of

the rationale for the graded recommendation. The supporting

tables provide detailed information on each trial that informed

an A-graded or B-graded recommendation (see Supporting

Information Table 2, 26-48

Supporting Information Table

3, 26-30,33,35,40-43,45-48,53-56,59,60,69,72-90

Supporting Information

Table 4,27-29,43,46-48,73-75,82-85,104-106,127,128 and Supporting

Information Table 561-65). Table 3 lists the clinical outcomes

and integrative therapy combinations that had insufficient

evidence to make a grade A, B, C, D, or H recommen-

dation.26,33,36,37,40,43,45-50,52,69,72,73,76,77,79,83,84,87-89,94,97,104,108,111,

113,129,130,133-135,138,139,149,198-301

Updated Recommendations

Although the majority of graded recommendations remain

the same as those in the previously published guidelines, 9

there are 5 noteworthy changes. For the outcome of anxiety

and stress reduction, the use of meditation moved from

grade B to grade A because of results from a fifth trial,26 in

Integrative Therapies During and After Breast Cancer Treatment

204 CA: A Cancer Journal for Clinicians

addition to the previously published 4 trials,27-30 showing

beneficial effects. The use of yoga for depression and mood

disturbance was downgraded from grade A to grade B

because of 4 new published studies demonstrating conflict-

ing results. 40,79-81

The use of yoga for improving QOL

changed from grade C to grade B, because 2 additional trials

demonstrated beneficial effects. 104,128

Finally, new trials

on the use of yoga40,80,104 and hypnosis97,98 for fatigue

upgraded previous recommendations from grade I to grade C.

Use of Integrative Therapies for Anxiety/Stress Reduction

Description of anxiety/stress

Patients with cancer may experience stress related to the life

changes associated with a cancer diagnosis, both during and

after treatment. Under the NCI’s Common Terminology

Criteria for Adverse Event (CTCAE) psychiatric disorders,

anxiety is categorized from grade 1 (mild symptoms and no

intervention required) to grade 4 (life-threatening). Stress is

often the result of life challenges that exceed the individual’s

perceived ability to cope and is a common and normal reac-

tion during cancer diagnosis and treatment. This stress is

associated with symptoms of anxiety and somatic complaints

that can significantly diminish QOL.302 Patients with anxi-

ety may worry more frequently, have difficulty relaxing, or

feel tense. Patients with cancer-related anxiety also may

have elevated heart rate, myalgias, headaches, sleep distur-

bances, changes in appetite, nausea, diarrhea, and difficulty

concentrating. The percentage of patients with breast cancer

who report anxiety ranges from 12% to 47%, and approxi-

mately 11% to 16% of patients experience combined symp-

toms of anxiety and depression.303-305 Evidence suggests

that effective anxiety management is associated with

improvements in QOL, psychological adjustment, under-

standing of the disease, decision making, and adherence to

treatment.306-308

Meditation (A grade)

Overview of meditation interventions for anxiety/stress

reduction. Meditation is recommended for reducing anxiety

in patients with breast cancer, including during radiation

therapy (grade A). Many uncontrolled trials have been pub-

lished, but this recommendation is based on 5 RCTs com-

pleted between 2009 and 2013 that used meditation to

reduce anxiety symptoms (see Supporting Information

Table 2).26-30 Anxiety was the primary outcome for 4 of

those trials. In all 5 studies, a meditation intervention was

compared with a usual-care control condition. Study partici-

pants included women undergoing radiation or chemothera-

py, breast cancer survivors who had completed treatment,

and older adult breast cancer survivors ages 50 years and

older. The study sample sizes ranged from 49 to 336 partici-

pants. Among these trials, 3 types of meditation

interventions were tested. Three trials implemented an

intensive, integrated MBSR program customized for

patients with breast cancer in which participants were

trained in mindfulness meditation and gentle yoga for body

awareness. 26,29,30

A fourth intervention was called the

Mindful Movement Program and was also an intensive,

integrated program customized for patients with breast can-

cer that included mindful walking/moving, group discus-

sion, exploration of body parts, specific and deliberate

movements, moving with intentional effort, active energetic

movement, and partner work.27 The fifth trial assessed a

brain wave vibration meditation28 or a mind/body training

technique that combined simple, rhythmic movements with

music, action, and positive messages. 26

A systematic review and meta-analysis examined medita-

tion in terms of its ability to reduce general psychological

distress and stress-related health problems in adult clinical

populations with a variety of health conditions; that analysis

included 47 trials with 3515 participants.309 Overall, mind-

fulness meditation programs demonstrated moderate evi-

dence of improved anxiety at 8 weeks and at 3 to 6 months

and showed low evidence of improved stress/distress and

mental health-related QOL. The findings of these reviews

across other patient populations and disease types support

our recommendations.

The earliest work in MBSR interventions specifically

demonstrated sustained benefits for individuals with anxiety

disorders, and more recent research has continued to show a

benefit for generalized anxiety. 310-312

The first study con-

ducted in patients with cancer, an RCT of 89 patients with

a variety of cancer types, found substantial decreases in anxi-

ety for the group that received MBSR compared with

results for a usual-care control group; results for the MBSR

interventions were maintained at 6-month follow-up.313,314

The reduction in anxiety observed in the above-described

trials, specifically those that used more traditional forms of

MBSR, provide support for the recommendation that medi-

tation can be beneficial for the management of anxiety in

women with breast cancer.

A recent systematic review and meta-analysis of 22 stud-

ies examined the effect of mindfulness-based therapy specif-

ically on symptoms of anxiety and depression in adult

patients with cancer and cancer survivors; of those 22 stud-

ies, 21 included either a substantial percentage of patients

with breast cancer or only patients with breast cancer.315

Overall, that review included 12 nonrandomized studies and

RCTs. In the nonrandomized studies, mindfulness-based

therapy was associated with significantly reduced symptoms

of anxiety postintervention with a moderate effect size,

while the pooled effects sizes of RCTs, including that dis-

cussed above, 29

resulted in a larger effect size (P < .001).

Although the review reported that overall study quality

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VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 205

varied among the studies included, there appears to be sound

evidence from carefully conducted RCTs (n 5 9) supporting

the use of mindfulness-based therapies for the management of

anxiety in patients with breast cancer and in breast cancer sur-

vivors. Another review of 9 studies (including 2 RCTs, a

quasi-experimental case-control study, and 6 single-group pre/

post-intervention studies) investigated the efficacy of MBSR

on mental health specifically in patients with breast cancer and

found an overall decrease in anxiety scores after MBSR (P <

.01). 174

That review provides further support for the use of

MBSR to manage anxiety, specifically in women with breast

cancer. Many other reviews reached similar conclusions,

reporting positive, moderate effect sizes of mind-body inter-

ventions (MBIs) on anxiety and distress in cancer.174,175,316

TABLE 3. Clinical Outcomes and Integrative Therapies With Insufficient Evidence to Form a Clinical Recommendation (I-Statement)

a

OUTCOME INTEGRATIVE THERAPIES

Adherence Acupressure,198 multimodal199

Anemia LCS101 combination botanical,200 RG-CMH combination botanical,201 shenqi fuzheng injection202

Anxiety/stress reduction Art therapy,203,204 comprehensive coping strategy,205 electrical nerve stimulation,206 healing touch,94,207

hypnosis,208 myofascial release,209 multimodal,210,211 reflexology,138,139,212 reiki,213 tai chi214

Cardiomyopathy N-acetylcysteine215

Chemotherapy-induced nausea and vomiting

Acupressure,216 aromatherapy,217 Agaricus sylvaticus,218 Cocculine (complex homeopathic Rx),219

comprehensive coping strategy,205 massage,52 Nevasic audio program,220 yoga43

Cognition Natural environment,221 Ginkgo biloba,222 meditation,72 yoga223

Constipation Self-management program224

Depression/mood Art therapy,203 Biofield Healing,225 comprehensive coping strategy,205 CoQ10,226 electrical nerve stimulation,206 Gandoderma lucidium,227 guarana,108 hypnosis,228 multimodal,199,210,229,230 myofascial release,209 qigong,135 reflexology,138,139 tai chi214

Fatigue Acupressure,198 acupuncture,50,231,232 Biofield Healing,225 comprehensive coping strategy,205 CoQ10,226

Gandoderma lucidium,227 light treatment,233 massage,87 meditation,72,76 mind-body cognitive therapy,234

movement,235 multimodal,230,236,237 multivitamin,238 polarity therapy,239,240 stress management,241 qigong,135

reflexology,139 relaxation,242,243 stress management,36 yoga40,46-48,79,83

Lymphedema CYCLO 3 FORT,244 electrotherapy,245 ginkgo forte,246 pentoxifyline and vitamin E,247,248 yoga249

Neuropathy Omega 3 fatty acids,250 vitamin E,251,252 acupuncture130

Neutropenia/leukopenia Cat’s claw,253 LCS101 combination botanical,200 RG-CMH combination botanical,201 mistletoe,133,134 shenqi fuzheng injection202

Pain Comprehensive coping strategy,205 stress management,36 vitamin D2,254 electrical nerve stimulation,206 cognitive and behavioral therapy,255 hypnosis,256 massage,88 myofascial release,209 reflexology139,212

Quality of life Acupressure,216 Biofield Healing225 calendula cream,257 cannabis,258 chlorella extract,259 CoQ10,226

curcuminoids,260 electrical nerve stimulation,206 electrotherapy,245 flaxseed,261 Ganoderma lucidum,227

gingko forte,246 guided imagery,262 healing touch,94 homeopathy,263-265 hypnosis,97 laser therapy,111 manual lymphatic draining,113 massage,87 meditation,26,72 movement,235,264 music therapy,89

multimodal,199,210,230,236,237,267 multivitamin,238 polarity therapy,239,240 relaxation,69,77 shenqi fuzheng,202 shark cartilage,268 soy,149 supportive-expressive group therapy,269 tai chi214,270-272

Physical functioning Mind-body cognitive therapy,234 music therapy,33 multimodal,199 myofascial release,209 reflexology,139 stress management,37 tai chi,270,272 yoga45,79,84,273

Radiation therapy-induced toxicity outcomes

Adlay bran extract,274 alpha ointment with henna,275 Aquaphor-Biafine-Radiacare,276b boswellia cream,277

calendula cream,257,278 chamomile,279 curcumin,280 glutamine,281 homeopathic pills,282 honey,283,284

hydration,285 massage,286 oil-in-water emulsion,287, glutathione and anthocyanin gel,288c wheat grass extract,289

pentoxifylline and vitamin E290,291

Sleep disturbance Acupuncture,49,50,129 calendula cream,257 meditation,72,292-294 qigong,135 stress-management techniques36

Vasomotor outcomes Black cohosh,295,296 flaxseed,261 homeopathy,264,265 hypnosis,297 magnetic therapy,298 meditation,73

peppermint,299 vitamin E,300 yoga104,301

Abbreviations: CoQ10, coenzyme 10Q; CYCLO 3 FORT, fluid extract of Ruscus aculeatus, hesperidin methyl chalcone, and vitamin C; LCS101, a botanical com- pound mixture; RG-CMH, a Chinese medicinal herb complex.

a Definition of the I Statement: Concludes that the current evidence is insufficient to assess the bal-

ance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. Read the Clinical Considerations section of the US Preventive Services Task Force Recommendation Statement. If the service is offered, then patients should under- stand the uncertainty about the balance of benefits and harms.

b Suppliers for these topicals are as follows: Aquaphor (Beiersdorf AG, Hamburg, Germany), Biafine

(Laboratoire Medix, Houdan, France), and RadiaCare (Medline Industries, Inc., Northfield, IL). c RayGel is a proprietary glutathione and anthocyanin gel.

Integrative Therapies During and After Breast Cancer Treatment

206 CA: A Cancer Journal for Clinicians

Risk/benefit assessment of meditation interventions.

Meditation therapies pose very little risk to participants in

this type of intervention. Few adverse events have been

reported in any trials, but there has been recent interest

within the meditation research community in exploring

adverse reactions to intensive meditation practice, particu-

larly in vulnerable individuals.317,318 Typically, potential

participants are screened through individual orientation

interviews before joining meditation group programs, and

participants who have serious mental health issues are often

redirected to individual counseling or psychiatric interven-

tion before or concomitant with MBI participation. Group

facilitators are typically mental health care professionals

trained to identify and manage psychological symptoms and

reactions that may occur during the training.

Participants in these meditation therapy groups typically

report that the sessions are enjoyable, and dropout rates are

often low and are comparable to the rates in other psychoso-

cial group programs. Because they are offered in group set-

tings, meditation interventions are more cost effective than

traditional individual counseling or psychotherapy and can

often achieve similar results. However, the literature on

meditation therapy is lacking in head-to-head comparisons

with other forms of therapy, including individual counsel-

ing, cognitive-behavioral therapy, or other MBIs. Hence,

the specificity of meditation therapy is not yet known. With

the exception of the trial reported by Carlson et al, 26

studies

have not compared MBIs with other effective interventions.

Other research suggests that the benefit is related to the

degree of the participant’s engagement in and commitment

to the practice,313,319 in that participants who practice more

at home often benefit more, but this area is still being inves-

tigated. 320

Drawbacks of these types of group interventions

are the requirement for highly trained facilitators and the

need for and ability of participants to attend in person, usu-

ally in large cities with tertiary cancer centers. In response to

these issues, online and home-based adaptations of MBIs

are being developed. For example, Zernicke et al 321

demon-

strated that an online, live MBI group in which rural

and remotely located patients who had cancer participated

weekly over 8 weeks had similar benefit to the on-site, in-

person version; and patients were highly satisfied with the

remote MBI adaptations.

Future research in meditation interventions for anxiety

reduction. Future research on the use of meditation inter-

ventions for anxiety can similarly test novel interventions in

populations that may not have ready access to in-person

meditation programs.

Music therapy (B grade)

Overview of music therapy interventions for anxiety/

stress reduction. Passive music therapy is recommended to

reduce anxiety during radiation therapy, chemotherapy ses-

sions, and postsurgery (grade B) based on results from

5 RCTs comparing music therapy interventions with stan-

dard care (see Supporting Information Table 2).31-35 Study

participants included patients with breast cancer who were

undergoing mastectomy, chemotherapy, and/or radiation

therapy. The sample sizes of these studies ranged from 30 to

170 participants. The music therapy interventions were

described as either passive or active music therapy, depend-

ing on the level of engagement required by the individual.

Four trials examined the effect of passive music therapy,

which was found to decrease anxiety scores in the interven-

tion group,31,32,34,35 including reducing sedation require-

ments during radiation therapy (measured as a secondary

outcome). 31,32,34

The fifth trial, which was conducted by

Hanser et al,33 examined active music therapy (which

required active engagement of the participant) and yielded

substantially different results from the 4 trials of passive

music therapy. In that study, active music therapy did not

result in decreases in anxiety. The discrepancy in trial results

between passive and active music therapy might have

occurred because the participant engagement required for

active therapy does not include the potential relaxing com-

ponents of passive music therapy (eg, listening to music).

A recent systematic review and meta-analysis by Boehm

et al 322

assessed the effect of different expressive therapies,

including passive and active music therapy, on improving

anxiety, depression, and QOL in patients with breast can-

cer. The review included 3 of the RCTs that formed the

basis for our recommendation of passive music therapy for

anxiety/stress reduction, of which 2 trials tested passive

music therapy,31,34 and the other tested active music thera-

py.33 Another recent meta-analysis included an additional

RCT evaluating art therapy. 204

Boehm et al found a clini-

cally and statistically significant mean difference (P < .01)

in the anxiety scores of patients who received music therapy

compared with the control group,322 thus further supporting

our recommendation of passive music therapy for reducing

anxiety. Passive music therapy has also been shown to

reduce anxiety among patients undergoing mammographic

screening, indicating that the recommendation may apply

broadly to adult women in a clinical cancer setting.323

Risk/benefit assessment of music therapy. Passive music

therapy is noninvasive, does not interfere with a patient’s

privacy, and has no reported deleterious effects. Further-

more, it does not require costly, technologically advanced

equipment and can be implemented in a variety of locations.

As such, passive music therapy can be safely and effectively

implemented in clinical settings for patients with breast can-

cer to help reduce short-term anxiety associated with receiv-

ing medical care for their cancer.

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VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 207

Future research in music therapy for anxiety reduction.

Future research should assess the long-term effects of pas-

sive music therapy on anxiety, because the trials reviewed

here only assessed short-term reductions in anxiety.

Although active music therapy may also have benefit, more

than one existing trial will be needed for a comprehensive

risk/benefit assessment. Trials that directly compare the

effect of passive versus active music therapy on anxiety are

needed to clarify whether the benefit is because of listening

to music in a relaxed state or participating in the creation of

music.

Stress management (B grade)

Overview of stress-management interventions for anxi-

ety/stress reduction. Stress management is recommended

to reduce anxiety in patients during breast cancer treatment

(grade B), but long-term stress-management group pro-

grams appear to be better than self-administered home pro-

grams. This recommendation is based on 4 RCTs, which

were completed between 2008 and 2013 among patients

with breast cancer, testing a stress-management intervention

compared with usual care using an improvement in anxiety

as the primary outcome.36-39 Study participants included

only patients who had breast cancer in 2 of the 4 trials 36,39

and a mixed group of patients with cancer that included a

significant proportion of women who had breast cancer in

the other 2 trials. 37,38

In all 4 trials, patients with breast can-

cer were included from defined periods along the continuum

of care, including before surgery, during chemotherapy, and

after cancer treatment. Patients thus were either undergoing

or had undergone surgery, chemotherapy, or radiation ther-

apy, either alone or in combination. The study sample sizes

for these trials ranged from 85 to 286 participants. Of the 4

trials, 2 indicated that the improvement was statistically sig-

nificantly different compared with the control group. 37,39

One trial found a similar improvement in both the interven-

tion and control groups with no statistically significant dif-

ferences across groups,36 and the fourth trial found no

improvement38 (see Supporting Information Table 2, Stress

Management).

Stress-management interventions varied among the stud-

ies (see Supporting Information Table 2). 36-39

One trial 38

implemented a self-administered stress-management inter-

vention before patients received chemotherapy. The inter-

vention included video and booklet information specific to

stress management and exercise and was delivered by a

doctoral-level psychologist. 38

A second trial 36

offered stress-

management modalities that included guided imagery tech-

niques, relaxation, meditative exercises, and counseling that

aimed to promote active coping, alert relaxation, and a posi-

tive attitude toward change. Instruction was given in person

and was complemented by audio CDs for use at home.

Face-to-face sessions lasted from 45 to 60 minutes each and

took place in the hospital.36 The stress-management portion

included information, demonstrations and instructions for

paced breathing, PMR with guided imagery, and the use of

coping strategies to manage stress. A third trial,37 which

took place at a multicenter community clinical oncology

program involving 20 clinical sites, was designed to deter-

mine whether a self-administered stress-management inter-

vention that was previously identified as beneficial for

patients with cancer would improve QOL and decrease psy-

chological distress (including anxiety and depression) in

patients receiving chemotherapy at community clinical cen-

ters. The study used a factorial design to test stress-

management training, exercise training, combined stress-

management and exercise training, and usual care. Patients

assigned to stress-management training were provided writ-

ten materials and videos on 3 techniques, including PMR

and guided imagery, abdominal breathing, and coping skills

training.37 A fourth trial39 examined the effects of a

cognitive-behavioral stress-management intervention (com-

prised of relaxation training, including meditation, guided

imagery, PMR and breathing techniques, cognitive restruc-

turing, and coping skills training) on late-afternoon serum

cortisol and relaxation indicators in women undergoing

treatment for nonmetastatic breast cancer.

A systematic review by Trijsburg et al evaluated the

effects of stress-management techniques on mental health

outcomes, including anxiety, across 22 studies using samples

from heterogeneous cancer populations that included 6

studies of breast cancer-only samples. 324

The interventions

assessed were all structured and included counseling and

coping components in addition to some interventions,

including PMR, guided imagery, self-hypnosis, and deep

breathing. Overall, the review found positive effects for

mental health outcomes, including anxiety scores.

Risk/benefit assessment of stress-management interven-

tions. Stress-management therapy is noninvasive, nontoxic,

and has no appreciable risk to patients. Stress management

does not require specialized equipment and can be imple-

mented in a variety of locations. Resources for providing

instruction on self-management practices are broadly avail-

able. Because the majority of trials discussed above tested

long-term interventions, the guideline recommendation is

specific to long-term stress-management programs. Howev-

er, this may be complicated by other factors, including a

potential increase in the cost of delivery for providers/facili-

tators as a result of the implementation of longer term pro-

grams, and it also could present a barrier to patients who

have access-to-care and other health care disparity issues.

Overall, it is recommended that stress-management therapy

can be safely and effectively implemented in clinical settings

for patients with breast cancer.

Integrative Therapies During and After Breast Cancer Treatment

208 CA: A Cancer Journal for Clinicians

Future research in stress-management interventions for

anxiety reduction. Future research in this area should com-

pare in-person, professionally led stress-management group

programs versus home-based, self-study, and internet-based

stress-management intervention options, which are less

costly and more broadly accessible. Research should also

examine long-term outcomes for each type of delivery

modality.

Yoga (B grade)

Overview of yoga interventions for anxiety/stress reduc-

tion. Yoga is recommended for reducing anxiety in

patients with breast cancer (grade B). This recommenda-

tion is based on 9 RCTs, completed between 2007 and

2014, in which a yoga intervention was implemented to

reduce physical symptoms and psychological distress,

including anxiety, which was assessed as the primary out-

come in 4 of the studies (see Supporting Information

Table 2). 40-48

Those 9 trials tested 5 different yoga inter-

ventions. The first intervention was an intensive, integrat-

ed yoga program customized for patients with breast

cancer, in which participants were led through slow

stretching and loosening exercises, various postures (asa-

nas), guided imagery specific to cancer, positive thought

provocation, chanting exercises, various breathing exer-

cises (pranayama), and soothing sound vibrations and

guided imagery (yoga nidra). 41-44

A second intervention

implemented Iyengar yoga, a traditional form of Hatha

yoga emphasizing postures and breathing techniques that

target symptom-specific concerns using passive inversions

(upside-down postures with the head lower than the heart)

and passive backbends (supported spinal extensions). 45

A

third intervention used Patanjali’s yoga sutras, which

included warm-up movements synchronized with breath-

ing, selected postures, deep relaxation techniques,

alternate-nostril breathing (pranayama), and meditation.48

The fourth intervention implemented meditation and

breathing exercises that focused attention on internal body

sensations as well as yoga exercises (modified asanas) com-

posed of gentle stretching and strengthening exercises. 40

Pranayama or yoga breathing practices were tested in the

remaining trials. 46,47

Study participants included women

who had been recently diagnosed with breast cancer, those

who were currently receiving radiation or chemotherapy or

a combination of both, and those who were experiencing

significant fatigue post-treatment. The study sample sizes

ranged from 23 to 98 participants.

Several recent reviews of yoga interventions for individu-

als with cancer have been published.325-328 The first meta-

analysis investigating the impact of yoga interventions on

psychological health outcomes329 identified 10 articles that

examined outcomes in patients with breast cancer (n 5 7

articles), patients with lymphoma (n 5 1), and mixed cancer

populations (n 5 2). Analyses involving 8 trials that assessed

anxiety found that lower anxiety was associated with the

yoga groups relative to controls (P 5 .009); and similar

results with yoga interventions were observed for distress

(P 5 .003) and stress (P 5 .006). However, because this

was a heterogeneous sample of patients, it was unclear

whether the results could be generalized specifically to

patients with breast cancer. More recently, a systematic

review and meta-analysis assessing the impact of yoga inter-

ventions on QOL and psychological health specifically in

patients with breast cancer and survivors was conducted. 330

Overall, 12 RCTs were included in the analysis with a total

of 742 participants. Analyses revealed short-term positive

effects of yoga interventions on improved psychological

health, including anxiety (P < .01), perceived stress (P 5

.03), and psychological distress (P < .01). However, it is

notable that these effects were applicable only to those who

engaged in yoga during active cancer treatment and not in

the post-treatment period. The authors stated that, based

on these positive preliminary results, a wide variety of yoga

practices could be recommended for this population.330

Finally, although the methodological quality across the trials

varied, it has been demonstrated that yoga is beneficial for

reducing psychological distress in a wide variety of non-

cancer clinical populations, including adult patients with

anxiety and depression.331,332

Risk/benefit assessment of yoga interventions. Yoga

interventions are noninvasive and, with proper instruction,

can be adapted to people who have functional and other

impairments without harm. Yoga interventions are low cost

and can be practiced at home with instructional videos;

however, in the context of breast cancer, they are best

undertaken under the guidance of certified yoga instructors

who have specific training in teaching patients with cancer

and cancer survivors. Such programs also have the ability to

be adapted and modified for people with medical conditions

or limited mobility.333 Older adults, individuals with limited

mobility, and those with chronic medical conditions should

proceed with yoga therapy only under the guidance of a cer-

tified instructor to minimize the potential risk of harms

such as strained muscles and dizziness if yoga postures are

attempted incorrectly or prematurely.

Future research in yoga interventions for anxiety reduc-

tion. Many of the studies investigating the impact of yoga

on psychological outcomes in individuals with cancer

should be interpreted with caution, because many of these

studies are small and preliminary. Furthermore, the studies

summarized above have some inconsistency of results; the

trials from India41-44 reported consistently positive results,

while the trials from North America40,45-48 reported less

consistent positive results. Nevertheless, many of the

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VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 209

studies and reviews that examined yoga interventions

reported overall positive outcomes in several physical, psy-

chological, and QOL measures. Future trials of yoga inter-

ventions for anxiety/stress reduction should focus on

testing forms of yoga that can be more easily applied and,

to improve the generalizability of the results, should test

the interventions in larger sample size and in minority and

underserved populations that may not have easy access to

yoga programs.

C-graded therapies for anxiety and stress reduction

Acupuncture,49-51 massage,52-55 and relaxation56-60 can be

considered for reducing anxiety and stress (grade C). Three

high-quality trials assessed acupuncture for anxiety and

stress reduction, which were secondary outcomes; 2 of the 3

positive trials were small, 49,50

and the other demonstrated

no effect.51 However, of 4 studies that examined massage

for anxiety, 3 with positive findings included fewer than 40

participants,52-54 and the other demonstrated no effect.55

Results were inconclusive regarding relaxation for anxiety

and stress reduction because of inconsistencies and small

sample sizes. Future directions in research can focus on eval-

uating these modalities in a large, high-quality trial assess-

ing anxiety as the primary outcome.

Use of Integrative Therapies for Depression/Mood Disturbances

Description of depression/mood disturbances

Both during and after cancer therapy, patients may experi-

ence symptoms of depression, as they often feel a sense of

loss of health and the life they had before their cancer diag-

nosis.302 The CTCAE categorizes depression as a psychiat-

ric disorder on a scale from 1 (mild) to 5 (death). Symptoms

of depression in patients with cancer may include persistent

feelings of sadness, numbness, nervousness, guilt, worthless-

ness, helplessness or hopelessness, difficulty concentrating

or behavior that includes being short-tempered or moody,

crying for long periods of time or many times each day,

lacking interest or pleasure in performing activities, and

having suicidal thoughts. Other symptoms may include

weight change, sleep disturbances, tachycardia, dry mouth,

increased perspiration, gastrointestinal symptoms, diarrhea,

changes in energy level, persistent fatigue, headaches, or

myalgias. The percentage of patients with breast cancer

reporting depression ranges from 3% to 34%, and 11% to

16% of patients experience combined depression and anxiety

symptoms, depending on the population studied.303-305

Effectively managing depression may improve QOL, psy-

chological adjustment, understanding of the disease, deci-

sion making, adherence with cancer treatment, and response

to cancer treatment. 306-308

Meditation (A grade)

Overview of meditation interventions for depression/

mood disturbances. Meditation, particularly MBSR, is

recommended for treating mood disturbance and depressive

symptoms in patients with breast cancer (grade A). This

recommendation is based on 10 RCTs, completed between

2009 and 2015, that used meditation to help reduce depres-

sive symptoms (see Supporting Information Table

3).26-30,72-76 Depression was the primary or secondary out-

come for all of these trials. In 8 of the 10 trials,27-30,72-74,76

a meditation intervention was compared with a usual care

group, a waitlist control group, or another active interven-

tion; 2 other trials used a 3-arm trial design.26,75 Study par-

ticipants included women undergoing current radiation

therapy or chemotherapy for breast cancer, breast cancer

survivors who had completed treatment, and adult breast

cancer survivors ages 55 years and older. The study sample

sizes ranged from 33 to 336 participants and tested 6 differ-

ent types of meditation interventions, including an inten-

sive, integrated MBSR program customized for patients

with breast cancer26,29,30,73,75; the Mindful Movement Pro-

gram73; brain wave vibration meditation28; Tibetan sound

meditation72; cognitively based compassion training76; and

Transcendental Meditation.74

In the meta-analysis examining the effect of mindfulness-

based therapy on psychological outcomes in adult cancer

populations, 315

compared with results in controls,

mindfulness-based therapy was associated with significantly

reduced depression postintervention, with a moderate effect

size in the nonrandomized studies and RCTs, including one

trial listed above29 (P < .001). By using evidence from 9

well conducted studies, the review and meta-analysis by

Zainal et al confirmed the use of mindfulness-based thera-

pies for the management of depression in patients with

breast cancer and survivors despite the heterogeneity in the

reviewed studies; the results of the meta-analysis identified a

significant pooled effect size for MBSR on depression scores

(effect size, 0.575; 95% confidence interval, 0.429-0.722

[P < .01]).174 In their study, Teasdale et al334 modified

traditional MBSR by combining it with principles of cogni-

tive behavioral therapy to create mindfulness-based cogni-

tive therapy, which was designed specifically to prevent

recurrence of depressive symptoms in individuals with

relapsed major depression.335 The intervention proved

effective for preventing depression relapse334 and has since

been widely applied and adapted to treat depression symp-

toms in a range of clinical samples.336 In patients with can-

cer, other RCTs of meditative interventions resulted in

decreased depressive symptoms,313 with results maintained

after 6 months of follow-up.314 The reduction in depressive

symptoms observed in the above-described trials comprising

these reviews and meta-analyses provide further support for

Integrative Therapies During and After Breast Cancer Treatment

210 CA: A Cancer Journal for Clinicians

the recommendation that meditation can be beneficial for

the management of depressive symptoms in women with

breast cancer.

Risk/benefit assessment of meditation interventions.

The risk/benefit assessment of the effects of meditation

intervention on depression and mood disturbance outcomes

is similar to the assessment of anxiety outcomes. Despite

these limitations, the evidence suggests that meditation and

MBSR could be added to treatment plans or in the post-

treatment period, provided that these interventions are facil-

itated by appropriately trained instructors and can be

adapted and modified if needed for individuals with cancer.

Future research in meditation interventions for depres-

sion/mood. Future research on meditation interventions to

improve mood disturbances/depression should focus on

understanding the type, duration, and lasting effects of spe-

cific meditation techniques on specific mental health

outcomes.

Relaxation (A grade)

Overview of relaxation interventions for depression/

mood disturbances. Relaxation therapy is recommended

for improving mood disturbances and depressive symptoms

when added to standard care (grade A). The recommenda-

tion put forth in the guidelines is based on results from 6

RCTs, completed between 1999 and 2007, which imple-

mented a relaxation program with or without guided imag-

ery as an intervention to improve mood disturbances and

treat depression (see Supporting Information Table

3).56,59,60,69,77,78 Five of the 6 trials measured depression as

the primary outcome. In all 6 trials, a relaxation therapy

intervention group was compared with a standard care

group. The interventions comprised some form of relaxation

therapy that included PMR and guided imagery or visuali-

zation techniques. One trial 56

assessed autogenic training,

which provided training in relaxation meant to induce

heaviness and warmth of limbs, calming of the heart and

breathing, abdominal warmth, and cooling of the forehead.

Limitations of all of these trials included the potential for

expectation bias attributable to the inability to blind partici-

pants and a lack of attention control groups, although one

study used a health education attention control.78 Partici-

pants in these studies included patients with breast cancer

who had undergone or were currently undergoing surgery,

chemotherapy, or radiation therapy. The study sample sizes

ranged from 31 to 183 participants.

The majority of pertinent systematic reviews combine

relaxation techniques with stress-management, psychosocial,

and psychological interventions for patients with breast can-

cer. Thus, a review specific to relaxation interventions that

includes PMR and guided imagery for depression/mood or

other psychological outcomes in patients with breast cancer

and survivors is warranted. A review of studies of guided

imagery as adjuvant cancer therapy broadly assessed 6 RCTs

and found the methodological quality inconsistent.337

Across trials, the results provided few details, and the stud-

ies were implemented with heterogeneous cancer popula-

tions, interventions, and outcome measures, which

ultimately precluded statistical pooling of the results.

Despite these limitations, the results indicated that guided

imagery as a sole adjuvant cancer therapy was supportive

and increased comfort in patients and had few risks.

Beyond decreasing depression, relaxation therapy may

also have a beneficial impact on other symptoms important

to women with breast cancer. For instance, PMR was effec-

tive in ameliorating sleep problems and fatigue in women

undergoing chemotherapy for breast cancer. 338

Other likely

benefits attributable to this therapy in breast cancer popula-

tions include reduced nausea and anxiety.339-342

Risk/benefit assessment of relaxation interventions.

Relaxation therapy is noninvasive and positively engages the

patient with very little potential for harm. The goal of this

treatment approach is to use principles of psychoneuroim-

munology to better regulate the hypothalamic-pituitary-

adrenal axis, modulate cortisol production, and decrease

stress, which may have other health benefits, including psy-

chological outcomes that may be affected by stress and dis-

tress (such as anxiety and depression/mood disturbances).

Some of the appeal of relaxation therapy includes its low

cost, safety, and portability. With adequate training,

patients themselves can apply this therapy when and where

they want without the need for supervision. However, the

durability of relaxation therapy and the frequency required

to sustain a long-term positive effect on depression remain

unclear. It seems that relaxation therapy is not only applica-

ble for those with breast cancer and depression but also has

been shown to be beneficial in other contexts, including the

ability to decrease depression in adults343,344 and depression

associated with cardiac disease.345 The minimal cost and

low potential for harm with relaxation therapy, in conjunc-

tion with its evidence of benefit, support an A grade recom-

mendation for depression.

Future research in relaxation interventions for depres-

sion/mood. In addition to the gaps in the literature

described above, future research on the use of relaxation

interventions to improve mood disturbances should focus

on how to use novel electronic communication strategies to

deliver low-cost relaxation techniques to diverse patient

populations.

Yoga (B grade)

Overview of yoga interventions for depression/mood dis-

turbances. Yoga is recommended for improving mood dis-

turbances and depressive symptoms in women with breast

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VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 211

cancer (grade B). This recommendation is based on the

results from 15 RCTs, completed between 2006 and 2015,

that used a yoga intervention to reduce physical symptoms

and psychological distress, including depression (see Sup-

porting Information Table 3). 40-43,45-48,79-85

Depression or

depressive symptoms were the primary or secondary out-

come for all studies included in this review. Study partici-

pants included women recently diagnosed with or having a

recurrence of breast cancer; women who were receiving radi-

ation therapy, chemotherapy, or a combination of both; an

ethnically diverse and underserved sample of female

patients; and women who had completed breast cancer

treatment. Five different yoga interventions were tested in

study samples ranging in size from 23 to 200 participants.

Five trials assessed an intensive, integrated yoga program

that was customized for patients with breast cancer, includ-

ing asanas, pranayama, and yoga nidra. 41-43,81,85

Five trials

implemented Iyengar yoga, a traditional form of Hatha

yoga, and passive backbends.45,80,82-84 Two trials assessed

Patanjali’s yoga sutras, which included warm-up movements

synchronized with breathing, selected postures, deep relaxa-

tion techniques, meditation, and alternate-nostril breathing

(pranayama) 48,79

; while 2 trials evaluated only the pra-

nayama practices.46,47 Finally, a yoga exercise intervention

implemented meditation and breathing exercises that

focused attention on internal body sensations as well as yoga

exercises (modified asanas) composed of gentle stretching

and strengthening exercises. 40

It has been shown that yoga is beneficial for reducing

depression in a wide variety of clinical populations, 332,346-348

and specifically among individuals with cancer.325-328 One

meta-analysis investigating the impact of yoga interventions

on psychological health outcomes 329

analyzed 8 trials of

yoga interventions for depression and showed improvement

in depressive symptoms in the yoga groups compared with

the control groups (P 5 .002) among a heterogeneous sam-

ple of patients. Specifically in patients with breast cancer

and in breast cancer survivors, a meta-analysis330 of 12

RCTs, representing a total of 742 participants, revealed

short-term effects of yoga interventions on improved psy-

chological health, including depression (P < .01). A caveat

was that the observed efficacy was only applicable for yoga

practiced during active cancer treatment and not necessarily

in the post-treatment period. Overall, the authors stated

that, based on these positive preliminary results, yoga thera-

py should be used in this population.

Risk/benefit assessment of yoga interventions. The risk/

benefit assessment of the effects of yoga on depression and

mood disturbance outcomes is similar to the assessment

for anxiety outcomes. Studies assessing yoga for psychologi-

cal outcomes in individuals with cancer are typically

small, not well controlled, and preliminary in nature.

Furthermore, comparability across studies is difficult,

because findings differ between populations from

India41-43,85 and North America.45,46,48,82-84 Despite these

limitations, the evidence suggests that yoga interventions could

be added to treatment plans or in the post-treatment period,

provided these interventions are facilitated by appropriately

trained yoga instructors and can be adapted and modified for

people with medical conditions or limited mobility. 333

Future research in yoga interventions for depression/

mood. Future trials of yoga interventions to improve mood

disturbances/depression should test the effects of different

types, doses, and durations of yoga on patient populations

with various degrees and types of mood disturbances and

depression in addition to including larger sample sizes and

testing across active controls.

Massage (B grade)

Overview of massage therapy interventions for depres-

sion/mood disturbances. Massage therapy is recom-

mended to improve mood disturbance in breast cancer

survivors after active treatment (ie, surgery, chemotherapy,

radiation; grade B). This recommendation is based on

results from 6 trials completed between 2004 and

2012.53-55,86-88 In the trial reported by Listing et al,87 the

primary outcomes focused on physical discomfort and

fatigue, with mood disturbance as a secondary outcome.

The other 5 trials assessed depression as the primary out-

come and had other secondary outcomes, including per-

ceived stress, QOL, pain, heart rate variability, and emesis.

In the 5 trials, the effect of massage therapy was compared

with the effect of standard care. The studies, which took

place in the United States,53 Germany,54,86,87 England,55

and Spain, 88

all included breast cancer survivors who had

completed active cancer treatment at least 3 months before

study enrollment. The study sample sizes ranged from 20 to

288 participants. In 3 of the 6 trials, the massage therapy

intervention was a variation of classic massage involving

rhythmic stroking, kneading, and acupressure at select areas

on the body. 54,86,87

The study by Fernandez-Lao used an

experienced and trained physical therapist to administer

manual massage therapy. 88

Wilkinson et al 55

included aro-

matherapy as part of the massage therapy, which was indi-

vidualized across study participants. Hernandez-Reif et al53

combined massage with acupressure and Trager, which uses

hundreds of small, rocking, and elongating movements that

release muscle tension. The number and frequency of mas-

sage therapy sessions varied across the studies.

All of the trials assessing classic massage therapy used the

same protocol of biweekly, 30-minute massages for 5

weeks, 54,86,87

with the exception of the trial by Fernandez-

Lao et al, in which a one-time, 40-minute massage session

was assessed. 88

Across these studies, compared with control

Integrative Therapies During and After Breast Cancer Treatment

212 CA: A Cancer Journal for Clinicians

groups, women in the intervention groups reported signifi-

cant improvement in mental health outcomes, including

reduced depression and mood disturbance scores particularly

in relation to anxious depression, anger, and tiredness.

These differences between groups, however, were not con-

sistently sustained across all studies. For example, in the

study by Fernandez-Lao et al, the improvements in depres-

sion outcomes with a single-session massage intervention

depended on the participant’s individual level of enthusiasm

for that intervention. The classic massage studies54,86,87 and

one trial that combined massage with aromatherapy 55

found

that the massage interventions significantly decreased

depression only immediately after the intervention but not

long term. The remaining study that combined massage

therapy with acupressure and Trager53 demonstrated a posi-

tive effect of the interventions on anxiety and depression,

with these effects sustained at long-term follow-up.

A systematic review and meta-analysis examined the role

of massage interventions in the management of treatment-

related side effects associated with breast cancer in terms of

improvement in overall QOL, including measures of

depression. 349

In total, 18 RCTs were included in this

review. Overall regular massage therapy was shown to have

positive effects on other outcomes, such as anger and fatigue

symptoms, but the meta-analysis of 8 trials, 3 of which are

summarized in this section,53,54,87 did not find significant

beneficial effects of massage therapy for depression. Howev-

er, that meta-analysis was limited by significant heterogene-

ity across the studies that assessed depression as the

outcome (P 5 .002) as well as by small and possibly under-

powered sample sizes, which may have accounted for the

nonsignificant results. An earlier systematic review of mas-

sage therapy in breast cancer populations that found no pos-

itive effect of massage on depression also concluded that few

rigorous trials have been conducted and that the risk of bias

in such trials is high. 350

Risk/benefit assessment of massage therapy interven-

tions. Classic massage is a noninvasive therapy that has lim-

ited adverse effects. For patients with cancer, massage

therapy by a trained massage professional appears to have

few risks and may reduce pain, promote relaxation, and

boost mood, at least in the short term.351 Since trained,

licensed therapists delivered the interventions tested in these

studies, the recommendation of massage for depression

applies specifically to massage by trained therapists.352,353

Some caution is needed, however, for individuals receiving

anticoagulation therapy because of their risk of bruising.

Women with breast cancer who have undergone radiation

therapy or surgery or have implanted medical devices also

may need to be cautious in having massage to the affected

regions. In addition, some women may be reluctant to dis-

robe because of altered body image, modesty, or

ethnocultural issues. Thus, important considerations include

appropriate draping of the individual and ensuring that the

massage therapist is sensitive to the treatment experiences of

women with breast cancer and develops a therapeutic rela-

tionship with the individual. Ensuring that the massage

therapist is the same gender as the patient is considered best

practice in the massage profession and may also increase an

individual’s comfort with receiving massage therapy. How-

ever, this practice was not tested in the studies included in

this review.

Future research in massage interventions for depres-

sion/mood. A 2008 systematic review of massage therapy

for depression in the general public concluded that evidence

to support massage as an effective treatment for this indica-

tion and population was lacking.354 However, a more recent

(2010) meta-analysis of 17 RCTs concluded that massage

therapy had a positive effect on individuals suffering from

depression. 355

That meta-analysis also highlighted the het-

erogeneity across massage therapy trials in terms of therapy

protocols, outcomes measurement, and populations and

underscored the need for standardization across future mas-

sage therapy trials. These issues are also true for the trials

assessing massage interventions for depression/mood in

patients with breast cancer. Future research on massage

therapy interventions to improve depression/mood distur-

bances should focus on understanding how best to dissemi-

nate cost-effective massage interventions in routine clinical

settings.

Music therapy (B grade)

Overview of music therapy interventions for depression/

mood disturbances. Passive music therapy is recommended

to improve depression/mood disturbances in patients with

newly diagnosed breast cancer (grade B). This recommenda-

tion is based on 4 RCTs, completed between 2000 and

2011, that tested a music therapy intervention to improve

mood/depression (see Supporting Information Table

3). 33,35,89,90

Depression/mood disturbances were assessed

either as the primary outcome or as a secondary outcome to

anxiety. In all 4 trials, a music therapy intervention group

was compared with either a waitlist or a standard care con-

trol group. Study participants included women with a breast

cancer diagnosis who had completed mastectomy, chemo-

therapy, or radiation therapy or who had metastatic disease.

The study sample sizes ranged from 8 to 170 participants.

Three trials examined the effect of passive music therapy,

which was found to decrease depression scores compared

with controls,35,89,90 and the fourth trial examining active

music therapy 33

yielded no clinically meaningful, long-term

effects between groups or over time. Active music therapy

resulted in immediate effects on happiness within the

intervention group that were not sustained over time.

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Therefore, the guideline recommendation is specific to pas-

sive music therapy.

Of the 5 studies combined in the meta-analysis described

above that assessed multiple types of art therapies for

improving anxiety, depression, and QOL among patients

with breast cancer322 (4 music therapy interventions, includ-

ing 2 trials identified in our review,33,204 and an art therapy

trial), a clinically and statistically significant mean difference

(P 5 .05) was observed across all depression scores in the

music therapy intervention groups compared with control

groups. Furthermore, a systematic review of music therapy

specifically for depression in the Cochrane Database of Sys-

tematic Reviews found that, although only 5 RCTs have

tested music therapy interventions for depression and have

met the review study inclusion criteria, this therapy is widely

accepted and beneficial to a broad range of individuals with

depression and is associated with improvements in mood

disturbances.356 Taken together, this literature supports our

recommendation of passive music therapy for reducing

depression and improving mood.

Risk/benefit assessment of music therapy interventions.

The risk/benefit assessment of passive and active music

therapy interventions for depression/mood among patients

with breast cancer is the same as that for anxiety depression

(see above).

Future research in music therapy interventions for

depression/mood. Future research in this area should

assess long-term effects of passive music therapy on mood

disturbances/depression, because the reviewed trials were

limited to assessing short-term improvement of mood/

depression after breast cancer treatments or during meta-

static cancer diagnosis. In addition, studies should attempt

to replicate the null findings of active music therapy inter-

ventions to formulate a comprehensive risk assessment

regarding active music therapy. Suggestions for future

research in music therapy for improving depression/mood

are similar to those for anxiety, as stated above (see Use of

Integrative Therapies for Anxiety/Stress Reduction).

C-graded therapies for depression/mood

Acupuncture,49-51,91,92 healing touch,93,94 and stress man-

agement36-38,95,96 can be considered for improving mood

and depressive symptoms (grade C). Five trials assessed acu-

puncture as a treatment for depression/mood (but as a sec-

ondary outcome), and only one trial was large, 51

with mixed

findings in terms of effect. Two studies assessed the effect

of healing touch on depression as a primary outcome, with

one small study showing no effect94 and a larger study

showing a positive effect.93 Although 5 large studies were

reviewed for the effect of stress management on depression/

mood, the findings were inconclusive because of inconsis-

tent results across trials. Future research directions should

include conducting trials with larger samples sizes and repli-

cating trials with these modalities to examine their impact

on depression symptoms and improving mood as the prima-

ry outcome.

Use of Integrative Therapies for Fatigue

Description of fatigue

Among patients with cancer, fatigue is commonly referred

to as cancer-related fatigue. Fatigue is a multifactorial con-

dition marked by extreme tiredness and an inability to func-

tion because of lack of energy.357 According to National

Comprehensive Cancer Network guidelines, ratings of

fatigue of 4 or higher on a scale from 0 to 10 (where 10 is

very severe fatigue) are further evaluated for known contrib-

uting factors, such as pain, emotional distress, anemia, sleep,

nutrition, and level of activity. These comorbidities are then

treated. The CTCAE measures fatigue from grade 1

(relieved by rest) to grade 3 (not relieved by rest, limiting

activities of daily living). Fatigue is the most frequent and

distressing side effect of common antineoplastic therapies,

including chemotherapy, radiation therapy, surgery, and

selected biologic response modifiers. 196

Although cancer-

related fatigue typically improves upon the conclusion of

treatment, it can last for months or years in up to one-third

of patients and may become a chronic condition that leads

to a variety of physical and psychological effects long into

survivorship. Symptoms of fatigue include feeling tired,

weak, worn-out, heavy, slow, or having “no energy or get-

up-and-go.” Cancer-related fatigue is different from com-

mon tiredness in both its magnitude and quality. Cancer-

related fatigue is not typically relieved by rest and is much

more profound than simply feeling tired. About 33% of

patients with breast cancer experience moderate to severe

fatigue. 358-360

Fatigue has disruptive consequences and can

have a negative impact on a patient’s QOL, mood, and self-

esteem. 192

Cancer-related fatigue can prevent patients from

taking part in daily activities, relationships, social events,

community activities, as well as work or school, which can

have financial consequences, such as loss of employment

and health insurance.

C-graded and D-graded therapies for fatigue

There are no A-graded or B-graded therapies to report for

fatigue. Trials evaluating hypnosis, 97,98

ginseng, 99,100

acetyl-

L-carnitine, 107

and guarana 108,109

have examined their

effects on fatigue during treatment. Two trials from a single

research group reported beneficial effects of hypnosis on

fatigue during treatment; therefore, hypnosis can be consid-

ered for fatigue during treatment (grade C). Neither acetyl-

L-carnitine nor guarana is recommended for improving

fatigue during treatment because of a lack of effect in clini-

cal trials among patients with cancer (grade D for both).

Ginseng received a grade C for fatigue during treatment

Integrative Therapies During and After Breast Cancer Treatment

214 CA: A Cancer Journal for Clinicians

based on a single, high-quality trial with a large sample

size.99 A previous large, high-quality, dose-finding study by

the same group indicated that a higher dose was more effec-

tive.100 In subset analyses in the subsequent trial, which

tested the receipt of ginseng by patients who reported

fatigue either during or after treatment, the results showed

that ginseng was more effective in patients undergoing

active treatment. Trials testing the effects of acupunc-

ture51,101-103 and yoga45,80,84,104-106 for post-treatment

fatigue yielded modest results (grade C). Four high-quality

acupuncture trials assessed fatigue as the primary outcome;

3 of those 4 trials included a large sample size.51,101-103 Acu-

puncture for post-treatment fatigue received a grade of C

mainly because of inconsistent comparison groups across the

trials, including sham acupuncture,101,103 standard of

care,51,102 self-administered acupuncture,102 and wait-list

control.103 Three trials evaluated yoga for post-treatment

fatigue as a primary outcome45,80,106; only one study had a

large sample size80 and the other 2 reported contrasting

results.45,106

Use of Integrative Therapies for QOL

Description of QOL

QOL is a multidimensional construct that typically mea-

sures the functioning of emotional, physical, role, and social

domains using validated questionnaires. 361

The majority of

patients with breast cancer report some level of diminished

QOL during cancer treatment and/or survivorship. 362

The

physical domain includes common physical side effects of

cancer and cancer treatment, including constipation and

diarrhea, fatigue, hair loss, fever, hot flashes and night

sweats, lymphedema, nausea and vomiting, poor nutrition,

oral complications, pain, and skin changes, as well as the

ability to function physically in everyday life. The emotional

domain includes psychological functioning with indicators

of anxiety, depression, distress, confusion, and memory

problems. The sexual functioning domain refers to patients’

perception of sexuality and sexual functioning, attractive-

ness, and fertility. Finally, the social domain refers to the

patients’ social functioning, their social role, and level of

social support. Each of the domains, either individually or

in combination, influences a patient’s QOL. 302,363-365

Dec-

rements in QOL may persist upon the conclusion of treat-

ment, during chronic/long-term hormonal and biotherapies,

and into survivorship.366

Meditation (A grade)

Overview of meditation interventions for QOL. Medita-

tion is recommended for improving QOL in patients with

breast cancer (grade A). This recommendation is based on 7

RCTs, completed between 2009 and 2013, which used

meditation for this indication (see Supporting Information

Table 4). 27-29,73-75,127

QOL was the primary outcome in 4

of those 7 trials.73-75,127 In 4 trials,27-29,74 a meditation inter-

vention group was compared with a usual care or waitlist con-

trol condition group, and 3 other trials73,75,127 used a 3-arm

design. Study participants included women undergoing radia-

tion therapy for breast cancer, patients with newly diagnosed

stage 0 through IV breast cancer, breast cancer survivors who

had completed treatment, and older adult breast cancer survi-

vors aged 55 years and older. The study sample sizes ranged

from 47 to 180 participants. These trials overlap with the trials

described under meditation interventions for anxiety/stress

reduction and depression outcomes (see above).

Previous research has supported the role of MBSR inter-

ventions for improved QOL in heterogeneous samples of

patients with cancer and survivors, with effect sizes ranging

from small to large on QOL scales.319,367,368 One review in

particular assessed the impact of MBSR on QOL in

patients with breast cancer.175 In that review, the authors

identified only 3 studies that met their criteria and also mea-

sured QOL as an outcome. 29,127,292

Of the 3 studies that

measured QOL, only one (also included in our review)

reported significant improvements after MBSR interven-

tion 29

relative to results in control or comparator groups.

The other 2 trials reported no significant improvements in

QOL after MBSR intervention or at follow-up. A second

systematic review and meta-analysis was conducted to inves-

tigate the effect of MBSR in the cancer care setting on sev-

eral psychological outcomes, including QOL. 316

The

analyses specific to the QOL outcome included 248 patients

in 6 studies and reported a small effect size (P < .01). The

authors suggest that, although these findings support the

use of MBSR for improving QOL, more well conducted

RCTs are required that implement adequate controls, lon-

ger follow-up periods, larger sample sizes, and obtainment

of patients’ psychological profiles.

Risk/benefit assessment of meditation interventions

There is very little risk to participants who use meditation

therapies to improve QOL and/or physical functioning.

Few adverse events have been reported in any trials involv-

ing meditation, with participants typically reporting positive

feedback about meditation, resulting in low dropout rates

from the programs. Group meditation formats and online

and home-based adaptations of MBIs321 are cost-effective

and beneficial therapies that can be used as adjuncts to tra-

ditional individual counseling or psychotherapy.

Future research in meditation interventions for QOL. To

improve specificity of the effective components of medita-

tion and to compare meditation interventions with other

MBIs, research assessing meditation as a treatment for

improved QOL and/or physical functioning should be

extended to directly compare meditation with other forms

of therapy, including individual counseling, cognitive

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behavioral therapy, and other MBIs, similar to the therapies

compared in the trial by Carlson et al.26

Yoga (B grade)

Overview of yoga interventions for QOL. Yoga is recom-

mended for improving QOL in patients with breast cancer

(grade B). This recommendation is based on 12 RCTs,

completed between 2006 and 2015, which tested a variety

of yoga programs (see Supporting Information Table

4).43,46-48,82-85,104-106,128 QOL was the primary outcome for 6

of those 12 trials.47,82,83,105,106,128 In 10 trials, a yoga interven-

tion group was compared with a usual care or waitlist control

condition group, and 2 other trials used brief supportive therapy

as a comparison group.43,85 Study participants included women

undergoing radiation therapy or chemotherapy for breast cancer,

patients with newly diagnosed breast cancer, and breast cancer

survivors who had completed treatment. The study sample sizes

ranged from 15 to 128 participants. Several of these trials over-

lap with those described under yoga interventions for anxiety

and depression outcomes (see above). In total, 4 different types

of yoga interventions were investigated, including: Iyengar or

Hatha yoga,82-84,104-106 an integrated yoga program,43,85,128 pra-

nayama or yoga breathing,46,47 and Patanjali’s yoga sutras.48

Another systematic review and meta-analysis assessed the

impact of yoga interventions on QOL and psychological

health specifically in patients with breast cancer and survi-

vors.330 Overall, 12 RCTs were included in that analysis

with a total of 742 participants. Analyses revealed short-

term effects on improved psychological health, including

anxiety (P < .01), perceived stress (P 5 .03), and psycholog-

ical distress (P < .01). However, it is notable that these

effects were only applicable to those who engaged in yoga

during active cancer treatment and not in the post-

treatment period. The authors state that, with these positive

preliminary results, yoga should be used in this population.

Risk/benefit assessment of yoga interventions. As stated

above regarding yoga for anxiety/stress and for depression/

mood disturbances, yoga can be adapted and modified for

use in this population with low risk to the patient. Overall,

yoga has shown preliminary efficacy in improving QOL and

is recommended for use in patients with breast cancer.

Future research in yoga interventions for QOL. As also

stated above, future trials of yoga to improve QOL/physical

functioning should examine the effects of different types,

doses, and durations of yoga on QOL outcomes. Higher

quality trials, including trials with larger and more diverse

samples, should be conducted.

C-graded and D-graded therapies for QOL

Trials in acupuncture,49,51,102,129,130 mistletoe,131-134

qigong,135,136 reflexology,137-139 and stress manage-

ment36-38,95,96,140,141 have assessed the effect of these

therapies on QOL and received a grade of C, indicating that

they can be considered for use. The 5 trials evaluating

acupuncture had mixed findings and small sample sizes; future

studies should replicate the trials of acupuncture that

compared real versus sham acupuncture, which were the study

designs that produced no effect.49,102 Two trials135,136 found

that qigong had beneficial effects on QOL; however,

those studies were fairly small and should be replicated in

larger and more diverse patient populations. Three large,

high-quality trials137-139 of reflexology for improving QOL

reported mixed findings. The trials of stress management had

conflicting results and used a broad range of control

groups.36-38,95,96,140,141

There is some evidence that mistletoe may improve QOL

in patients with breast cancer.131-134 However, although the

trials have study quality and sample sizes that could merit a

grade of B, the final decision to assign a grade of C is

because of 2 areas of uncertainty. First, while several differ-

ent preparations and formulations have been found to be

effective in trials of moderate size, the assessment does not

result in a higher grade because of the nonspecificity and

variability in formulations of the agents tested. Second,

mistletoe is an injected bioactive compound with a potential

for a differential risk/benefit ratio because of toxicities and

drug interaction with standard cancer therapies that may not

be detected in smaller studies; a similar stringency need not

to be applied to MBIs, because they have lower risk profiles.

The grade C recommendation is based on 4 RCTs, complet-

ed between 2004 and 2014, which tested the use of mistletoe

for improving QOL.131-134 QOL was the primary outcome

in all 4 trials in which a mistletoe product group was com-

pared with a placebo 131,132

or standard care 133,134

control

group. The mistletoe products tested, all of which injected

subcutaneously, included PS76A2,131,132 Helixor A,134 and

Iscador.133 Study participants included women who were

receiving chemotherapy for breast cancer, and sample sizes

ranged from 61 to 352 participants. To improve specificity

of the effectiveness of mistletoe as a treatment for improved

QOL in patients with breast cancer, double-blind trials need

to directly evaluate and compare the different products

available and also should assess long-term benefit and safety

from the use of mistletoe products. Trials of bioactive agents

carry the additional requirement of adequate size and

statistical power to exclude drug interactions and attenua-

tion of cancer outcome benefits of concurrently adminis-

tered, adjuvant treatments. Two systematic literature

reviews 178,369

of controlled clinical trials of mistletoe,

including a Cochrane database analysis, did find an

improvement in survival in the adjuvant setting. Although

this outcome was outside the scope of this current review,

the 2 reviews suggested a QOL benefit and called for

further confirmatory trials. 178,369

Integrative Therapies During and After Breast Cancer Treatment

216 CA: A Cancer Journal for Clinicians

Use of Integrative Therapies for CINV

Description of CINV

CINV is experienced by some patients with cancer after

they receive chemotherapy.197,370,371 Acute CINV is typi-

cally defined as occurring during the first 24-hour period

after chemotherapy administration. It is believed that

delayed or late CINV is mediated by different mechanisms

compared with acute CINV372 and occurs more than 24

hours after chemotherapy administration. In a large, pro-

spective study of patients with breast cancer who were

receiving chemotherapy, 37% reported any nausea, and 13%

reported any vomiting during the first 24-hour period. 373

In

the 2 to 5 days after chemotherapy administration, 70%

reported any nausea, and 15% reported any vomiting.195,373

The consequences of CINV include dehydration, serious

metabolic derangements, nutritional depletion and anorexia,

deterioration of physical and mental status, withdrawal from

potentially useful and curative antineoplastic treatment, and

decreases in self-care and functional ability. CINV is con-

sidered to be one of the most severe and feared adverse

effects of cancer treatment by patients and can have a signif-

icant impact on QOL. 370,374-376

Standard of care antiemet-

ics for managing CINV have changed considerably in the

last 5 years, thus many of the trials evaluating integrative

approaches are not tested with the newest and most effective

standard treatment regimen. 197,371

Most contemporary

studies use as the endpoint the proportion of patients

achieving a complete response, defined as no emesis or use

of rescue medication. In addition, antiemetics themselves

have side effects, such as headaches, constipation, and neu-

ropsychiatric effects, and thus merit study designs that

replace medications with integrative approaches and use

equivalence or nonsuperiority designs for the CINV and

medication side-effect endpoints.

Acupressure (B grade)

Overview of acupressure interventions for CINV. For

patients with breast cancer who are receiving chemotherapy,

acupressure can be considered as an addition to antiemetics

to help control nausea and vomiting (grade B). This recom-

mendation is based on results from 3 RCTs, reported

between 2000 and 2007, of an acupressure intervention used

in conjunction with antiemetics to treat CINV (see Sup-

porting Information Table 5).61-63 Acute and delayed nau-

sea and vomiting were the primary outcomes for all 3 trials.

In 2 trials, 61,63

the acupressure plus usual care intervention

group was compared with a usual care group. The third tri-

al62 was a 3-arm trial comparing: 1) true acupressure at the

P6 and SI3 points in addition to usual care; 2) sham acu-

pressure, or placebo acupressure on a different acupressure

point, in addition to usual care; and 3) usual care only. (Of

note, the use of sham controls in acupressure and

acupuncture studies is an attempt to control for the experi-

ence of receiving the treatment; if it is implemented well,

participants will not be able to discern between the true and

sham techniques.) Study participants included patients with

breast cancer undergoing the first, second, or third cycle of

chemotherapy. The study sample sizes in the trials ranged

from 17 to 160 participants. The acupressure interventions

included self-acupressure61,62 using a finger and wearing

acupressure wristbands.63 Across the 3 trials, acupressure

therapy produced significant decreases in nausea, retching,

and vomiting (P < .05 for multiple outcomes assessing

CINV) (for details, see Supporting Information Table 5).

A review assessing acupressure as a nonpharmacologic

adjunctive intervention for CINV control across all cancers

concluded that acupressure should be strongly recom-

mended as an effective intervention along with standard

care for CINV control.377 Other studies of acupressure to

reduce nausea and vomiting have shown efficacy in other

populations, including pregnant women and postoperative

patients, including after thyroidectomy.378 All of these stud-

ies were conducted with acupressure wristbands placed on

both the patient’s arms at the PC6 acupoint.379 A review of

acupuncture and acupressure for CINV control among

patients with breast cancer concluded that the therapies are

both safe and effective.380 A secondary data analysis of the

multicenter study by Dibble et al 62

concluded that patients

with breast cancer whose nausea intensity started higher

from the acute phase continued to experience higher symp-

tom intensity during the 11 days after chemotherapy admin-

istration and required more frequent acupressure on

acupressure point PC6 even after the peak of nausea. 381

However, a recent publication by Molassiotis, a lead author

of one of the included trials in our review, and colleagues382

suggests an overall placebo effect in the study of acupressure

for control of CINV, although this interpretation included a

mix of cancer populations and was not limited to patients

with breast cancer.

Risk/benefit assessment of acupressure interventions.

Self-administered acupressure is easy to perform, safe, cost

effective, noninvasive, does not interfere with a patient’s pri-

vacy, and has no deleterious effects on patients. Acupressure

can be performed anywhere with little or no equipment.

Future research in acupressure interventions for CINV.

Future research in this area could assess how to identify the

best patients who can be instructed to perform self-

administered acupressure, when acupressure can be per-

formed, and whether additional points can be administered

along with PC6 to increase the effectiveness of self-

administered acupressure to reduce nausea and vomiting.

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VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 217

Electroacupuncture (B grade)

Overview of electroacupuncture interventions for CINV.

Electroacupuncture or acustimulation can be considered as

an addition to antiemetics to control CINV in patients with

breast cancer during chemotherapy (grade B). This recom-

mendation is based on 2 RCTs, published in 2000 and 2012

(see Supporting Information Table 5),64,65 as well as the

1997 National Institutes of Health Consensus Conference

on acupuncture.383 However, most of those trials predated

the use of newer agents, including, 5-hydroxytriptamine

type 3 (5-HT3) and neurokinin-1 (NK1) receptor antago-

nists, which have become standard antiemetic therapies for

patients who receive highly emetogenic chemotherapy. We

do not have a body of evidence to evaluate whether the

addition of acupuncture to contemporary antiemetics yields

added benefit. Participants in the trials in this analysis

included patients with breast cancer who had received mod-

erately high or highly emetogenic chemotherapy without a

5-HT3 or NK1 receptor antagonist.197 Both trials used

PC6 and ST36 acupoints and sham controls, and both trials

evaluated the effects of these acupoints on acute and delayed

CINV. One trial also used acupoint LI4 and found that

electroacupuncture was no better than sham electroacupunc-

ture and that a likely contributor to the lack of effect of elec-

troacupuncture in CINV was the that the study evaluated

only feasibility with a minimal electroacupuncture interven-

tion and without a no-acupuncture arm. 64

The second trial

indicated that the patients receiving electroacupuncture

experienced significantly fewer emesis episodes over the 5

days of the acupressure intervention than the patients

receiving mock therapy or antiemetics alone (P < .001). 65

Between-group differences in the number of emesis epi-

sodes were also significant for electroacupuncture versus

minimal needling (P < .001) and for minimal needling ver-

sus antiemetics alone (P 5 .01).

A multicenter study by Yang et al384 that compared ST36

electroacupuncture plus antiemetics with antiemetics alone

in 246 patients with heterogeneous cancers indicated an

additive effect with the use of electroacupuncture (P < .01),

with greater decreases in nausea and vomiting scores (P <

.001) compared with the use of antiemetics alone. Two early

studies by Dundee and colleagues385,386 reported signifi-

cantly less CINV with a PC6 electroacupuncture interven-

tion, although the investigators noted that the brevity of

emetic action was a major problem. In a recent review of

acupuncture studies, including those that evaluated CINV,

investigators concluded that only the electroacupuncture

study by Shen et al65 had a low risk of bias.160 In addition,

an earlier meta-analysis by Ezzo et al387 determined that

electroacupuncture, but not manual acupuncture, was bene-

ficial for first-day vomiting and that needle insertion as part

of manual and electroacupuncture provides greater intensity

of stimulation and produces more beneficial effects than sur-

face electrostimulation.

Risk/benefit assessment of electroacupuncture interven-

tions for CINV. With proper administration, electroacu-

puncture has been shown to be both safe and

effective. 119,388-392

In addition to possibly reducing CINV,

PC6 stimulation has been associated with other positive

benefits, including analgesic,119 sedative,393 and anxiolytic

effects.394 Furthermore, because CINV is drug-specific

rather than disease-specific, these benefits should extend to

CINV in other cancer patient populations, as suggested in

the study by Yang et al, 384

with participants who had a vari-

ety of cancers. Practical issues to consider are that electroa-

cupuncture should not be used in patients with a pacemaker

or implantable defibrillators and that special attention is

required when treating patients who are pregnant, have sei-

zure disorders, or are disoriented.160

Future research in electroacupuncture interventions for

CINV. Future trials on the use of electroacupuncture inter-

ventions for CINV in patients with breast cancer can focus

on testing the use of electroacupuncture with new standard-

of-care treatment regimens as well as the dissemination and

implementation of this technique in the clinical setting. In

addition, nausea that is unrelated to chemotherapy is also a

common problem in patients with cancer, and this modality

could be tested and compared with less potent antiemetics

or best supportive care when other therapies are ineffective.

C-graded and D-graded therapies for CINV

Three trials of ginger 66-68

and 2 trials of relaxation 59,69

have

examined their effects on CINV as a primary outcome.

Although the number of trials was limited, the results sug-

gested enough of an effect to result in a grade C recommen-

dation stating that ginger and relaxation can be considered as

an addition to antiemetics for the control of acute CINV.

Future directions in research should focus on replicating trials

of these modalities for CINV as the primary outcome. Gluta-

mine is not recommended for improving CINV because of a

lack of effect from 2 trials70,71 in which CINV was assessed

as a secondary outcome (grade D).

Use of Integrative Therapies for Acute Radiation Dermatitis

Because radiation is a localized, targeted therapy, side effects

are most often locoregional within the targeted area. How-

ever, damage to normal local tissues and adjacent organs at

risk can result in fatigue as the body expends energy in nor-

mal tissue repair. The most common side effect in patients

with breast cancer is acute skin irritation. Late changes to

normal tissue can occur years after therapy and can include

soft tissue fibrosis, lymphedema, lung, and heart and chest

wall damage.395 Not all patients experience one or all of the

Integrative Therapies During and After Breast Cancer Treatment

218 CA: A Cancer Journal for Clinicians

side effects of radiation, but patients who do experience

acute side effects of radiation typically see the effects go

away several weeks after treatment.395 Acute radiation der-

matitis can occur with radiation therapy and may result in

reactions ranging from faint erythema; to dry, itchy, and

peeling skin; and ultimately to moist desquamation and

ulceration. 396

The Cooperative Group Common Toxicity

Criteria (CGCTC) is the most common scale to measure

acute radiation skin toxicity that is used by cooperative

groups during cancer clinical trials and grades skin reactions

from 0 to 4 with, grade 1 indicating erythema and grade 4

indicating ulceration. Most patients with breast cancer

develop mild-to-moderate acute skin reactions of grade 1

through 3 during and shortly after a course of radiation

therapy. These reactions usually resolve quickly but can

cause significant symptoms, especially with higher grade

toxicity.396

D-graded therapies for acute radiation dermatitis

There are no therapies graded A, B, or C to report for acute

radiation dermatitis after treatment. Aloe vera gel and hya-

luronic cream are not recommended as a standard therapy

to prevent or treat acute radiation dermatitis simply because

of lack of effect (grade D). Our review consisted of 2 quality

studies for each product with large sample sizes for both the

aloe vera 22,23

and hyaluronic cream 24,25

trials. Each trial

assessed the acute skin reaction from radiation therapy as its

primary outcome.

Use of Integrative Therapies for Vasomotor Outcomes

Vasomotor symptoms are common in patients with breast

cancer and include hot flashes, intense sweating, and flush-

ing on the face and chest, and they may come with heart

palpitations and anxiety. 397

These symptoms occur episodi-

cally, including nocturnally, when night sweats can signifi-

cantly disrupt women’s sleep. According to the NCI, about

two-thirds of postmenopausal women with a history of

breast cancer experience hot flashes. These symptoms may

occur naturally or as a consequence of surgery, chemothera-

py, or endocrine therapy.398 While vasomotor symptoms

may resolve on their own, 20% of affected women suffer

from persistent hot flashes 4 years after their last menses.397

Together, vasomotor symptoms can significantly impact

women’s QOL.398

C-graded and D-graded therapies for vasomotor outcomes

There are no A-graded or B-graded therapies to recom-

mend for vasomotor outcomes. Acupuncture can be consid-

ered as a therapy for hot flashes based on 9 trials that

assessed acupuncture for hot flashes (grade C). 49,91,92,143-148

Seven of those trials assessed hot flashes as the primary out-

come,91,92,143-146,148 and only one trial148 had more than

100 participants. Overall, the literature showed mixed find-

ings; however, the single, large trial demonstrated signifi-

cant reductions in hot flashes in their electroacupuncture

group compared with sham and control groups. The use of

soy as a therapy for hot flashes is not recommended because

of lack of effect (grade D). Three large trials149-151 assessed

soy for the treatment of hot flashes as the primary outcome

and showed a lack of effect.

Use of Integrative Therapies for Lymphedema

Lymphedema

Lymphedema is a condition after treatment, such as sur-

gery or radiation therapy, in which parts of the lymph sys-

tem become damaged or blocked, leading to an

accumulation of lymph fluid that does not drain properly,

builds up in tissues, and causes swelling. 166

The CTCAE

grades edema of the limbs from grade 1 (5%-10% interlimb

discrepancy) up to grade 3 (>30% interlimb discrepancy).

Lymphedema commonly affects the arm or leg but can also

impact other parts of the body. For patients with breast

cancer and survivors, lymphedema is most common in the

upper extremities and sometimes in the breast and/or chest

wall, and it can occur up to 30 years after treatment.

Because of differences in diagnosis, characteristics of the

patients studied, and inadequate follow-up, the overall

incidence of arm lymphedema after breast cancer reported-

ly ranges from 8% to 56%.399 Breast cancer survivors with

arm lymphedema in particular have been found to have

decreased QOL and increased psychological distress and

disability compared with survivors without

lymphedema. 399-401

C-graded therapies for lymphedema

There are no A-graded or B-graded therapies to report for

lymphedema. Two trials assessed low-level laser thera-

py,110,111 and 7 trials assessed manual lymphatic drain-

age112-118 for the treatment of lymphedema as a primary

outcome. The 2 trials that evaluated low-level laser therapy

were small in sample size and showed mixed findings. Only

2 of the 7 trials that assessed manual lymphatic drainage

had a sample size greater than 100 participants.113,118 Over-

all, the literature suggests that manual lymphatic drainage

and compression bandaging are equivalent. 114-116

Thus,

either therapy can be considered as treatment options for

lymphedema, with manual lymphatic drainage being con-

sidered for those who have sensitivity to bandaging (grade

C).

Use of Integrative Therapies for CIPN

CIPN

Cancer treatments, including chemotherapy, may cause

damage to the peripheral nerves, resulting

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VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 219

in neuropathy.402 The CGCTC categorizes neuropathy

under neurologic-sensory and grades it from 0 to 3, with 3

indicating severe objective sensory loss or paresthesias that

interfere with function. Sensory neuropathy can include

symptoms of pain, tingling, numbness, or a pins-and-

needles feeling, the inability to feel a hot or cold sensation,

or the inability to feel pain. Motor neuropathy can include

problems with balance, weak or achy muscles, twitching,

cramping or wasting muscles, and swallowing or breathing

difficulties. Autonomic nerve damage can cause dizziness

or faintness and digestive, sexual, sweating, and urination

problems.402

H-graded therapies for CIPN

There are no A-graded or B-graded therapies to report for

the prevention or treatment of CIPN. Acetyl-L-carnitine is

not recommended as a standard therapy to prevent or treat

CIPN because of harm (grade H). A single, large, high-

quality study107 assessing the use of acetyl-L-carnitine cap-

sules to prevent CIPN after taxane therapy as a primary out-

come found that acetyl-L-carnitine administered during

taxane chemotherapy was associated with worse CIPN

symptoms.

Use of Integrative Therapies for Pain

Pain

According to the International Association for the Study of

Pain, pain can be defined as “an unpleasant sensory and

emotional experience associated with actual or potential tis-

sue damage.”403 The CTCAE grades pain from 1 (mild) to

3 (severe, limiting self-care). Pain can be caused by cancer

therapies, including surgery, radiation therapy, chemothera-

py, targeted therapy, supportive care therapies, and/or diag-

nostic procedures. 404

Pain is commonly experienced by

patients who have breast cancer with a prevalence ranging

from 40% to 89%. 403

Pain management requires proper

assessment, including measurement of intensity. 404

It is also

important to evaluate the impact of pain on the patient’s

physical, mental, and social health, because pain can nega-

tively impact their functional status and QOL. Pain man-

agement can include both pharmacologic and

nonpharmacologic modalities. Proper education about treat-

ment and longitudinal follow-up are essential.

C-graded therapies for pain

There are no A-graded or B-graded therapies to report for

pain. Healing touch93 for pain after chemotherapy; music

therapy,31,34 hypnosis,125,126 and acupuncture119 for pain

after surgery; and acupuncture 120-124

for pain related to aro-

matase inhibitor-associated musculoskeletal symptoms were

examined, and each received a grade of C, indicating that

they can be considered as a therapy for pain. A single, large

trial assessed healing touch93 for pain after chemotherapy as

a secondary outcome and demonstrated small positive

effects favoring the therapy. Similarly, trials that assessed

music therapy,31,34 hypnosis,125,126 and acupuncture119 for

pain after surgery as a primary outcome demonstrated small

positive effects favoring the therapy. However, there is a

lack of multiple, large trials to support each therapy. Finally,

5 trials evaluated acupuncture for pain related to aromatase

inhibitor-associated musculoskeletal symptoms as the pri-

mary outcome. 120-124

All of those trials had small sample

sizes and reported mixed findings.

Use of Integrative Therapies for Sleep Disturbance

Sleep disturbances

Studies have shown that nearly one-half of all patients with

breast cancer have sleep-related problems from a range of

causes, including side effects of antineoplastic medications,

long hospital stays, or stress.405,406 In addition, growing

numbers of patients with breast cancer are obese,407 which

increases the incidence of sleep apnea, a major cause for

insomnia. Insomnia, a specific sleep disorder of initiating

and maintaining sleep, is most common in patients with

cancer and often occurs along with anxiety and depres-

sion. 408

The CTCAE measures insomnia under psychiatric

disorders from grade 1 through grade 3, with grade 3 indi-

cating severe difficulty falling asleep, staying asleep, or wak-

ing up early.

C-graded therapies for sleep disturbance

There are no A-graded or B-graded therapies to report for

sleep disturbance. Yoga can be considered for sleep distur-

bance (grade C). Five trials assessed yoga for sleep distur-

bance45,48,79,84,172; and, in 4 of those trials, sleep was a

secondary outcome. Two trials were of high quality, with

more than 100 participants.79,142 Overall, the body of litera-

ture showed no greater effect on sleep quality for health

education classes, stretching groups, and wait-list controls.

Conclusion

In this review, we closely examined and described the RCTs

that provide support for the highest graded therapy recom-

mendations for the use of integrative therapies during the

patient experience of breast cancer and for side effects relat-

ed to breast cancer treatment. High levels of evidence sup-

port the routine use of mind-body practices, such as yoga,

meditation, relaxation techniques, and passive music thera-

py, to address common mental health concerns among

patients with breast cancer, including anxiety, stress, depres-

sion, and mood disturbances. In addition, it has been dem-

onstrated that meditation improves QOL and physical

functioning; yoga improves QOL and fatigue; massage

improves mood; and acupressure and electroacupuncture

decrease CINV. Given the high level of evidence of benefit

Integrative Therapies During and After Breast Cancer Treatment

220 CA: A Cancer Journal for Clinicians

coupled with the relatively low level of risk, these therapies

can be incorporated as an option into patient care, especially

when there is poor symptom control. As is the case with

many standard therapies, the impact of integrative

approaches on symptom management is highly individual-

ized. Therefore, a patient-centered trial and evaluation

approach may be needed and can be guided by the grade of

recommendations and altered as needed along with the

incorporation of patient preferences. In addition to the

modalities discussed in this review that were given a lower

grade (C or D), patients are using many other forms of inte-

grative therapies with little or no supporting evidence; this

serves as a compelling call for further research to support

patients and health care providers in making more informed

decisions that avoid harm. In the meantime, while further

clinical evaluation is underway, clinicians and patients need

to be cautious about the use of therapies that received a

grade of C or D and need to fully understand the potential

risks and benefits of use, including the risk associated with

not using a conventional therapy that may effectively pre-

vent or treat the condition. For example, in a patient with

incurable disease who has marked symptoms not adequately

managed with conventional therapies, carefully monitored

use of a grade-C therapy could be medically reasonable,

although more research clearly would be needed to apply

this broadly across a patient population. This review and

others support referral or provision of clinical services to

include both evidence-based conventional and integrative

therapy options.

The limited numbers of integrative modalities with

grades of A or B emphasize the need for all cancer care pro-

viders to initiate a dialogue early in their relationship with

patients to develop a framework for how evidence forms the

basis for all clinical decisions. Patients and clinicians should

engage in shared decision making based on the best avail-

able evidence on the benefits and harms while reflecting

patient values and preferences. A careful appraisal of the evi-

dence base for integrative therapies can help allay a patient’s

concern that their care team is informed and is not over-

looking options that may be of interest to them. In addition,

such an appraisal of the evidence will offer those modalities

that do merit consideration and allow for better personaliza-

tion of care and shared decision making.

This systematic review with grades of evidence adds to a

growing literature base that includes reviews of integrative

therapy for patients with breast cancer and other cancer

populations. For example, numerous reviews support the

use of integrative therapies, including passive music thera-

py,322 stress-management programs,324 various yoga practi-

ces,329 meditation and MBSR,315 massage,349 and

relaxation techniques, 337

as adjunctive therapies for psycho-

logical outcomes, specifically the anxiety/stress and

depression/mood outcomes assessed in this review. Acupres-

sure for CINV is also well supported in the review literature

across all populations of patients with cancer. 377

There are

mixed findings in the areas of meditation and MBSR for

QOL 175,316

and electroacupuncture for CINV, 160

which

suggests overall low quality or too few studies. Thus, future

research on the impact of these integrative therapies on the

relevant clinical outcomes is warranted. A limitation to the

generalizability of our findings is that the majority of partic-

ipants in the clinical trials we evaluated were non-Hispanic

white women with high socioeconomic status relative to the

general population. In addition, none of the trials examined

age-related responses and or differential responses in pre-

menopausal versus postmenopausal women. There is a clear

need to design well powered, controlled trials using the best

standard treatment control or an appropriate placebo.

Challenges of Implementing Integrative Therapies in Breast Oncology

Patients with cancer face several psychological and physical

challenges as they move through cancer diagnosis, treat-

ment, and survivorship. According to National Comprehen-

sive Cancer Network guidelines, comprehensive clinical

programs should systematically screen for cancer-related

symptoms and side effects in the process of mandated screening

for distress. This review and others support subsequent referral

or provision of clinical services to include both evidence-based

conventional and integrative therapy options. 194,409

On the basis of recent estimates from the US National

Health Interview Survey, 75% of individuals with a history

of cancer use one or more complementary and integrative

therapies. 410

Many North American cancer centers now

operate formal integrative oncology programs. Because most

of these services are not reimbursable by insurance, the

methods and models of funding and implementing these

programs vary; some programs and services are fully funded

and are provided free of charge to patients, some are entirely

paid for out-of-pocket by patients, and some are a combina-

tion of both. Often, mind-body therapies already are avail-

able from trained clinical staff at cancer centers, such as

oncology nurses or social workers, and hence are more read-

ily accessible at low or no cost. Others, such as massage

therapy and acupuncture, may be covered by some forms of

insurance, varying by country, province/territory, and state.

Implementing complementary and integrative therapies

in a clinical setting requires not only funding and infrastruc-

ture but also well trained, knowledgeable providers. Many

of the integrative therapies do not have a one-size-fits-all

approach and need to be provided and administered by

appropriately trained practitioners who can evaluate which

are the best forms and techniques to use with a specific

patient. Although training and credentialing for many

CA CANCER J CLIN 2017;67:194–232

VOLUME 67 _ NUMBER 3 _ MAY/JUNE 2017 221

integrative providers varies by jurisdictions, best practices

suggest that providers be trained to the highest standard of

their profession, even if that exceeds the state-based or

province-based standards, such as a requirement for institu-

tional credentialing that may include proctoring. As the

fields of integrative therapies are expanding, there are now

new professional associations that specialize in oncology, for

example, the Society for Oncology Massage and the Oncol-

ogy Association of Naturopathic Physicians.411,412

Future Research

Rigorous clinical research that appropriately reflects integra-

tive care as it is used in the community and at integrative

cancer centers is needed to responsibly move this field for-

ward. Integrative modalities can be tested in addition to

standard supportive treatments, or even in place of them, if

the standard therapy is associated with side effects or signifi-

cant costs and the trial design allows for early discontinua-

tion in the event of futility. Clinical trials designed to test

efficacy in tightly controlled, academic research settings are

often testing protocols that are not realistically implement-

able in the community setting. Implementation and dissem-

ination research designs to consider include pragmatic trials

that involve multimodal therapies applied in the manner in

which they are typically offered in clinical settings. This

approach, while unable to pinpoint clear causal relationships

between specific interventions and outcomes, allows an

exploration and evaluation of clinical impact that is more

truly generalizable. Head-to-head comparisons of different

integrative therapies and conventional symptom-

management therapies would help provide some specificity

and direction for health care providers making recommen-

dations to patients. Comparative-effectiveness research test-

ing integrative modalities in relationship to pharmacological

and other approaches would also be informative in provid-

ing options as well as comparisons of toxicities and cost

effectiveness. Studies that examine mechanism of action are

also needed; however, the emphasis here is on trials of

agents that are actively in use, unlike novel pharmacological

therapies. Importantly, interventions need to be tested in

economically and culturally diverse patient populations to

understand the applicability of an intervention to the grow-

ing population of cancer survivors.

Future studies need to include systematic assessments of

treatment toxicities, including toxicities from both the inte-

grative and the conventional therapies. In this review, when

possible, the NCI CTCAE are used to describe cancer treat-

ment side effects. However, many of the trials did not report

toxicities or adverse events; and, among the trials that did,

the majority did not assess toxicities and adverse events sys-

tematically. The CTCAE are a set of criteria for the standard

grading and classifications of adverse effects of drugs used in

cancer therapy and the US Food and Drug Administration is

increasingly using CTCAE patient-reported outcomes

(CTCAE-PROs) to monitor treatment side effects. 413,414

Ideally, trials will include systematic evaluation of both pro-

vider (ie, CTCAE) and patient (ie, CTCAE-PROs) assess-

ments of adverse events. If future trials do not use these

methods, at minimum, validated measurement tools need to

be used to allow for ongoing quantitative assessments of

adverse events using robust statistical analyses.

Ongoing challenges include the inability to blind partici-

pants to most of the integrative modalities studied, because

most measures are subjective and thus are susceptible to sug-

gestive biases in which patients perceive benefit to an inter-

vention simply because they are receiving it. By using a

mixed-methods model of research, including both qualita-

tive inquiry that explores the patient’s experience of their

treatments and quantitative data, will be helpful to validate

and better justify the use of integrative therapies. In addi-

tion, the use of both subjective and objective patient-

reported outcomes should be used within a mixed-methods

model. This approach can be used in both clinical trials and

in prospective observational studies. To better enable real

clinical uptake and change, knowledge translation experts,

patients with cancer, policy makers, and decision makers

should be involved in both study design and interpretation

to better enable integration of these therapies into clinical

practice.

In conclusion, awareness of the base of evidence for com-

plementary and integrative therapies based on the recently

published SIO guidelines and the emerging literature

should be a core competence for the cancer care provider

and should be applied in decision making for patients with

breast cancer who require supportive care. Billions of dollars

are spent each year on complementary and integrative health

therapies with unknown benefits and on those that have

thus far been shown to be ineffective.410 Research in this

area could save large amounts of health care dollars and

resources and, more importantly, can redirect patients to

treatments with known benefits and better safety profiles.

This article provides greater depth of discussion of these

interventions, such that clinicians and patients can begin the

process of integration based on patient needs in their spe-

cific setting and context. �

Acknowledgements: We thank the following internal and external reviewers for their insightful comments and critiques: Internal reviewers: Executive Com- mittee of the Society for Integrative Oncology; Board of Trustees of the Society for Integrative Oncology; Donald Abrams, MD (University of California at San Francisco), Ting Bao, MD (Memorial Sloan Kettering Cancer Center), Gustav Dobos, MD (Duisberg-Essen University), Petra Klose, MD (Duis- berg-Essen University), Omer Kucuk, MD (Emory University), Jodi MacLeod (University of Pennsylvania), Gregory Plotnikoff, MD (Minnesota Personal- ized Medicine), and Santosh Rao, MD (Banner MD Anderson Cancer Cen- ter). External Society for Integrative Oncology reviewers included Gabriel Hortobagyi, MD (The University of Texas MD Anderson Cancer Center), Shelley Hwang, MD (Duke University), and Anna Wu, PhD (University of Southern California).

Integrative Therapies During and After Breast Cancer Treatment

222 CA: A Cancer Journal for Clinicians

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