Personalized Therapy In Cancer Related
Fatigue: Targeting Mechanisms, Role Of
Corticosteroids, And Combination Therapy

Sriram Yennu, M.D., M.S. (syennu@mdanderson.org)

Objectives
Frequency of fatigue
 New Definition of CRF
 Etiology of Cancer related fatigue
 Assessment
 Management of CRF
 Personalized Therapy In Cancer Related
FatigueYennu 2013

Symptom Prevalence, Summarized from the Palliative Symptom Grid
Symptoms

CancerAIDS

Heart
disease

COPD

Renal
DiseasePain

35–96%

63–80%

41–77%

34–77%

47–50%

Depression

3–77%

10–82%

9–36%

37–71%

5–60%

Anxiety

13–79%

8–34%

49%

51–75%

39–70%

Confusion

6–93%

30–65%

18–32%

18–33%—

Fatigue
Breathlessness

32–90%

54–85%

69–82%

68–80%

73–87%

10–70%

11–62%

60–88%

90–95%

11–62%

Insomnia

9–69%

74%

36–48%

55–65%

31–71%

Nausea

6–68%

43–49%

17–48%—

30–43%

Constipation

23–65%

34–35%

38–42%

27–44%

29–70%

Diarrhea

3–29%

30–90%

12%

—

21%

Anorexia

30–92%

51%

21–41%

35–67%

25–64%

Minimum-maximum range of prevalence (%) is shownJoao Paulo Solano, et al
Journal of Pain and Symptom Management,2006

Ontario's cancer system Data: trajectory of Edmonton Symptom
Assessment System (ESAS) symptom scores for Patients With
Cancer During the Last Six Months of Life
Hsien Seow et al. Clinical Oncology 29, no. 9 (March 2011) 1151-1158.

Prevalence
Frequency of CRF ranges from 60% to 90%
Chemotherapy – 30% to 91%
Radiotherapy – 25% to 93%
Combined modality – 59% to 83%
Palliative Care Setting – 48% to 75%

Lawrence DP, 2004

SignificanceSignificant Impact on Quality of Life more than 91% reported that they could notlead normal lives because of it.
 fatigued patients were absent an average of
4.2 days per month during and immediately
after treatment, due to fatigue
Vogelzang, Cella 1997
Curt, 2000

Definition
Distinguish fatigue from depression, delirium,
drowsiness, psychomotor retardation andweakness.
 Psychomotor retardation involves a slowingdown of thought and a reduction of physicalmovements in an individual Weakness is a term commonly used todescribe a state of lack of physical or muscle
or motor strength
DEFINITION[Version 1:2010]

Cancer-related fatigue is a distressing
persistent, subjective sense of physical,
emotional, and/or cognitive tiredness or
exhaustion related to cancer or cancer
treatment that is not proportional to recent
activity and interferes with usual functioning.

Piper BF, Cella D JCCN 2010 +Deconditioning

Cachexia
Mood Disorders

Renal/Hepatic/Heart Disease

FATIGUE

Bioimmunotherapy/
Chemotherapy/
Radiotherapy

Inflammation/Cytokines

Dehydration
Drugs(including opiods)
Infection
Tumor Byproducts

AnemiaCancer related symptoms

Chrussos 1995

Dantzer, et al., 2004

Capuron & Miller 2011

Capuron & Miller 2011

MASCC Biomarker Group
Saligan et al JSCC 2015

Tumor Mass

Somatic nerves

Tumor Function

Autonomic
nervesTumor
byproducts

Host immune
cells

Cytokines

BRAIN

Cancer related
FatiguePredictors of Severity of Fatigue in Advanced
cancer (N=1778;Yennu 2013)

Causes of CRF in Advanced Cancer

Multifactorial
Cancer related symptoms
Physical symptoms:1) pain, 2) dyspnea, 3)nausea 4) insomnia,
5)anorexia, 6)drowsiness
Psychological distress: 1) anxiety and 2)depression
 Low Albumin ? Inflammatory cytokines(IL-6, TNF-A, IL-1b)
 Hemoglobin levels, sleep disturbance not contributory in
Advanced Cancer
Yennurajalingam 2008
Yennurajalingam 2010
Oh, 2011
Minton, 2011

Objectives
Characterize patients with fatigue
 New Definition of CRF
 Etiology of Cancer related fatigue
 Assessment
 Management of CRF
Assessment
Screening for clinically significant fatigue
Use of 0-10 scale e.g., ESAS Tool
 Multidimensional tool
Use of multidimensional fatigue tool e.g.,
MFI( multidimensional fatigue inventory)
 Ideally tools should capture the various
dimensions, contributors of CRF & impact
on function based on the proposed modelYennu & Bruera JAMA 2007

Assessment of Fatigue








Multidimensional Fatigue Inventory
Multidimensional Fatigue Symptom
Inventory
Revised Piper Fatigue Scale
Brief Fatigue Inventory
Patient Reported Outcome (PROMISE)
Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-F)Investigations
Medical Condition

Assessment Modality

AnemiaComplete blood count, serum vitamin B12 , folate, iron, transferring
saturation, ferritin levels, fecal occult blood tests, and, if
positive, further evaluation for blood loss

Medication side effects andpolypharmacy

Anticholinergics, antihistamines, anticonvulsants, neuroleptics,
opioids, central α antagonists, beta-blockers, diuretics, SSRI
and tricyclic antidepressants, muscle relaxants andbenzodiazepines

Cognitive or functional
impairment

Assessments such as ADL, IADL, MMSE, and “get up and go” test

Mood disorders

Assessment of depression and anxiety following the DSM IV
criteria

Side effects of primarydisease treatment

Recent radiation therapy, chemotherapy, surgery

Malnutrition

Serum albumin, pre-albumin, cholesterol

Infections

Blood cultures, urine culture, chest radiography, HIV antibody, RPR,
PPD skin test

Other contributing medical
conditions

Directed based on clinical finding

Yennu & Bruera JAMA 2007

Objectives
Characterize patients with fatigue
 New Definition of CRF
 Etiology of Cancer related fatigue
 Assessment
 Management of CRF
CRF Management

Specific treatment ofunderlying causes Cachexia
Autonomic
failureAnemia
InfectionHypoxia
Hypogonadism
Depression
Others

Symptomatic Treatment
Pharmacological &ComplementaryNon-pharmacologicalEnergy conservation

CorticosteroidsPhysical Activity (Aerobic orResistance)*; Yoga*

Psychostimulants(?)



Psychosocial:New agents-Ginseng?

-

Cognitive Behavioral therapy*(CBT-BT-CBT-I)-

Mindfulness based stress
reduction-

Psycho-educational-

Supportive Expressive Therapy



Massage?



Acupuncture?



Qigong?

* Level 1 evidencePhysical Activity and Cancer
Exercise results in significant increases in: Cardiovascular capacity
 Improved QOL
 Less fatigue
 Fewer sleeping problems and Increased self-reported physical functioning,well-being, self esteem, and energy.

Randomized Controlled Trials andPhysical Activity
Segal et al.(2009) both resistance and aerobic
exercise - improvement of fatigue, QOL,
strength, triglyceride levels, and body fat
 Cochrane meta-analysis (28 clinical trials2000pts) - PA improved fatigue, both during
and after treatment for cancer (SMD -0.27)
Cramp F, 2012

Physical Activity
Exercise program: both endurance and resistance
exercise[Kangas M et al. 2008; Cramp F 2008] 150min/week
30 min of moderate activity most days of the week May require a referral to Physical therapy if:
h/o CAD, recent surgery, bony metastasis, immunosuppression/fever, thrombocytopenia, risk of falls, anemia
 Advanced cancer- optimal type, intensity, timing of exercise
intervention needed (Cramp F, 2012)Oldervoll LM, 2011
RCT, N= 231 patients with incurable cancer and alife expectancy of three months to two years
 Exercise (60 minutes twice a week for eight weeks)
 Significant improvement in physical performance asassessed by a hand grip strength test and the
shuttle walk test
 No significant improvement in Fatigue after 8 weeks
of treatment
Ligibel 2016
Cancer 2016;122:1169–77

RCT, N= 101 patients with metastatic breast cancer
 Moderate intensity exercise (150 min a week for 16 weeks) Improvement in physical performance as assessed by aminutes of weekly exercise, Bruce Ramp Treadmill test, andphysical functioning (EORTC QLQ 30)
 No significant improvement in Fatigue (FACIT-F subscale)after 16 weeks of treatment
Psychostimulants
Fatigue Opioid induced sedation*
 Depression
 Hypoactive delirium* Level 1Ollie Minton , Alison Richardson , Michael Sharpe , Matthew Hotopf , Patrick C. Stone
Psychostimulants for the Management of?Cancer-Related Fatigue: A Systematic Review and Meta-Analysis
Journal of Pain and Symptom Management Volume 41, Issue 4 2011 761 - 767
http://dx.doi.org/10.1016/j.jpainsymman.2010.06.020

METHYLPHENIDATE AND/OR A NURSING TELEPHONE
INTERVENTION FOR FATIGUE IN PATIENTS WITHADVANCED CANCER:
A RANDOMIZED PLACEBO-CONTROLLED PHASE II
TRIAL

Eduardo Bruera, Sriram Yennurajalingam*, J. Lynn Palmer, Pedro E PerezCruz, Susan Frisbee-Hume, Julio Allo, Janet Williams, and Marlene Z.
Cohen

Objectives
Primary: To determine the affect of
methylphenidate on advanced cancer patients with
CRF as compared to placebo.
 Secondary: Investigate role of nursing telephoneintervention (NTI) in the improvement of CRF.
 Rationale: Prior research by our group suggeststhat methylphenidate and a NTI are both capable ofsignificantly reducing fatigue (Bruera et. al., JCO
2006).


Methods
Patients:
 Advanced cancer patients with fatigue ≥ 4/10 on the
Edmonton Symptom Assessment Scale (ESAS), Normal cognition evidenced by the Mini Mental State
Examination (MMSE),
 No evidence of major depression and hemoglobin ≥ 8
are eligible.
 The primary endpoint was fatigue as measured by
the change in Functional Assessment of Chronic
Illness-Fatigue (FACIT-F) subscale scores,
administered at baseline and day 15.

* Only Grade ≥3 adverse events (AE’s) related to the study treatment
were summarized.
† No significant differences were found in the incidence of grade ≥3
toxicities between patients who received methylphenidate and those
who received placebo (p=0.06).

Conclusions
Neither MP or an NTI alone nor the two combined
was superior to PL for improving CRF.
 Future research on MP in the advanced cancer
setting should focus on subgroups of patients withhigher levels of anxiety or depression.
Modafinil vs Placebo
Placebo controlled; Double blind RCT, 1:1—100mg D114; 200mg D15-28
Eligibility
NSC Lung Ca, stg >3
PS<3
Fatigue NRS >/=5
No chemo or Rtx in last 4 weeks

Who responds to Methylphenidate?
Aims
 To identify the specific patient characteristics
associated with response to methylphenidate
 To compare day 1 response with day 8 response.

Methods
Pooled analysis of patients in two prospective
controlled clinical trials who had received
methylphenidate for cancer-related fatigue.
 Baseline patient characteristics, symptoms (asassessed by ESAS and FACIT-F), and response(change in fatigue) at the end of Day 1 treatment
were analyzedResults: Patient Characteristics(N = 82)
Patient Characteristic
GenderFemaleMale
Ethnicity
White
Hispanic
African-American
Asian

Frequency (%)
54 (66)28 (34)61 (74)11 (13)
7 (9)
3 (4)

Primary Cancer Diagnosis
Lung

5 (6)

Breast30 (36)

Gastrointestinal

4 (5)

GU

5 (6)

Melanoma

1 (1)Hematologic

10 (12)Gynecologic

5 (6)Head and Neck Cancer

12 (16)

Other*

10 (12)*Sarcoma, brain, skin, unknown primary cancer

Associations between Change in FACIT-F
Fatigue Subscale and ESAS Baseline Symptoms,
N=82
ESAS Symptom*

Spearman correlation coefficient,significancePainr = 0.12, P = 0.25

Fatiguer = 0.36, P = 0.0009

Nausear = -0.05, P = 0.67

Depressionr = 0.08, P = 0.45

Anxietyr = 0.07, P < 0.51

Drowsinessr = -0.03, P = 0.79

Dyspnear = -0.07, P = 0.5

Anorexia

r = -0.007, P = 0.94

Insomniar = 0.001, P = 0.98

Feeling of well-beingr = -0.13, p = 0.24

*Edmonton symptom assessment scale**Functional assessment of chronic illness therapy - fatigue subscale

Associations between Change in FACIT-F
Fatigue Subscale and Baseline FACT-G
subscales, Daily opioid use, Day 1 Response
FACT- Physicalr = -0.12, p = 0.28

FACT- Socialr = -0.07, p = 0.24

FACT- Emotionalr = -0.07, p = 0.54

FACT- Functionr = -0.065, p = 0.56

FACIT-F subscaler = -0.475, p<0.0001

Daily opioid use [MEDD*]

r = 0.13, p = 0.24

Day 1 ESAS response**r = -0.39, p = 0.0004*Morphine equivalent daily dose** Similar findings (opposite direction) were found for change in day 1 ESAS(F)response and change in Day 8 ESAS(F) response (r=0.47, p<0.0001)

Hematopoetic Growth Factors and
PRBC Transfusion
Most Studies (open labeled) showed benefit in
improving fatigue
 Erythropoetin and Darbepoetin improves fatigue inpatients receiving chemotherapy(12gm/dl) (Minton
2008) Safety concerns – Thrombovascular events, tumor
growth (June 2008)
 RBC transfusions - immediate correction of thehemoglobin levelFunded by American Cancer Society Career Development award Grant

Rationale
CRF associated with inflammation (Miller,2008;
Seruga, 2008)
 Preliminary steroid studies show benefit!
 No steroid study to date with CRF as a
primary outcome
 No steroid study to date which assessed CRF
using a validated outcome measureTreatment Schema

Eligible
Patients

Treatment Group
Dexamethasone 4
mg orally twice
daily x 14 days
Placebo Group
Placebo one tablet
orally twice daily x
14 days

Trial Registration clinicaltrials.gov Identifier: NCT00489307

Objectives
To compare the effects of dexamethasone
and placebo on CRF
 To determine the role of dexamethasone onanorexia, anxiety, depression, and overall
symptom distressEligibility Criteria: Inclusion
History of Advanced Cancer
 Fatigue ≥ 4 on the Edmonton Symptom Assessment
Scale (ESAS; a 0-10 scale) Two other fatigue related symptoms (pain, nausea,
loss of appetite, depression, anxiety, or sleep
disturbance) at a score of ≥ 4/10 (ESAS)
 Normal cognition
 Hgb ≥ 9g/dl
 Life expectancy 4 weeks or morePatient Characteristics
No. of Patients

Characteristics
Dexamethasone (n=67)

Placebo (n=65)

Total (n=132)

p

60.5

60

60

0.438

Male

25

37

62

0.024

Female

42

28

70

White

42

39

81

Hispanic

11

10

21

Black

13

10

23

Asian/Other

1

6

7

Breast cancer

7

6

13

Head&Neck, Lung cancer

24

21

45

Gastrointestinal cancer

15

24

39

Genitourinary cancer

6

4

10

Sarcoma cancer

6

3

9

Gynecological cancer

4

5

9

Other

5

2

7

Age, years
MedianSex, nRace, n0.252

Diagnosis, n
0.528

FACIT-Fatigue subscale score
Mean

18.40

21.57

PRESENTED BY: SRIRAM YENNU MD., MS

19.64

0.069

Mean improvement in the FACIT –F fatigue
subscale in the dexamethasone and placebo
arms*p=0.005; **p=0.008

Results
Instrument*

Dexamethasone(N=43)

Day 15 Baseline

Placebo (N=41)

Dexamethasone(N=43)

Day 15 Baseline

Placebo (N=41)

Day 8 - Baseline Day 8 - Baseline

Mean

SD

Mean

SD

PƗ

FACIT Fatigue
Subscale

9.0

10.30

3.1

9.59

FACIT Physical

5.25

6.01

1.32

FACIT Social/family

-0.05

5.50

FACIT Emotional

1.85

FACIT-Functional
FACIT-F total Score

SD

PƗ

Mean

SD

Mean

0.008

8.01

7.81

3.06

7.28

0.005

5.52

0.002

4.37

5.14

1.34

4.50

0.007

0.2

4.77

0.820

-0.22

4.06

0.52

3.58

0.40

4.93

1.18

4.49

0.490

0.59

3.57

1.44

4.07

0.33

1.3

6.21

1.51

5.17

0.820

0.55

5.20

1.11

4.80

0.56

18.16

22.88

7.87

19.93

0.030

13.37

13.22

7.5

14.04

0.06

*As values were normally distributed, data are presented as means and standard deviation (SD); Ɨ Paired t-test; the ESAS
psychological scores were not normally distributed, so Wilcoxon two-sample tests were used in those analyses. FACIT-F Functional Assessment of Chronic Illness Therapy –Fatigue

Results
Instrument*

Dexamethasone(N=43)

Day 15 Baseline

Placebo (N=41)

Dexamethasone(N=43)

Day 15 Baseline

Placebo (N=41)

Day 8 - Baseline

Day 8 - Baseline

Mean

SD

Mean

Mean

SD

Mean

SD

PƗ

ESAS Physical-10.15

9.8

-5.39

10.56

0.046

-7.52

8.2

-3.95

10.85

0.08

ESAS Psychological

-1.48

4.67

-2.08

4.73

0.76

-1.26

4.68

-1.81

5.01

0.91

ESAS Symptom
distress

-12.2

13.49

-8.86

15.91

0.22

-10

12.28

-6.95

16.38

0.23

HADS Anxiety

-0.66

3.45

-1.00

3.54

0.75

-0.85

3.16

-1.09

2.32

0.59

HADS Depression

-1.39

3.59

-0.31

3.90

0.29

-1.23

4.02

-0.43

3.12

0.65

FAACT

15.22

19.7

6.46

19.52

0.04

9.12

14.21

5.53

16.06

0.31

SD

PƗ

*As values were normally distributed, data are presented as means and standard deviation (SD); Ɨ Paired t-test; the ESAS psychological scores were not normally distributed, so Wilcoxon twosample tests were used in those analyses. FAACT- Functional Assessment of Anorexia/Cachexia Therapy; ESAS - Edmonton Symptom Assessment Scale HADS – Hospital Anxiety Depression
Scale.

Adverse Events

No significant difference in the number ofgrade ≥3 adverse events(CTC V.3.0)
between dexamethasone vs. placebo group(17/62 vs. 11/58, P=0.27)

Conclusions
Dexamethasone is more effective thanplacebo in reducing CRF in patients withadvanced cancer.
 There was a significant improvement in qualityof life, physical well-being, and physicaldistress.
 Larger long-term efficacy and safety studies
are needed.
Conclusions
FAD cluster showed significant improvementwith dexamethasone
 These findings suggest that fatigueanorexia/cachexia- and depression share acommon pathophysiologic basis.
 Further studies are needed to investigate
this cluster and target with antiinflammatory therapies.
Psychosocial Interventions
Cognitive behavioral therapy
 Energy conservation
 Yoga/meditation, acupuncture, massage
INTEGRATIVE MEDICINE AND CANCERRELATED FATIGUE:

ROLE OF GINSENG

“ginseng”
ginseng has been used medicinally in the Far East for several

millennia.
 Is currently one of the most widely used botanical dietary
supplements in the U.S.
 Standardized extracts and other commercial products areprepared from dried root, Preparation by either drying or bleaching with sulfur dioxide,
or by steaming and then air drying, create the white and red
types, respectively.
 Other plant species also go by the common name “ginseng”,
are American ginseng, Panax quinquefolius L., and Siberian
ginseng, Eleutherococcus senticosus (Rupr. & Maxim).

Dharmananda S, 2002

“ginseng”
"standardized" - consistent amounts oflabeled total ginsenosides, Rb1/Rg1 ratios
demonstrated greater variation.
 This variability - different pharmacologic
effects.
 P. ginseng and P. quinquefolium (American
ginseng), where the ratio of Rg1 to Rb1 ishigher in P. ginseng.
Dharmananda S, 2002

Mechanism of Action on Fatigue
ginseng reduces fatigue by action on:a) CNS, including cognition/memory, sleep
disturbance, anxiety/ depression,b) Pain, andc) Inflammatory cytokines

Phase III evaluation of American ginseng(panax quinquefolius) to improve cancerrelated fatigue: NCCTG trial N07C2.
Patients:
Inclusion
 Patients with cancer undergoing or having completed curative
intent treatment and experiencing fatigue Rated at least 4 on a numeric analogue fatigue scale (1-10)for ≥1 month, were eligible.
Exclusion
 CNS lymphoma, Brain malignancies, or prior use of ginseng or chronicsystemic steroids.
 Other etiologies for fatigue, such as pain and sleep, were also
excluded.

Research Design
Design &Treatment
 Patients were randomized to receive, in a double blind
manner, 2,000 mg/d of American Ginseng or placebo in BID
dosing for 8 weeks.
The primary endpointchange from baseline in the general subscale of theMultidimensional Fatigue Symptom Inventory (MFSI) at 4 & 8
weeks.
Other MFSI subscales, the fatigue-inertia subscale of theProfile of Mood States (POMS) and Brief Fatigue Inventory
were also analyzed.

Results
Change scores (SD)

FatiguemeasureWeeks

Ginseng
n=147

Placebon=152

p value

MFSI - general4

14.4 (27.1)

8.2 (24.8)

0.07378

20.0 (27.0)

10.3 (26.1)

0.00294

1.6 (15.9)-0.4 (14.7)

0.39428

3.0 (17.9)-1.7 (18.2)

0.00434

4.1 (13.4)

2.1 (12.9)

0.20618

6.7 (14.0)

3.7 (14.6)

0.01934

14.5 (25.0)

7.7 (23.6)

0.07958

18.6 (24.8)

10.2 (26.1)

0.0083MFSI physical
MFSI – total
POMS –
fatigue/inertia

Results
Subgroups – Patients receiving cancer
treatment improved at Week 4 and Week8(p=0.02)
 There were no statistically significant
differences in any grade of toxicity or self
reported side effects between ginseng andplacebo.
TumorBurden--Tumor
Function++

Tumor Byproducts
Macrophages,
Cytokines
IL-1, IL-6, TNF-α andINF-γSomatic Nerves
Autonomic Nerves++
Panax ginseng

Fatigue++

PhysiologicalSymptoms-

Cognitive Dysfunction/
Memory, Sedation
Pain, Anorexia/
Cachexia,
Quality of life

PsychologicalSymptoms
Anxiety/Depression

Objectives
Primary* To evaluate the safety and tolerability ofhigh-dose, standardized PG extract for the
management of CRF.
 Secondary*To examine the effects PG on QOL
measures including cancer related fatigue
Patient Eligibility














Patients must have been diagnosed with cancer and currently undergoingoutpatient chemotherapy at the cancer center
Experiencing CRF with an average intensity of ≥ 4 on the Edmonton
Symptom Assessment Scale (ESAS; a 0-10 scale) during the 24 hours
CRF was described as being present every day for most of the day for aminimum of 2 weeks.

Other important eligibility criteria were as follows:
Normal cognition; no infections;
Hemoglobin ≥ 8 g/L within 2 weeks of enrollment
Zubrod performance status of ≤2
No current uncontrolled pain or depressive symptoms
No uncontrolled diabetes or treatment with anticoagulants or systemic
steroids

Intervention
Eligible patients were given a 29-day supplyof 400-mg PG capsules.
 They were directed to take one capsuleorally twice a day for 4 weeks.
 The patients were instructed to take one
capsule of the study medication in morningand one capsule prior to 3 pm daily so as to
avoid interference with sleep.
Patient Characteristics at Baseline (N=30)
Characteristic

Mean

SD

FACIT-Fatigue subscale score

23.08

9.29

FACT-G

70.7

16.66

HADS – Anxiety score

6.17

3.44

HADS – Depression score

6.80

3.47

ESAS Pain

3.10

2.69

ESAS Fatigue

6.20

1.73

ESAS Nausea

1.33

2.04

ESAS Depression

1.34

2.06

ESAS Anxiety

2.13

2.06

ESAS Drowsiness

3.33

2.35

ESAS Shortness of Breath

1.67

2.42

ESAS Appetite

4.10

2.92

ESAS Sleep

4.97

2.46

ESAS Feeling of Well-being

4.53

2.09

ESAS Physical distress score

19.73

8.32

ESAS Psychological distress score

3.50

3.83

ESAS Symptom distress score

23.67

10.61

Abbreviations: FACIT-F- Functional Assessment of Chronic Illness Therapy-Fatigue; HADS- Hospital
Anxiety Depression Scale; ESAS- Edmonton Symptom Assessment Scale; SD –Standard Deviation

Comments
High-dose PG was safe and tolerable, and noadverse events related to the study drug werereported.
 CRF and other symptoms including pain, appetite,and overall QOL improved with PG treatment for 4
weeks.
 Unclear the effects are due to psycho-stimulation
and/ or immuno-modulatoryStudy Objectives and Design
Objectives
A.1. To explore effects of 800mg of P. ginseng as compared to placebo on cancer-related fatigue as
determined by FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue) at the end of 29
days.
A.2. Exploratory Objectives
To explore its effect on physical activity as measured by Six minute walk test.



To explore its impact on quality of life-related variables, mood (HADS -- Hospital Anxiety andDepression Inventory), quality of life domains ( (FACT-G)), neurocognitive function (SDMT), and Global
Symptom Evaluation (GSE) in these patients.

Study Design

Ginseng 400mg
PO BID X 29 days

Placebo 1
tablet PO BID X
29 daysOpen Label Phase

Ginseng
400mg
PO BID X
29 days

JCCN, 2017 (IN PRESS)Eligibility Criteria

Patient Demographics and Clinical Characteristics at Baseline
Characteristic
Median age (IQR), years
Women, %(N)Placebo(%, N =64)

Ginseng(%, N =62)

Total
( N =126)

P*

61.0 (53.25–66.75)

61.5 (55.50–67.25)

61.0 (54.0–67.0).6646.8% (29)

42.1% (53).29

37.5% (24)Race/Ethnicity, %(N)

.30

White

84.4% (54)African American

4.7% (3)Asian/other

9.4% (6)0 (0)4.8% (6)Hispanic

1.6% (1)

16.1% (10)8.7% (11)15.0 (13.0–16.0)

14.5 (12.0–16.0)

Median education (IQR), years

14.0 (12.0–16.0)

77% (47)
6.5% (4)80.8%(101)
5.6% (7)Diagnosis

Breast Cancer
GI Cancer
GU Cancer
Gynecologic Cancer
Hematological Cancer
SarcomaThoracic Cancer
Other

.57

.007
6.3% (4)0% (0)
76.6% (49)
1.6% (1)0% (0)

14.5% (9)4.8% (6)54.8 (34)

65.9%(83)0 (0)0.8% (1)3.2 (2)

1.6% (2)

1.6% (1)0 (0)7.8% (5)12.9 (8)4.8 (3)

6.3% (4)

10.3% (13)9.7% (6)0.8% (1)
10.3% (13)5.6% (7).27

Zubrod Performance Status Score0

7.9 (5)15.0 (9)11.4 (14)1

74.6 (47)61.7 (37)68.3 (84)2

17.5 (11)23.3 (14)20.3 (25)JCCN, 2017 (IN PRESS)JCCN, 2017 (IN PRESS)

Conclusions
Both PG at a dose of 800mg orally andplacebo daily resulted in significant
improvement in CRF with minimal sideeffects.
PG was not significantly superior to placebo
after 4 weeks of treatment

JCCN, 2017 (IN PRESS)Multimodal Therapy for CRF
Most individual treatments (pharmacological &nonpharmacological) have mixed results
 Physical Activity (PA); erythropoetin (EP) havepositive effect but have low clinical relevance suchas a) compliance (PA), b) low effect size (PA), c)
toxicity(EP) ? COMBINED THERAPIES TARGET
MULTIDIMENSIONAL CRF RATHER THAN
INDIVIDUAL THERAPIESMultimodal Therapy and CRF
P.J. de Raaf, JCO, 2013
 152 fatigued patients with advanced cancer
 RCT-protocolized patient-tailored treatment (PPT)of symptoms or care as usual Fatigue dimensions, fatigue NRS score, interferenceof fatigue with daily life, symptom burden, quality oflife, anxiety, and depression were measured atbaseline and after 1, 2, and 3 months.
Multimodal Therapy and CRF
P.J. de Raaf, JCO, 2013 (condt.)
 PPT significantly improved general fatigue(P = .01)
 Significant group differences in favor of PPT at month 1(effect size, 0.26; P = .007) and month 2 (effect size, 0.35; P= .005).
 PPT also resulted in improvement of “reduced activity” and“reduced motivation,” fatigue NRS, symptom burden,
interference of fatigue with daily life, and anxiety (all P ≤ .03).
Multimodal Therapy for the Treatment of Cancer
Related Fatigue in Patients with Prostate Cancer
receiving Androgen Deprivation Therapy and Radiation.
Sriram Yennu, Karen Basen-Engquist, Valerie Klairisa Reed, Cindy L. Carmack,
Andrew Lee, Usama Mahmood, Seungtaek Choi, Kenneth R. Hess, Jimin Wu, Janet
L. Williams, Zhanni Lu, David Cella*, Deborah A. Kuban, Eduardo Bruera
The University of Texas MD Anderson Cancer Center, Houston, TX; *Feinberg School of Medicine: Northwestern University,
Chicago, IL

ASCO 2017
J Clin Oncol 35, 2017

Fatiguemanifestations/fatigue
dimensions

CausesRadiation Therapy(radiation injury, inflammation)






Tumor mass/tumor function patterns

Physical/Behavioral/
Sensory
Cognitive Dysfunction
Sleep Disturbances
Sedation
Pain/Cachexia
Function/Activity
Deconditioning
Affective/Emotional/
Psychological
Anxiety/Depression
Physiological/
Biochemical Cytokines
IL-1β, IL-6, TNF-α,
IL-10
CRP

Host factors, accumulation of metabolites

Social/situational/environment/life event
patterns

Symptom/physiological/psychologicalpatterns



Activity/rest patterns

Fatigue(FACIT-F)

(+)

(-)
(-)

Methylphenidate

(-)

Exercise(-)

Cognitive Behavioral
TherapyObjectives
Primary objective:
Aim 1. To obtain preliminary estimates of the effects of various
treatments[exercise, CBT, Methylphenidate] and combinations oftreatments in MMT in reducing CRF in patients with prostate cancer
receiving RT, as measured by change in FACIT-F subscale scores taken atbaseline and on Day 57.
Secondary objectives:
Aim 2. To explore the effect of MMT on anxiety (Hospital Anxiety
Depression Scale [HADS]), depressed mood (HADS), physical activity(accelerometer), and function (handgrip dynamometer), before and after
treatment with various fatigue treatment combinations of MMT;
Aim 3. To determine the safety of MMT (type, frequency, and severity of theadverse events).

Multimodal therapy for CRF
Inclusion Criteria(1) Have a diagnosis of prostate cancer and are scheduled to receive
radiotherapy with androgen deprivation therapy.

(2) Rate fatigue 1 or higher on a scale of 0-10.
(3) Describe fatigue as being present every day for most of day for aminimum of 2 weeks(4) Have no clinical evidence of cognitive failure as evidenced by
Memorial Delirium Assessment Scale (MDAS) score of </=13 atbaseline.
(5) Have a hemoglobin level of >/=10 g/dL within 2 weeks of enrollment.

(6) Have a Zubrod performance status of 0 to 2.

Exclusion Criteria(1) Have a major contraindication to MP (e.g., allergy/hypersensitivity to study medications or

their constituents), exercise (e.g., cardiac disease), cognitive behavioral therapy (e.g.,
schizophrenia), or conditions making adherence difficult as determined by the attending
physician.
(2) Be currently taking MP or have taken it within the previous 10 days.
(3) Are regularly engaged in moderate- or vigorous-intensity exercise for at least 150 minutes
per week.
(4) Regularly used cognitive behavioral therapy in the last 6 weeks.
(5) Need monoamine oxidase inhibitors, tricyclic antidepressants, or clonidine.
(6) Have glaucoma.
(7) Have with history of severe cardiac disease (New York Heart Association functional class
III or IV).
(8) Have tachycardia and/or uncontrolled hypertension(9) Be currently receiving anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin,primidone), phenylbutazone, and/or tricyclic drugs (imipramine, clomipramine, or
desipramine).
(10) History of uncontrolled hypothryoidism as evidenced by thyroid test (TSH) within the lastmonth, hypercalcemia or hyperglycemia (within the last 15 days).

Consort

Table 1 Patient
Characteristics (N=69)
Age; (median, IQR)
Race; %(N)
African American
Asian
Caucasian
Other
Marital; %(N)
Divorced
MarriedSingle/Lives with a partner
Single/Never Married
WidowedNot Reported

66. (60,71)

4.3 (3)0 (0)95.7 (66)0 (0)7.2 (5)88.4 (61)
0 (0)

.25*

.68*

.44*

0 (0)
0 (0)
4.3 (3)

Education; %(N)Less than High School
0 (0)High School/Tech School
10.1 (7)
Associate Degree/some
31.9 (22).68*college
Bachelors’ Degree
31.9 (22)
Advanced Degree
24.6 (17)
Not Reported
1.4 (1)
Employment; %(N)Full-time
37.3 (26)Homemaker
0 (0)Part-time
2.9 (2).66*
Retired46.4 (32)
Unemployed
0 (0)
Other
13.0 (9)*P-value: The median differences across 8 groups. The significance level is.05.

Table 2
Symptom Severity at
Baseline‡ ESAS Pain

Total
(N=69)
0 (0,1).70

ESAS Fatigue

4 (2,5).19

ESAS Nausea

0 (0,0).66

ESAS Depression

0 (0,1).51

ESAS Anxiety

0 (0,2).53

ESAS Drowsiness

1 (0,2).91

0 (0,1).18

0 (0,2).40

3 (2,5).46

1 (0,3).86

8 (3,14).72

3 (1,6).47

2 (1,4).36(Median, IQR)

ESAS Shortness ofBreathESAS Appetite
ESAS Sleep
ESAS Feeling of Well
Being
‡ESAS Symptom
Distress
HADS Anxiety

HADS DepressionP**P-value: The median differences across 8 groups, Kruska Wallis test. The significance level is .05.
‡ ESAS (Edmonton Symptom Assessment System): pain, fatigue, nausea, depression, anxiety, drowsiness,
dyspnea, anorexia, sleep disturbance, and feelings of well- experienced by patients during last 24 hours,
rated on a numerical scale of 0-10 (0 = no symptom, 10 = worst possible severity).
‡ ESAS Symptom Distress: Sum of the scores for pain, fatigue, nausea, depression, anxiety, drowsiness,
dyspnea, lack of appetite, and lack of well-being.

Results 62/69 (89%) randomized patients were evaluable There were no differences in the demographics andbaseline fatigue between groups
 The adherence rates for pills, exercise and CBT were
96.5%, 67%, and 90% respectively
 No significant difference in adverse events by groups(p = .29)

Table 3

Comparison AUC by Treatment
AUC FACIT-F
median scoresand p-value

AUC FACT-G

2328 vs. 2095
(p=0.0536)

4923 vs. 4532
(p=0.042)

Placebo
Exercise vs control 2143 vs 2285
exercise(p=0.59)4667 vs 4813
(p=0.37)

CBT vs control
CBT4710 vs 4722
(p=0.84)

Interventions

Methylphenidatevs2247 vs 2197
(p=0.4)(median scoresand p-value)Results
 No significant difference between the 8 randomized groups AUC
FACIT-F subscale (p = 0.25), and FACT-G (p = 0.06) scores [due tosmall sample]
 For Patients receiving drug compared to placebo, the median AUC was
2328 vs 2095 (p = 0.053)
 The drug effect (estimate, 95% CI) in Patients who received:- Exercise was 596 (68.3, 1125), p = 0.029- CBT was 354 (-121, 830), p = 0.12
- Combined Exercise and CBT was -187 (-802,427), p = 0.52
- Control Exercise, control CBT was 294 (-192,781), p = 0.21

Conclusion
 Methylphenidate containing combinations were superior tono drug combinations.
 Methylphenidate + Exercise provided the best signal andshould proceed to large randomized control trials.

De Raaf, 2013

Personalized Therapy
In Cancer Related
FatigueFatigue 8/10
Depression

Patient 1(%)
60

Patient 2(%)
10

Pain

10

50

Cachexia

1010Anemia20

0

Opioids

030

Definition- ASCPRO

Assessing the Symptoms of Cancer Using Patient-Reported
Outcomes (ASCPRO): searching for standards
J Pain Symptom Manage. 2010 Jun;39(6):1077-85.

Subjective (self report)
 Physical sensation (tiredness) Impact on functioning (difficulty completingtasks)
 Unpleasant emotions (distress)
 Decreased cognitive ability (decreased
attention)
 Temporal variability (pervasive)Descriptors Applied to Fatigue
Related to a
Sense ofEnergy or
Vitality

Related to
Cognitive
ChangeRelated to
Sleep

Related toStrength

Related to
MoodFatigue

Clouded or
Confused

Somnolent or
SleepyWeakness

Irritability

Lack of Energy

Apathetic

Nonrestorative
Sleep

Fatigability ofMusclesLability

Lethargic

Inattentive

Post-exertional
breathlessness
or exhaustion

Depressed

Tiredness

Poor
ConcentrationExhaustion

Poor Memory

Portenoy, et al. Pain consortium.nih.gov Interactive textbook of symptom research

Subtypes
Adjuvant
Chemo/RT

Survivor

Advanced
Chemo

Chemo/Targeted -

+++

+?

++

Radiation -

+++

0

++

Deconditioning -

+

++

++

Depression/Anxiety -

++

++

++

Cachexia -

0

0

+++

Opioids -

0

0

++

Anemia -+0++

Metabolic -

+

0

+

Cytokines -

++

+

++

Tumor Products -

0

0

++

Future Trials for Treatment of
CRF
Role of combined therapy
Brain- methylphenidate, donepezil
Mood- mirtazapine- or other SNRI?
Inflammation- thalidomide, dexamethasone, melatonin
Anemia- blood transfusions, EPO
Anaerobic- 02
Muscle- testosterone, Myostatin receptor agonists?,
Ghrelin Agonists?
Deconditioning- exercise

CausesPatient related factors
Social/situational/
environment/life event
patterns
Symptom/physiological(androgen)/psychological patterns
Activity/rest patterns

Tumor and host interaction
Cancer Therapy

Tumor mass/tumor function
patterns,
Inflammatory cytokines,
accumulation of metabolites(Cytotoxic/radiation
injury, inflammation)

Fatiguedimensions
Physical/Behavioral/Sensory
Cognitive Dysfunction(SDMT)
Sleep Disturbance(PSQI)
Sedation(ESAS)
Pain/Cachexia(ESAS)
Function/Activity(Actigraphy/HD
Deconditioning(Vo2 max)

(-)

(-)

(-)

Affective/Emotional/
Psychological
Anxiety/Depression(HADS)(-)(-)

Physiological/
Biochemical
inflamatory cytokines(IL-1β, IL-6, TNF-α, IL-10)
serum and induced
monocytes)

(-)

(-)

(-)

(-)

Methylphenidate+/_Light
therapy(+)

Exercise+/- Antiinflammatory therapy+/_ Melatonin(+)

Cognitive Behavioral
TherapyProgress towards Personalized Therapy
In Cancer Related Fatigue
Physical – Advanced Cancer- Short Course
Dexamethasone (Yennu et al J Clin Oncol 2013) +/Exercise
 Clusters: Fatigue + Anorexia + Depression –Dexamethasone (Yennu et al. Oncologist 2016)
 Fatigue + Insomnia – Yoga [ Mustian et al. J Clin Oncol 35,
2017 (suppl; abstr 10007)] Fatigue+ RTX+Androgen Deprivation - ? Methylphenidate +Exercise (Yennu et al. ASCO 2017;J Clin Oncol 35, 2017)Summary
Identify cancer related fatigue, subtype
 Investigate for correctable causes (lytes, sx’s) Co-manage with patients on a daily basis !
 What helps? Combined Approach based on the predominantdimension- Physical Activity enhancement –Sleep hygiene- Psychosocial interventions e.g., behavioral therapy- Nutrition –Acupuncture- Massage therapy-Yoga- Refractory cases- Trial of steroids/ psychostimulants