Download Fatigue Presentation

RTOG 1115
Fatigue:
Assessments & Considerations
Mylin A. Torres, M.D.
1
Background
• Fatigue is a frequent, distressing symptom
related to cancer and its treatment
• Fatigue has profound effects on daily
functions and activities
• 2.3 million survivors of prostate cancer
• Most of the research has been conducted
in survivors of breast cancer
2
Background
• Up to 80% of prostate cancer patients
develop fatigue during radiotherapy (RT)
• As many as 40% of patients report
clinically relevant fatigue 1 year after
completing RT
3
Background
• Up to 80% of prostate cancer patients
develop fatigue during radiotherapy (RT)
• As many as 40% of patients report
clinically relevant fatigue 1 year after
completing RT
• However, fatigue has been rarely studied
in patients undergoing combined RT and
androgen deprivation therapy (ADT)
4
Background
• Fatigue is one of the most common adverse
effects of TAK-700
• Phase I/II clinical trials in men with metastatic
prostate cancer treated with TAK-700 found that
fatigue developed in 16 of 26 patients with
metastatic castration-resistant prostate cancer,
but only one of these patients developed
> Grade 3 fatigue
5
Background
• The high prevalence of fatigue after combined
modality therapy for prostate cancer and its
association with poor quality of life mark it as a
significant problem that requires further study
6
Primary Objective
• To evaluate the difference in overall
survival in men with clinically localized
prostate cancer between
a) standard treatment (ADT + RT) and
b) standard treatment with the addition
of 24 months of TAK-700
7
Secondary Objective: Fatigue
• To measure the change in severity of
fatigue from baseline to 1 year, as
measured by PROMIS
8
PROMIS
• Developed by the Patient-Reported Outcome
Measurement Information System (PROMIS)
Network
• Short Form consists of 7 items which were
selected for consistency in the response scale,
broad coverage across the fatigue continuum,
and good precision of measurement
• The criteria for a minimally clinically important
difference in patients with advanced-stage
cancer is a 3 to 5 point difference in raw score
9
PROMIS
10
PROMIS
• Raw scores are converted
to T-scores which rescale
the raw score into a
standardized score with a
mean of 50 and a standard
deviation of 10.
• A higher PROMIS T-score
means more fatigue
11
Fatigue Correlate Measures:
Depression (EQ-5D)
12
Fatigue Correlate Measures: GodinLeisure Time Exercise Questionnaire
13
Timing of Fatigue Assessments
Baseline
1 wk prior to XRT
Last wk of XRT
12mos post ADT start
30 mos post ADT start
Prostate Cancer
N=410 initially
mandatory
PROMIS-Fatigue
EQ-5D
PSQI
GLTEQ
Blood: 1. DNA*
2. Inflammatory Markers
3. NF-kB DNA Binding
PROMIS-fatigue
EQ-5D
PSQI
GLTEQ
PROMIS-fatigue
EQ-5D
PSQI
GLTEQ
PROMIS-fatigue
EQ-5D
PSQI
GLTEQ
Blood: 1. Inflammatory
Markers
2. NF-kB DNA Binding
PROMIS-fatigue
EQ-5D
PSQI
GLTEQ
Blood: 1. Inflammatory
Markers
2. NF-kB DNA Binding
Legend: PROMIS-Fatigue (Patient-Reported Outcome Measurement Information System.; EQ-5D – EuroQol (Anxiety/Depression Item); PSQI – Pittsburgh Sleep
Quality Index; GLTEQ – Godin Leisure-Time Exercise Questionnaire – level of physical activity measured using 3 items; ADT – androgen deprivation therapy
*If site missed this collection time point, they may collect this specimen at any other time point.
14
Timing of Fatigue Assessments
Baseline
1 wk prior to XRT
Last wk of XRT
12mos post ADT start
30 mos post ADT start
Prostate Cancer
N=410 initially
mandatory
PROMIS-Fatigue
EQ-5D
PSQI
GLTEQ
Blood: 1. DNA*
2. Inflammatory Markers
3. NF-kB DNA Binding
PROMIS-fatigue
EQ-5D
PSQI
GLTEQ
PROMIS-fatigue
EQ-5D
PSQI
GLTEQ
PROMIS-fatigue
EQ-5D
PSQI
GLTEQ
Blood: 1. Inflammatory
Markers
2. NF-kB DNA Binding
PROMIS-fatigue
EQ-5D
PSQI
GLTEQ
Blood: 1. Inflammatory
Markers
2. NF-kB DNA Binding
Legend: PROMIS-Fatigue (Patient-Reported Outcome Measurement Information System.; EQ-5D – EuroQol (Anxiety/Depression Item); PSQI – Pittsburgh Sleep
Quality Index; GLTEQ – Godin Leisure-Time Exercise Questionnaire – level of physical activity measured using 3 items; ADT – androgen deprivation therapy
*If site missed this collection time point, they may collect this specimen at any other time point.
15
Hypothesis
• Change in PROMIS fatigue scores
between baseline and 1 year will not differ
significantly between the control group and
the experimental group receiving both a
GnRH agonist and TAK-700
16
Fatigue: Inflammatory Mechanisms
& Mediators
17
Innate Immunity/Inflammation
Endothelial cell
Leukocyte
Diapedesis
Local Effects
Adhesion molecules
Chemokines
Stromal
cell
- Increased vascular permeability
- Vasodilation
- Chemokine production
- Expression of adhesion molecules
- Pain
tumor
rubor
calor
dolor
Local
TNF, IL-1, IL-6 IFN-alpha
Macrophage
NF-κB
Antigen
(e.g. bacteria,
ADT)
Toll-like
receptors
(TLRs)
TNF
IL-1
IL-6
IFN-alpha
Systemic
Effects on Brain
Effects on Liver
Courtesy of Andrew H. Miler M.D.
Acute Phase Response
- C-reactive protein
- serum amyloid A
- Fever
- Fatigue
- Anorexia
- Anhedonia
- Altered sleep
sickness behavior
Conservation of energy resources to promote increased
18
metabolic demands of fighting infection and mounting a fever
Fatigue & Inflammation
• Growing evidence that pro-inflammatory
cytokines play a role in cancer-related fatigue
• Most commonly implicated cytokines are IL-1,
IL-6, TNF alpha, sTNFr2, and IFN alpha with the
majority of data from breast cancer studies
19
Fatigue & Inflammation
• Growing evidence that pro-inflammatory
cytokines play a role in cancer-related fatigue
• Most commonly implicated cytokines are IL-1,
IL-6, TNF alpha, sTNFr2, and IFN alpha with the
majority of data from breast cancer studies
• Small pilot studies of circulating cytokines, RT,
and fatigue in men with prostate cancer, but
there is very little data on the relationship
between circulating inflammatory markers and
fatigue in men undergoing ADT
20
Fatigue, Inflammatory Markers, and
Radiation
Bower et al. Clinical Cancer Research 2009
21
Single Nucleotide Polymorphisms
and Fatigue
• SNPs in the promoters of cytokine genes, IL6,
IL1, and TNF alpha have been associated with
fatigue in breast and prostate cancer survivors
• SNPs found in genes integral to the
inflammatory response will be assessed to
identify patients at risk for fatigue development
22
Single Nucleotide Polymorphisms,
ADT, & Fatigue
Jim et al. Brain, Behavior, and Immunity 2012
23
Single Nucleotide Polymorphisms,
ADT, & Fatigue
Jim et al. Brain, Behavior, and Immunity 2012
24
NF-Kappa B
• NF-Kappa B DNA Binding
has been found to correlate
with fatigue in women
undergoing breast RT
• Increased transcripts with
response elements for
Nf-kappa B previously found
in fatigued vs. non-fatigued
breast cancer survivors
25
PBMC Isolation
1. Collect ~6 ml whole blood with purple top
tube
2. Dilute blood 1:1 with phosphate buffered
saline (PBS)
Before and After
Centrifugation (Step 4)
Before
After
3. Carefully add diluted blood on top of
lymphocyte separation medium (LSM, aka
Ficoll), avoid mixing
4. Centrifuge (see before/ after figure at right).
5. Collect PBMCs
6. Wash PBMCs twice with PBS
7. Store PBMCs in freezing serum at -80°C
8. Refer to detailed protocol for more
information
B = Whole Blood
F = Ficoll (aka Lymphocyte Separation Medium)
P = Plasma
W = PBMCs
R = Red Blood Cells/Ficoll mixture
26
Fatigue & Inflammation
• Activation of the inflammatory response may be
a fundamental consequence of ADT and RT
leading to fatigue
27
Clinical Relevance
1. Inform patients and providers about the trade-off
between QOL and enhanced survival.
2. Longitudinal research in cooperative group setting
provides an ideal platform to study the natural
history of cancer-related fatigue and confirm the
association between inflammatory markers and
fatigue in the context of combined therapy for
prostate cancer
3. Findings from this research could inform the timing
of intervention to alleviate fatigue
4. Findings may facilitate rational, evidence-based
intervention for cancer-related fatigue.
28
Thank You
29
Inflammatory Markers
• 5 mL of anticoagulated whole blood in EDTA
tube (purple/lavender top)
• Centrifuge within one hour of collection in a
standard clinical centrifuge at ~2500 RPM for 10
minutes at 4 degrees celsius preferred
• Submit as frozen plasma samples containing
0.5mL per aliquot in 1mL cryovials (5 to 10)
• Send on dry ice via overnight carrier to the
RTOG Biospecimen Resource
30
NF-κB DNA binding ELISA
p65/p50
Peripheral Blood Mononuclear Cells
31
Active Motif
PBMC Kit Contents
1. Lymphocyte separation medium, 100 ml
2. 1 X PBS, 500 ml
3. Pack of 50 ml conical tubes (8 per pack)
4. Pack of 15 conical tubes (32 per pack)
5. Blunt transfer pipettes (8 per pack)
6. Thin tip transfer pipettes (8 per pack)
7. Freezing serum, 12 ml
8. 2 ml cryovials (8 per pack)
32
SNP Analysis
• DNA will be extracted from whole blood.
• Send on dry ice via overnight carrier to the
RTOG Biospecimen Resource Center
• DNA will be extracted from the buffy coat
33
Fatigue & Prostate Cancer Survivors
Krydalen et al. The Prostate 2010
34