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Transcript of Review of the FACT: Analytic Strategies to Improve Sensitivity David Cella, Ph.D. Evanston...
Review of the FACT: Analytic Strategies to Improve Sensitivity
David Cella, Ph.D.Evanston Northwestern Healthcare
and Northwestern University
www.facit.org
Buchanan et al, JCO, 2005
• QOL assessment in Sx trials is rising without good justification
• Single symptom improvement often fails to improve overall QOL
• Acceptable rationales– Gauge importance patients assign to symptom relief– Gain dx information about offsetting tx effects– Advance a compelling conceptual model of the
relationship between symptoms and QOL
04/18/23
Conceptual Framework: Relationship Conceptual Framework: Relationship Among Patient Outcome MeasuresAmong Patient Outcome Measures
Biological and PhysiologicalVariables
Symptoms Functional Status
GeneralHealth Perceptions
Overall QOL
Characteristics of the Individual
Characteristics of the Environment
Values / Preferences
From: Wilson & Cleary (1995)
Symptom-targeted interventions can have overall QOL benefits
FACT-G changes overtime
-4-202468
10
Baseline 1-3 months 4-5 months after 6 monthsFAC
T-G
diff
eren
ce (s
core
ove
r tim
e -
scor
e at
bas
elin
e)
Intervention Attention-control Control
Velikova et al., JCO, 2004.
Some, not all, benefit in emotional well-being
Changes in FACT-EWB over time
-0.50
0.51
1.52
2.5
Baseline 1-3 months 4-5 months After 6months
FA
CT
-EW
B d
iffe
ren
ce
(s
co
re o
ve
r ti
me
- s
co
re a
t b
as
elin
e)
Intervention Attention-control Control
Velikova et al., JCO, 2004.
Some studies actually suggest overall QOL benefit without target
symptom benefit
• Osterborg, JCO, 2002– Placebo vs epo beta for CIA– No difference in FACIT-Fatigue– Significant difference in overall QOL
QOL Model
HRQoLHRQoL
PWBPWB MWBMWB SWBSWB
Total/OverallTotal/Overall(aggregated)(aggregated)
GlobalGlobal(synthesized)(synthesized)
Adapted from WHO
Symptoms Function Symptoms Function Concerns Function
Overall versus Global HRQLBoth have problems in symptom trials
• Overall (Total score)– Tension between content validity and focused
relevance– Unresponsiveness caused by mistargeted questions
• Global rating– Intuitively appealing but coarse– Vulnerable to several cognitive biases that affect
reporting of general well-being and satisfaction
Are we doomed to be happy?• Life satisfaction research consistently places people near
the 75% of satisfaction/happiness scales• Short term improvements in environmental conditions,
wealth, etc, have a modest effect• Most human happiness is independent of life’s ups and
downs• Implications for measuring GLOBAL QOL in cancer
trials– May see small short term benefits, unlikely to see lasting effect
– Background noise caused by positive cognitive bias
– Background noise caused by “doing something”
Thoughts drawn from Cummins & Nistico, 2002
General Population NormsMales and Females Combined
(N=1075)
T-S
core
0
10
20
30
40
50
60
70
0 1 2 3 4 5 6Well Being
Physical
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Social / FamilyWell Being
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Mean for Cancer Patients
Well BeingEmotional
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Well BeingFunctional
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
0
10
20
30
40
46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98100102104106108
FACT-GTotal
5
15
25
35
45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 97 99101103105107
FACT Profile of Cancer Patients (n=2,236) Referenced to General Population (n=1,075)
Symptom Prevalence Among Patients with Cancer or HIV
0 20 40 60 80 100
Fatigue
Pain
Anxiety
Depression
Nausea
HIV (n=433) Cancer (n=2791)
Cella D, 1998Percentage Reporting Symptom, any severity
FACT/NCCN Survey ResultsNumber of times symptom is in “top 5”
lack of energy (fatigue) 9/9
pain 8/9
nausea 7/9
losing weight 5/9
worry condition worse 5/9
content w/ QOL 4/9
certain areas experience pain 3/9
swelling/cramps in stomach 3/9
able to enjoy life 2/9
short of breath 2/9
trouble meeting needs of family 2/9
Clinically Significant Symptoms in NSCLC Patients With Provider-Rated PS0-1 at Baseline (E5592)
0
5
10
15
20
25
30
35
40
45
Baseline 6 weeks 12 weeks 6 months
Fatigue Pain Weight loss Appetite loss
Clin
ically S
ign
ifican
t S
ym
pto
ms (
%)
Clinically Significant Symptoms in NSCLC Patients With Provider-Rated PS0-1 at Baseline (E5592)
0
5
10
15
20
25
30
35
40
45
Baseline 6 weeks 12 weeks 6 months
Depression Hopelessness Anhedonia Bothered by treatment side effects
Clin
ically
Sig
nifi
cant
Sym
pto
ms
(%)
Symptoms and QOL (N=1,163)
50
60
70
80
90
100
Very much Quite a bit A little Not at all
FA
CT
-G T
otal
pain
insomnia
weakness
nausea
Diarrhea
Side Effect Bother and QOL
50
60
70
80
90
100
Very much Quite a bit Somewhat A little Not at all
FAC
T-G
(2
6-i
tem
s)
Breast (n=529)
Colon (n=254)
Head/Neck (n=233)
FACIT measurement systemFACIT measurement system
Functional Assessment of Chronic
Illness TherapyAn array of multidimensional self-report
quality-of-life questionnaires
Over 400 itemsOver 400 items
Over 50 languages (selected scales)Over 50 languages (selected scales)
Over 30 targeted subscalesOver 30 targeted subscales
www.facit.org
Disease Symptoms
Emotional
Physical
Social
Functional
Framework for FACT
Trial Outcome Index = Physical + Functional + Symptoms
(e.g., 36-item FACT-L includes 17 symptoms)
FACT-G (Version 4)FACT-G (Version 4)Below is a list of statements that other people with your illness have said Below is a list of statements that other people with your illness have said
are important. By circling one (1) number per line, please indicate how true are important. By circling one (1) number per line, please indicate how true each statement has been for you each statement has been for you during the past 7 daysduring the past 7 days
Physical wellbeingPhysical wellbeing
GP1GP1 I have a lack of energyI have a lack of energyGP2GP2 I have nauseaI have nausea
GP3GP3 Because of my physical Because of my physical condition, I have troublecondition, I have troublemeeting the needs of mymeeting the needs of myfamilyfamily
GP4GP4 I have painI have pain
GP5GP5 I am bothered by side I am bothered by side effects of treatmenteffects of treatment
GP6GP6 I feel illI feel ill
GP7GP7 I am forced to spend I am forced to spend time in bedtime in bed
Not at allNot at all
0000
00
00
00
00
00
A little bitA little bit
1111
11
11
11
11
11
SomewhatSomewhat
2222
22
22
22
22
22
Quite a bitQuite a bit
3333
33
33
33
33
33
Very muchVery much
4444
44
44
44
44
44
FACT Cancer-Specific Scales
• Breast cancer• Bladder cancer• Brain tumor• Colorectal cancer• CNS cancer• Cervical cancer• Esophageal cancer• Endometrial cancer
• Head and neck cancer• Hepatobiliary cancer• Lung cancer• Leukemia• Lymphoma• Ovarian cancer• Prostate cancer• Vulvar cancer
www.facit.orgwww.facit.org
FACT-Lung SubscaleFACT-Lung Subscale
• I have been short of breath
• I am losing weight
• My thinking is clear
• I have been coughing
• I have a good appetite
• I feel tightness in my chest
• Breathing is easy for me
Short of breathShort of breath Self-conscious about dressSelf-conscious about dress One or both arms swollen or tenderOne or both arms swollen or tender Sexually attractiveSexually attractive Bothered by hair lossBothered by hair loss Other family members might get same illnessOther family members might get same illness Effect of stress on illnessEffect of stress on illness Bothered by change in weightBothered by change in weight Feel like a womanFeel like a woman
FACT-Breast Subscale
FACIT symptom-specific subscalesFACIT symptom-specific subscales
AnemiaAnemiaAnorexia/cachexiaAnorexia/cachexia
DiarrheaDiarrhea
FatigueFatigue
Endocrine symptomsEndocrine symptoms
Fecal incontinenceFecal incontinence
Urinary incontinenceUrinary incontinence
Fatigue subscaleFatigue subscale Feel fatiguedFeel fatigued Feel weak all over Feel weak all over Feel listless Feel listless Feel tiredFeel tired Have trouble starting things Have trouble starting things Have trouble finishing things Have trouble finishing things Have no energyHave no energy Able to do usual activities Able to do usual activities Require sleep during day Require sleep during day Too tired to eat Too tired to eat Need help doing usual activitiesNeed help doing usual activities Frustrated/too tired for usual activitiesFrustrated/too tired for usual activities Must limit social activity because too tiredMust limit social activity because too tired
04/18/23
Littlewood et al (JCO 2000) Epoetin alfa Trial Treatment Schema
150 IU/kg (if Hb 150 IU/kg (if Hb 1 g/dL or 1 g/dL or reticulocytes reticulocytes 40,000/40,000/L) L) at Week 4at Week 4
300 IU/kg (if Hb 300 IU/kg (if Hb <1 g/dL and <1 g/dL andreticulocytes reticulocytes <40,000/ <40,000/L)L)at Week 4at Week 4
Chemo-Chemo-therapy*therapy*
44 88 1212 1616 2020 2424 282800
PlaceboPlacebo
WeeksWeeks
150 IU/kg 150 IU/kg epoetin alfa epoetin alfa
ororPlacebo (if Hb Placebo (if Hb 1 g/dL or 1 g/dL or reticulocytes reticulocytes 40,000/40,000/L) L) at Week 4at Week 4
Double placebo (if Hb Double placebo (if Hb <1 g/dL and <1 g/dL andreticulocytes reticulocytes <40,000/ <40,000/L) L) at Week 4at Week 4
*Chemotherapy duration 3-6 cycles; includes 3-4 weeks after the last dose of chemotherapy*Chemotherapy duration 3-6 cycles; includes 3-4 weeks after the last dose of chemotherapy
04/18/23
FACT-G, FACT-An: Fatigue, andFACT-An: Anemia Scores
Change From Baseline to Last Assessment
-5
0
5
n=192
n=87
n=200
n=90
n=200
n=90
FACT-G:TotalP<.05
FACT-An:FatigueP<.01
FACT-An:AnemiaP<.01*
Ch
ang
e in
Sco
re
Epoetin alfa Placebo
2.42
-3.31
2.97
-2.18
4.02
-2.64
Decrease in FACT-G Total Vs No History of Specified Illnesses
(-0.34) (0) (0.34) (0.69) (1.03) (1.37) 1.71)
Decrease in FACTG (Effect size)
Baseline
FinalAssessment
FACIT-Fatigue Subscale
26 31 36 41 46
His
tory
of C
ance
r
His
tory
of C
ance
r
No
His
tory
of I
llnes
s
No
Hist
ory i
f Illn
ess
Plac
ebo
His
tory
of A
nem
ia
EPO
EPO His
tory
of A
nem
ia
Plac
ebo
All Res
pond
ents
All Res
pond
ents
EPO = Erythhropoeitin
Baseline
FinalAssessment
FACT-G Total
68 73 78 83 88
His
tory
of C
ance
r
His
tory
of C
ance
r
No
His
tory
of I
llnes
s
No
Hist
ory o
f Illn
ess
Plac
ebo
His
tory
of A
nem
ia
EPO
EPOHis
tory
of A
nem
ia
Plac
ebo
All
Res
pond
ents
All
Res
pond
ents
EPO = Erythhropoeitin
FACT-Endocrine Symptoms Subscale Hot flashes Hot flashes Cold sweatsCold sweats Night sweatsNight sweats Vaginal dischargeVaginal discharge Vaginal itching/irritationVaginal itching/irritation Vaginal bleeding or spottingVaginal bleeding or spotting Vaginal drynessVaginal dryness Pain or discomfort with intercoursePain or discomfort with intercourse Lost interest in sexLost interest in sex Gained weightGained weight Lightheaded/dizzyLightheaded/dizzy VomitingVomiting BloatedBloated Breast sensitivity/tendernessBreast sensitivity/tenderness Mood swingsMood swings IrritableIrritable
3Entry 6 12 18 24
75
74
73
72
71
70
69
68
67
66
Visit (months)
Mea
n TO
I
AnastrozoleTamoxifenCombination
324331319
287304281
288309285
267276264
249252250
239 244242
ATAC Trial: Trial Outcome Index
Fallowfield et al. 2002, 2003Fallowfield et al, JCO, 2004
ATAC Trial: FACT-ES Scores
3Entry 6 12 18 24
64
62
60
59
57
Visit (months)
Mea
n E
S
63
61
58
322
330
323286309286
292306295
271279269
252254257
244249241
AnastrozoleTamoxifenCombination
Fallowfield et al. 2002, 2003Fallowfield et al, JCO, 2004
ATAC Trial: Specific Symptoms
Fallowfield et al. 2002, 2003Fallowfield et al, JCO, 2004
0 5 10 15 20 25 300.0
0.2
0.4
0.6
0.8
1.0Probability
Log rank p=0.034Wilcoxon p=0.012
CP/CP+GCE
Time (months)
E 5592: Overall Survival
Baseline to 12-week change in LCS score by best overall response
-2
-1
0
1
2
3
CR/PR (n=95) SD (n=82) PD (n=102)
Best response to treatment
CR/PR > PD
LCS change
CR/PR, complete response/partial response; SD, stable disease; PD, progressive diseaseTime to completion was 12 weeks Cella et al, JCE, 2002
Baseline to 12-week change in LCS score by time to progression
-2
-1
0
1
2 Late > EarlyLCSchange
Late (>116 days)
(n=196)
Early (<116 days)
(n=69)
Time to progression
Time to completion was 12 weeks Cella et al, JCE, 2002.
E5592 - Lung Cancer SubscaleProgression status
10
12
14
16
18
20
22
24
base. 6 wk 12 wk
Laterprogressors
Earlyprogressors
(Range: 0-28)
FACT Symptom Indexes:Undoing the Original Structure
• Most FACT site-specific scales assess about 50% symptoms and 50% function/perception
• FACT-G includes most common symptoms (e.g., pain; fatigue; nausea)
• FACT disease subscales focus on sympoms unique to that condition
• Common and unique need to be brought together to index the symptom burden of each specific cancer
Colorectal Distribution of Items (n=66)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
losing hope
worry condition worse
able to work
control of bowels
spend time in bed
feel ill
enjoy life
content w/ QOL
good appetite
swelling/cramps in stomach
nausea
diarrhea
pain
losing weight
lack of energy (fatigue)
Ite
ms
% Endorsed (top 5)
(chance probability=21%)
Head and NeckDistribution of Items (n=65)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
trouble meeting needs of family
worry about dying
eat foods I like
losing hope
unhappy w/ appearance of face/neck
worry condition worse
content w/ QOL
eat solid foods
nausea
communicate w/ others
trouble breathing
pain in face/neck
lack of energy (fatigue)
swallow naturally/easily
pain
Item
s
% Endorsed (top 5)
(chance probability=19%)
Ovarian Distribution of Items (n=60)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
losing hope
good appetite
spend time in bed
able to enjoy life
control of bow els
trouble meeting needs of family
w orry about dying
feel ill
losing w eight
cramps in stomach
content w / QOL
w orry condition w orse
sw elling in stomach
nausea
pain
vomiting
lack of energy (fatigue)
Ite
ms
% Endorsed (top 5)
(Chance probability=19%)
Lung Distribution of Items (n=66)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
worry about dying
good appetite
tightness in my chest
nausea
able to enjoy life
spend time in bed
content w/ QOL
breathing easy for me
bone pain
coughing
losing weight
pain
lack of energy (fatigue)
short of breath
Item
s
% Endorsed (top 5)
(chance probability=20%)
Why is more precision needed?• Cancer is many diseases and has many effects
upon HRQL– Most instruments can’t cover all important content
• Disease trajectory includes– Diagnosis (acute anxiety)– Active treatment (various and chronic symptoms)– Disease-free survivorship (emerging social issues and
stress responses, negative and positive)– End of life (emerging physical, social and existential
issues)
• Most instruments have floor and/or ceiling effects
•Item Banking
•Computerized Adaptive Testing (CAT)
Looking ahead 5-10 years:Standardizing Metrics and Improving
Precision
National Item Banks Are Coming
NIH Roadmap Cooperative Group:
Patient Reported Outcome Measurement Information System
(PROMIS)
A Better Mousetrap?
• PROMIS and the future of (some) outcome measures– Fatigue– Pain– Physical Function– Social Role participation– Emotional Distress– ???
www.NIHPROMIS.org