Transcript PG2 Pivotal study for CRF

Pharmacological and Nonpharmacological Approach to
Cancer Related Fatigue
Cheng-Shyong Chang, MD
Division of Hematology-Oncology,
Department of Internal Medicine
Changhua Christian Hospital,
Changhua, Taiwan
Agenda
• Epidemiology
• CRF symptom and Pathophysiology
• Pharmacological and Non-pharmacological
Approach
• Conclusion
Fatigue
Estimated Number of Cancer Survivors in the
United States From 1971 to 2006
From SEER
Long-term trends of standardized incidence and
mortality rates for all cancers in Taiwan
Goals for Cancer Treatment
Cure
治癒
QOL
Palliation
緩解
Control
控制
QOL
Cancer treatment goals depend on the patient’s status,
but quality of life is important in all stages of cancer.
Epidemiology -1
• 43% of cancer patients had little awareness that
there were interventions to assess and treat their
fatigue
• That rate of fatigue as high as 90% have been
reported for those undergoing treatment for various
types of cancer
Psychosomatics 2008; 49:283–291
Prevalence and Intensity of Side Effects
J Pain Symptom Manage 2005:30:433–442
Frequency of Side Effects – C/T
The Oncologist 2000;5:353–360
Likelihood of Reporting Chronic Fatigue by
Cancer Type
Cancer 2005;104:2022–2031.
Temporal profile of fatigue evaluated using the Multidimensional
Fatigue Symptom Inventory (MFSI) during anthracycline-based
therapy for breast cancer
©2007 by AlphaMed Press
Jean-Pierre P et al. The Oncologist 2007;12:11-21
Epidemiology - 2
• More clearly correlated with complaints of fatigue
during breast cancer treatment are symptoms of both
depression and anxiety
• Further exacerbating factors for cancer related fatigue
(CRF) include pain, sleep disruption, and anemia
Psychosomatics 2008; 49:283–291
Multidimensional Fatigue Inventory (MFI) subscale scores among
patients with cancer with/without anemia and healthy controls
©2007 by AlphaMed Press
Jean-Pierre P et al. The Oncologist 2007;12:11-21
Fatigue after Treatment
• Evidence of fatigue rates in the range of
17%–38%
• May be sustained several years after treatment
• Longer-term fatigue may lead to adverse impacts on
patients’ quality of life and a delayed return to work
CRF Symptom
CRF Symptom
Table 5
Symptom experience of cancer-related fatigue
Domain
Symptom
Physical
Muscle fatigue
Lack of strength
Lowered energy
Cognitive
Poor concentration
Limited attention span
Lack of interest in activity
Inertia
Emotional
Diminished enjoyment of usual leaisure activities
Decreased sense of fulfillment at work
Data from Butt Z, 2008; Del Fabbro E, 2006; National Comprehensive Caner Network 2008.
Prim Care Clin Office Pract 36 (2009) 781–810
The Psychological and Emotional Impact
of CRF
Table 1. The impact of cancer-related fatigue on emotional health in patients (n=301)
undergoing treatment for cancer
Aspect reported in at least 50% of patients
Patients (%)
Having to push yourself to do things
77
Decreased motivation or interest in usual activities
62
Sadness, frustration, or irritability because of fatigue
53
Diminished interest in normal activities
51
Mental exhaustion
51
From Curt GA, Breitbart W, Cella D et al. Impact of cancer-related fatigue on the lives
of patients: New findings from the Fatigue Coalition. The Oncologist 2000;5:353-360.
The Oncologist 2000;5:353–360.
Differential Diagnosis: Fatigue or Depression?
TABLE 3.
Symptoms of Global Medical Illness Overlapping
With Those of Depression
Cytokine-Induced
Sickness Behavior
Anhedonia
Social isolation
Fatigue
Anorexia
Weight loss
Sleep disturbance
Disturbed cognition
Decreased libido
Psychomotor retardation
Hyperalgesia
Symptoms Common to
Major Depression
Anhedonia
Social isolation
Fatigue
Anorexia
Weight loss
Sleep disturbance
Disturbed cognition
Decreased libido
Psychomotor retardation
Depressed mood
Guilt/worthlessness
Suicidal ideation
Psychosomatics 2008; 49:283–291
Contributing Factors for CRF
Activity level
Malnutrition
Sleep
disorders
Emotional distress
• Depression
• Anxiety
Noncancer comorbidities
• Endocrine dysfunction (hypothyroidism)
• Infection
• Cardiac dysfunction
• Pulmonary dysfunction
• Renal dysfunction
• Hepatic dysfunction
• Neurologic dysfunction
Figure 1. Treatable contributing factors for cancer-related fatigue. Based on National Comprehensive Cancer Network guidelines [19].
The Oncologist 2007;12(suppl 1):43–51
Neuroendocrine: Are cytokines the culprit?
• Imbalances in inflammatory and inhibitory
mechanisms induced by cancer treatment
• Pro-inflammatory responses: interleukin (IL)-1, IL-6,
and Tumor Necrosis Factor- (TNF-); or
• Promoting anti-inflammatory actions: IL-4, IL-10,
and IL-13
Psychosomatics 2008; 49:283–291
Proposed Pathophysiological Mechanisms in the
Development of Cancer Related Fatigue
cancer cells
+
↑ chronic
+
altered HPA-axis
activity
+
pro-inflammatory
activity
tumor hypoxia
+
cancer-related
anemia
altered 5-HT
metabolism
+
+
cancer related fatigue
EUROPEAN JOURNAL OF CANCER 4 4 ( 2 0 0 8 ) 1 7 5 –1 8 1
Algorithm for Assessment and Management
of CRF(NCCN)
Fatigue level 4-10
Screening
Comprehensive assessment
• Review of body systems
• Review of medications
• Assessment of comorbidities
• Nutritional or metabolic assessment, or both
• Assessment of activity level
(Initial and periodic)
0-10 scale
Fatigue level 0-3
Education and periodic
reassessment
Fatigue level 4-10
Primary assessment:
ascertain medical history
and do physical examination
• Disease status and treatment
• In-depth fatigue assessment
• Assessment of primary factors—ie.
anaemia, emotional distress, sleep
disturbance, pain, hypothyroidism
Treat identified
problems
Management of fatigue
• Refer as indicated
• Reassess regularly
Correction of possible causes
• Treatment of the
primary factors
• Management of
comorbidities,
malnutrition,
deconditioning
Symptomatic therapy
Non-pharmacological
Reassess degree
of fatigue
Reassess fatigue
Pharmacological
Mangements
Education and counseling of
patient and family
Nonpharmacologic
management
Pharmacologic
interventions
CRF Treatment Interventions
TABLE 2.
Cancer-Related Fatigue Treatment Interventions
Nonpharmacologic interventions
Pharmacologic interventions
Psychosocial (Category 1)
• Education
• Support groups
• Individual counseling
• Coping strategies
Stimulants
• Methylphenidate
• Modafanil
Antidepressants
• Selective serotonin
re-uptake inhibitors
Paroxetine
• Stress management training
• Individualized behavioral intervention
Sertraline
Exercise (Category 1)
Sleep Therapy
• Behavioral Therapy
Stimultus Control
Sleep Restriction
Sleep Hygiene
Acupuncture
• Other antidepressant
Bupropion
Steroids
J Gen Intern Med 24(Suppl 2):412–6
CRF Management
Non-pharmacological interventions
Activity enhancement
Psychosocial interventions
Attention-restoring therapy
Sleep therapy
Nutrition consultation
Family interaction
Karin Ahlberg, The Lancet 2003
Exercise and Psychosocial Intervention
Breast Cancer Rehab: MRM
• Phases I Exercises postop
–
–
–
–
–
–
–
Shoulder shrugs
Shoulder rolls
Front bar lifts
Side bar lifts
Back bar lifts
Active shoulder flexion
Wall walking
10
Breast Cancer Rehab: MRM
• Phase II (3-6 weeks)
–
–
–
–
–
Rotator cuff elevation
Side triceps extensions
Shoulder extensions
Shoulder abduction
Sidelying horizontal
arm lifts
– Sidelying shoulder ER
– Bilateral shoulder
flexion
Breast Cancer Rehab: MRM
• Phase III
–
–
–
–
–
–
(6-10 weeks post-surgery)
Continued bar lifts, ER, arm lifts
Internal rotation towel stretching
Forward ball stretch
Shoulder rotation with ball
Bridging
Shoulder pullovers
Evaluation of a Counseling Service in Psychosocial
Cancer Care:
A Pioneer Program and Study in Taiwan
Nai-Chih
Liu
Department of Psychology,
National Chengchi University,
Taipei
Chia-Ning
Lu
Department of Psychology,
National Chengchi University,
Taipei
Central Hill Medical
Group
ChengShyong
Chang
Chun-Yu
Huang
Division of HematoOncology, Department of
Internal Medicine,
Changhua Christian
Hospital
Department of Psychology,
Chung Yuan Christian
University
Wei-Ting
Wang
Wen-Yaw
Hsu
Department of Psychology,
National Chengchi University,
Taipei
Department of Psychology,
National Chengchi University,
Taipei
Shu-Hsien
Wang
Results
Physical Health Component Score (PCS) and Mental Health Component Score (MCS).
Results
PCS
MCS
CRF Management (Cont’d)
Pharmacological therapy
Erythropoietin
Treatment of Anemia-Related
Fatigue
Psychostimulants
Cancer-related fatigue
•Methylphenidate
•Dexmethylphenidate
•Modafinil
Fatigue in multiple sclerosis
•Pemoline
Insomnia
•Sleep medications
Hypothyroid conditions
Thyroid replacement hormone
PG2 Injection
Fatigue is worse in anemic cancer patients
Spivak, Gascón, LudwigThe Oncologist 2009;14(suppl 1):43–56
Blood contaminants
Spivak, Gascón, LudwigThe Oncologist 2009;14(suppl 1):43–56
Epoetin alfa phase IV studies in tumorassociated anemia: Incremental increase in
quality of life and hemoglobin (Hb) level
Spivak, Gascón, Ludwig, The Oncologist 2009;14(suppl 1):43–56
Mean change in FACT-An total fatigue subscale
score stratified by baseline total fatigue
subscale score
Jpn J Clin Oncol 2009;39(3)163–168
Analyses of recombinant erythropoietin
therapy in cancer patients
Spivak, Gascón, LudwigThe Oncologist 2009;14(suppl 1):43–56
Three major concerns
• Tumor progression resulting from stimulation
of tumor cell EPO receptors,
• Higher risk for TE events,
• Shorter survival duration because of
recombinant EPO itself.
The cost-effectiveness of treatment with erythropoietin
compared to red blood cell transfusions for patients with
chemotherapy induced anaemia: A Markov model
S. Borg et al. Acta Oncologica, 2008; 47: 10091017
Psychostimulants
Psychostimulants versus placebo, outcome
Cochrane Database Syst Rev. 2010 Jul 7;(7):CD006704
41
Psychostimulants
Methylphenidate on CRF
• Methylphenidate, a stimulant drug that improves
concentration, is effective for the management of cancer
related fatigue but the small samples used in the
available studies mean more research is needed to
confirm its role.
Cochrane Database Syst Rev. 2010 Jul 7;(7):CD006704
42
Efficacy and Safety of Modafinil in CRF
Treatment
Table 1. Summary of Clinical Trials
Fatigue Rating (mean)
Reference
Pts.
(N)/Malignancy
Cancer Treatment
Modafinil
Regimen
Baseline
Posttreatment
p Value
Morrow (2005)1
51/breast cancer
23.5 mo post unknown
treatment
200 mg/day for 1 mo
6.9 (0-10
scale)
3.7
<0.1
Morrow (2006)13
82/breast cancer
22.8 mo post
radiotherapy
200 mg/day for 1 mo
5.1 (BFI)
3.2
<0.001
Morrow (2006)14
30/cerebral tumors
post neurosurgical
resection, radiotherapy,
chemotherapy
200 or 400 mg-day for 3 wk;
washout 1 wk; 8-wk open
extension
5.2 (FSS)
50.2 (MFIS)
4.0 (VAFS)
3.5
28.9
6.7
0.0003
<0.0001
0.0005
Morrow (2008)12
888/unknown
concurrent
chemotherapy
200 mg/day or placebo
numeric
data/
scale not
published
numeric data not
published
0.03
BFI = Brief Fatigue Inventory; FSS = Fatigue Severity Scale; MFIS = Modified Fatigue Impact Scale; VAFS = Visual Analogue Fatigue Scale.
Ann Pharmacother 2009;43:721-5.
Antidepressants
Bupropion/Paroxetine on CRF
The Oncologist 2007;12(suppl 1):43–51
Cochrane Database Syst Rev. 2010 Jul 7;(7):CD006704
J Clin Oncol, 2003
44
Others
Steroids on CRF
• This indicated no difference between progestational steroids
and placebo for the treatment of CRF.
Cochrane Database Syst Rev. 2010 Jul 7;(7):CD006704
• Pain improvement by methylprednisolone.
The Oncologist, 2007
45
Others
L-carnitine on CRF
 Oral levocarnitine 4 g daily, for 7 days
 Levocarnitine supplementation may be effective in
alleviating chemotherapy-induced fatigue
This compound deserves further investigations in a
Br J Cancer, 2002
randomised, placebo-controlled study
46
Others
Guarana (Paullinia cupana) improves Fatigue
in Breast Cancer Patients undergoing C/T
 Guarana 50 mg by mouth twice daily for 21 days
 Guarana is an effective, inexpensive, and nontoxic
alternative for the short-term treatment of fatigue in BC
patients receiving systemic chemotherapy fatigue.
Alternative and Complementary Medicine. June 2011, 17(6): 505-512.
47
PG2 Injection

An IV injectable extracted from Astragalus membranaceus
(黃耆)
- Polysaccharide of Astragalus membranaceus
- One of the most popular TCM, and is said to benefit the deficiency of qi (vital
energy) of the spleen that symptomatically presents with fatigue, diarrhea, and
lack of appetite

Indication:
Relieving moderate to severe cancer-related fatigue among
advanced patients

The first NDA approved botanical new drug in Taiwan
PG2 for advanced NSCLC patients undergoing
platinum-based chemotherapy
Conclusion
Astragalus-based Chinese herbal medicine may increase effectiveness (by
improving survival, tumor response, and performance status) and reduce
toxicity of standard platinum-based chemotherapy for advanced non–smallcell lung cancer.
PG 2 phase I/II clinical trial
Efficacy:
Cytokine Concentrations Percentage Change from Pre-Chemotherapy
First Cycle (PG2 Treatment Arm)
N=20
Day 8
after
Chemotherapy
Day 14
after
Chemotherapy
Second Cycle (No-treatment Arm)
Day 8
after
Chemotherapy
Day 14
after
Chemotherapy
G-CSF
174.17 ± 290.52
131.81 ± 230.58
271.17 ± 336.72
228.28 ± 232.36
IL-6
398.72 ± 1011.82
138.9 ± 258.32
538.91 ± 2161.98
216.79 ± 631.6
•Relative lower IL-6 and G-CSF percent change from chemotherapy
to day 8 and day 14 after chemotherapy in the PG2 treatment arm
than those in the control arm was detected.
•The cytokine results further support that PG2 can reduce the chemotherapy –
induced myelosuppression.
PG2 Pivotal study for CRF (I)
Double-Blind, Randomized,
Placebo-Controlled
Open-Labeled
The 2nd Treatment Cycle
The 1st Treatment Cycle
PG2 plus SPC Arm
1st week
3 doses
2nd week 3rd week
3 doses
3 doses
4th week
1st week
3 doses
3 doses
PG2 Treatment
(n=30)
Placebo plus SPC Arm
1st week
3 doses
2nd week
3rd week
3 doses
3 doses
Placebo Treatment
(n=30)
2nd week
3 doses
3rd week
4th week
3 doses
3 doses
PG2 Treatment
(n=30)
4th week 1st week
3 doses
3 doses
2nd week
3 doses
3rd week
4th week
3 doses
3 doses
PG2 Treatment
(n=30)
Population
• Advanced progressive cancer patients
• Under standard palliative care (SPC) at hospice setting
• Have no further curative options available
PG2 Pivotal study for CRF (II)
The Fatigue Improvment Rate Between Cydes in PP
Population (Baseline: Visit 1 of Cyde 1)
*
*: P=0.020 (The comparison
between two cycles in the Control
Group by McNemar’s test)
*
• PG2 treatment significantly improved fatigue among cancer patients when compared with
placebo treatment.
• The
of the fatigue status for the Treatment Group sustained for 8 weeks.
PG2 Pivotal study for CRF (III)
The Results of Patient’s Fatigue Improvement Evaluation at the end of
Cycle 1 in PP Efficacy Subset Population
P=0.034*
29%
Method Chi-square Test (Compared between the two groups)
Higher fatigue improvement response rates in the Treatment Group as 29% more than
that of the Control Group at the end of the First Treatment Cycle.
Conclusion
•
•
•
•
High prevalence of among cancer patients receiving
cancer treatment
Fatigue has a significant psychosocial and economic
impact
Current therapeutic options include the assessment
and treatment of any underlying causes
Several non-pharmacological and pharmacologic
approaches have the potential to provide relief for
patients suffering from CRF
Conclusion
•
•
The non-pharmacological treatment shows to be
promising with measures such as cognitivebehavioral therapies (ECAM), physical exercises and
maybe sleep therapies.
The pharmacological treatment has shown promising
results that include the use of psycho-stimulants
such as methylphenidate and dexmethylphenidate,
modanafil (in patients with severe fatigue), PG 2 in
advanced cancer patients and ESA in patients with
CT-related anemia and hemoglobin < 10 mg/dL.
Thank you!