Treatments for cancer related fatigue: How can you help

your patients?

Debra Barton RN, PhD, AOCN, FAANMary Lou Willard French Endowed Professor of

Oncology NursingUniversity of Michigan School of Nursing

Ann Arbor, MI

Disclosures

Funding from the National Cancer Institute and the Breast Cancer Research Foundation

Wisconsin ginseng and placebo donated by the Ginseng Board of Wisconsin

©2011 MFMER | 3105994-2

The problem of fatigue

Fatigue can be a prevalent, distressing and persistent effect of cancer diagnosis and treatment (Lawrence, JNCI monographs, 2004)

Descriptive studies report up to 100% of patients experience fatigue at some point during treatment (Hofman M, The Oncologist, 2007; Fulton C, Eur J Cancer, 2000)

Fatigue exists before and after treatment

24% patients severely fatigued before curative intent treatment (GI,BC, PC)

(Goedendorp, BrJCa, 2008)

May not return to baseline and can persist several years after diagnosis (10 yrs)

(Bower, Cancer, 2006; Hjermstad, JCO, 2005; Adams, Current Hem Malig Report, 2007; Johansson, ONF, 2010)

Clinical GuidelinesOrganization-date Effective (highest

evidence)Likely effective (lower level evidence)

Not effective or no evidence

National Comprehensive Cancer Network,updated 2015

Physical activityMassage therapyCBTPsycho-educationalMindfulnessSupportiveexpressive

Does not distinguish other levels of evidence

Lists “considerpsychostimulantsafter ruling out other causes of fatigue” does not put level of evidence

Oncology Nursing Society, updated2014

Exercise-Physicalactivity

Psycho-educationalTreat comorbiditiesCBTRelaxation MeditationStress reductionStructured rehabYogaWisconsin ginseng

Lists erythro stimagents and dex as benefit balance harmOther pharm as “effect not established”

Clinical guidelines continued

©2011 MFMER | 3105994-6

Organization -date

Effective (highest evidence)

Likely effective (lower/some evidence)

Not effective or no evidence

American Society of Clinical Oncology, new, 2014

Physical activityPsycho-educationTreat comorbiditiesCognitive behavioral therapyPsychostimulants-advanced disease, during active treatment

Mindfulness based approaches Yogaacupuncture

Psychostimulantsfor post treatment fatigueMasageMusic therapyRelaxationReikiQigongginseng

Pan-Canadian Group, updated2015

Physical activityCBTGeneral education-energy conservation

Psycho-education Pharmacologicacupuncture

Pharmacologic Treatment

Role of pharmacologic treatment is primarily for managing diagnosed comorbidities:

painhypothyroidismanemiacardiac and pulmonary issues

Psychostimulants – just a word Psychostimulants MPH – Bulk of RCT’s negative (Moraska, JCO,

2010; Mar Fan, Supp Care Ca, 2008; Escalante, JCO, 2012)

Modafanil – 2 RCT negative (Morrow, Cancer, 2010; Fife, JCO, 2013)

Armodafanil – 1 RCT MM is negative (Berenson, Supp Care Cancer, 2015)

©2011 MFMER | 3105994-8

Steroids (Yennurajlingam, 2014)

Dexamethasone 8 mg/day orally and methylprednisolone 32 mg/day orally

Population of advanced cancer (N=132, 40) Over two weeks Improvement in fatigue Latest study (Yennu, 2013) demonstrates

improvement was not mediated by mood, but was a physical improvement

©2011 MFMER | 3105994-9

Fatigue Physiology – What is known Immune system: inflammation

pro-inflammatory cytokinesgenetic polymorphisms

(Bower, JCO, 2013; Bower, JCO, 2011)

Hypothalamic pituitary adrenal system:flattened cortisol slopeblunted cortisol response acute stressdecreased glucocorticoid response

(Bower, Br Beh Imm, 2007; Bower, Psychoneurodendo, 2005; Bower, Psychosomatic Med, 2005)

Mechanistic link Psychostimulants stimulate various

neurotransmitters in the brain to promote wakefulness: histamine (HA), norepinephrine (NE), serotonin (5-HT), dopamine (DA), and orexin systems are likely targets.

Not consistent with what is known about CRF

Steroids are potent anti-inflammatories which is consistent; more research is needed to understand inflammation as a mediator

©2011 MFMER | 3105994-11

Ginseng – Likely effective per ONS and mentioned in ASCO and NCCN

Genus: Panax, Araliaceae family, perennial plant

Used in Traditional Chinese Medicine

Requires 4+ years of growing

Active constituents: ginsenosides

Why Ginseng Inhibits MAPkinase - MCF-7 cells

(King & Murphy, Jrnl Exp Ther and Onc, 2007; Duda, Jrnl Surg Onc, 1999)

Decreased HPA activation and pro-inflammatory cytokines in mice with LPS induced depression

(Kang, Journal of Neuroinflamm, 2011)

Increased aerobic endurance while exercising at 70% Vo2 max

(Wang, Planta Medica, 1998)

SchemaRandomization

Matching Placebo by mouth BID for 8

weeks

Panaxquinquefolius 2,000 mg by mouth BID

for 8 weeks

Ginseng was provided in capsules Both doses taken before noonStandardized to 3% ginsenoside content

(Barton et al, JNCI, 2013)

Eligibility Inclusion Adults with fatigue ≥ 4 for ≥ 1 month, curative

intent Other causes of fatigue ruled out (thyroid,

anemia (hgb >11), pain, insomnia)

Exclusion Chronic systemic steroids, opioids, infections Stop or start anti-cancer therapy Dietary supplements for fatigue

Primary Endpoint

Multidimensional Fatigue Symptom Inventory – Short Form (Stein, 2004)

General Subscale: pooped, worn out, fatigued, sluggish, run down, tired

0 “not at all” to 4 “extremely”

Secondary Endpoints

Side effects

MFSI-SF other subscales and total score

Profile of Mood States: fatigue-inertia

Analysis Change from baseline at 4 weeks, 8 weeks

Two sample, two sided, t-test

150 pts/arm = 90% power, 38% times SD

Stratified by: current treatment, baseline fatigue, days of prior treatment, tumor type

Consort Diagram364 Patients Enrolled

from 40 sites

Placebo 181 patientsGinseng 183 patients

12 cancelled

171 patients started study

133 Completed Treatment per protocol

11 cancelled

170 patients started study

147 available for primary endpoint

analysis

153 available for primary endpoint

analysis

128 Completed Treatment per protocol

Patient DemographicsGinseng N=170

Placebo(N=169)

p value

Age 0.76

Mean (SD) 55.2 (12.7) 55.9 (11.8)

Gender 0.18

Female 138 (81.2%) 127 (75.1%)

Race 0.35

White 154 (90.6%) 156 (92.3%)

Black or African American 10 (5.9%) 8 (4.7%)

Native Hawaiian or Other Pacific Islander 2 (1.2%) 0 (0%)

Asian 1 (0.6%) 3 (1.8%)

American Indian or Alaska Native 1 (0.6%) 2 (1.2%)

Menopausal Status 0.71

Pre 37 (21.8%) 31 (18.3%)

Post/natural-surgical 95 (56%) 89 (53%)

NA (Male) 32 (18.8%) 42 (24.9%)

Disease CharacteristicsGinseng N=170

Placebo(N=169)

p value

Time since current cancer diagnosis 0.84

< 180 days 62 (36.5%) 64 (37.9%)

180 – 360 days 47 (27.6%) 42 (24.9%)

> 360 days 61 (35.9%) 63 (37.3%)

Type of Cancer 0.46

Breast 110 (64.7%) 95 (56.2%)

Colon 20 (11.8%) 17 (10.1%)

Prostate 5 (2.9%) 8 (4.7%)

Hematologic 8 (4.7%) 9 (5.3%)

Gynecologic 5 (2.9%) 7 (4.1%)

Combination/Unknown/Other 22 (12.9%) 33 (19.5%)

Treatment CharacteristicsGinseng N=170

Placebo(N=169)

p value

Current Treatment 0.96

Yes 83 (48.8%) 82 (48.5%)

Duration of all prior cancer treatment 0.99

≥180 days 87 (51.2%) 86 (50.9%)

Current Endocrine Therapy 0.49

Tamoxifen 23 (13.5%) 22 (13.0%)

Aromatase Inhibitor 27 (15.9%) 32 (18.9%)

Anti-androgen 2 (1.2%) 5 (3.0%)

Other 7 (4.1%) 3 (1.8%)

None 111 (65.3%) 107 (63.3%)

MFSI Mean Change from Baseline at 4 and 8 weeks0-100, higher is better

GinsengN=170

PlaceboN=169

MFSI-general 4 weeks 14.4 (27.1) 8.2 (24.8)8 weeks 20.0 (27.0) 10.3 (26.1)

0

10

20

30

40

50

4 wks 8 wks

GinsengPlacebo

p=.07 p=.003

MFS

I-SF

gene

ral s

ubsc

ale

(Barton, JNCI, 2013)

MFSI Mean Change from Baseline at 4 and 8 weeks0-100, higher is better Ginseng (S.D.)

N=170Placebo (S.D.)N=169

p-value

MFSI-physical 4 weeks 1.6 (15.9) -0.4 (14.7) 0.39

8 weeks 3.0 (17.9) -1.7 (18.2) 0.004

MFSI-Mental 4 weeks 2.0 (15.2) 0.6 (16.1) 0.41

8 weeks 2.8 (16.5) 3.4 (15.2) 0.80

MFSI-Emotional 4 weeks 0.5 (16.1) 0.5 (16.7) 0.99

8 weeks 3.0 (17.4) 2.3 (17.4) 0.68

MFSI-Vigor 4 weeks 1.8 (19.0) 0.4 (15.5) 0.70

8 weeks 4.6 (20.5) 2.5 (17.6) 0.71

MFSI-Total Score 4 weeks 4.1 (13.4) 2.1 (12.9) 0.21

8 weeks 6.7 (14.0) 3.7 (14.6) 0.02

P=.08

P=.008

0

10

20

30

40

50

Fatigue/Inertia 4 wks Fatigue/Inertia 8 wks

GinsengPlacebo

Other Fatigue EndpointsChange from baseline, 0-100, higher is better

Subgroups Fatigue Endpoints Change from Baseline 4 & 8 Weeks (0-100)

P=0.02

P=0.01

P=0.86

P=0.07

0

5

10

15

20

25

30

35

40

45

50

MFSISF General 4 weeks MFSISF General 8 weeks

Ginseng Ca TxPlacebo Ca TxGinseng Post TxPlacebo Post Tx

0

(Barton, JNCI, 2013)

Patient Reported Side Effects at 4 and 8 Weeks, 0-100

-50

-40

-30

-20

-10

0

10

20

30

40

50

Nau

sea

4 w

ks

Nau

sea

8 w

ks

Vom

iting

4 w

ks

Vom

ting

8 w

ks

Loos

e S

tool

4 w

ks

Loos

e S

tool

8 w

ks

Trou

ble

Sle

epin

g 4

wks

Trou

ble

Sle

epin

g 8

wks

Anx

ious

4 w

ks

Anx

ious

8 w

ks

Ner

vous

ness

4 w

ks

Ner

vous

ness

8 w

ks

GinsengPlacebo

What we learned Wisconsin ginseng has activity against cancer

related fatigue Demonstrated more consistently and earlier in

patients receiving treatment for cancer Wisconsin ginseng is not associated with

discernible toxicity Physical fatigue is improved No evidence of improvement in cognitive or

emotional elements Attention to potency

Physical Activity - Exercise Numerous meta-analyses over 4,000 patients

(60-ish studies) Effect size moderate at best .28-.45 Various types of cancer, aerobic and resistance,

during and after treatment Dose not evaluated but most studies over 12

weeks, 3 times per week, 45 minutes each session

(McMillan, Appl Physiol Nutr Metab, 2011; Tomlinson, American J Phys Med Rehab, 2014; Brown, Ca Epid Biomarkers Prev, 2011)

©2011 MFMER | 3105994-29

How can providers help? (Park, Cancer, 2015)

RCT to evaluate impact of oncologists’ recommendations for exercise over 4 wks1: Recommendation alone 2: Recommendation with exercise pkg3: Usual care control

162 early stage breast and colorectal pts. Outcome: AMOUNT of exercise Control -39 min/wk; REC 0.99 min/wk; REC +

PKG 48 min/wk

©2011 MFMER | 3105994-30

Physical Activity Prescription What is your patient doing regularly right now? Plan activity of choice and implementation plan

(when, where and motivators) Aim for 3 to 4 times per week 30 to 45 minutes

each Tailor for those already active versus those not

at all active BABY steps, overwhelming goals are not

achievable

©2011 MFMER | 3105994-31

Psycho-education Psycho-education: what is fatigue,

strategies to manage, usually included energy conservation (Barsevick, 2004)

What: Deliberate, planned management of personal energy to prevent depletion

How: priority setting, scheduling activities around energy peaks, scheduling rest periods, pacing

©2011 MFMER | 3105994-32

Energy Conservation Activity Management(Barsevick, Cancer, 2004)

N=396 Energy conservation and activity management (ECAM) vs healthy diet education

Various cancers, 28% stage ¾ receiving tx

3 phone calls, centrally administered with homework total of 75 minutes

Fatigue measures: POMS, Schwartz Cancer Fatigue Scale, General Fatigue Scale (investigator developed)

Findings ECAM group used more energy conservation

strategies (uptake) All three fatigue measures demonstrated

significantly lower fatigue in the ECAM group using intent to treat analyses

No difference in functional status but did find less disruption in usual activities

Replicated by Ream JPSM, 2006 – N=103 heterogeneous pop, 58% getting palliation, main difference usual care control and did not measure uptake

Cognitive Behavioral therapy Most studies have a kitchen sink approach Components include relaxation and stress and

sleep management, cognitive restructuring Many options: meditation, mindfulness, yoga,

progressive muscle relaxation, imagery Studies without PA or energy conservation

were not really positive

(Armes, Cancer, 2007; Brown, AJCO, 2006; Gaston-Johansson,Ca Nrsg, 2000; Kwekkeboom, JPSM, 2012)

©2011 MFMER | 3105994-35

Summary Lack of clear physiology hampers discovery of

effective interventions – For many strategies the “jury is still out”

For advanced patients, a short trial of a steroid is reasonable

Physical activity discussions and planning are needed

Principles of energy conservation are helpful

American ginseng may be a reasonable thing to try

©2011 MFMER | 3105994-36

Merci Beaucoup