Quantifying Treatment Benefit Quantifying Treatment Benefit from the Patient’s Perspective: from the Patient’s Perspective:
From quality of life to symptom reliefFrom quality of life to symptom relief
David Cella, Ph.D.David Cella, Ph.D.
Evanston Northwestern Healthcare and Evanston Northwestern Healthcare and Northwestern UniversityNorthwestern University
FDA Position: OncologyFDA Position: Oncology
Two primary endpointsTwo primary endpoints– SurvivalSurvival– Quality of LifeQuality of Life
Secondary endpointsSecondary endpoints– Response rateResponse rate– Disease free survivalDisease free survival– Time to progressionTime to progression
Key Strategies in Trial DesignKey Strategies in Trial Design
Concealed randomizationConcealed randomization Controlled by placeboControlled by placebo Clinically-relevant assessmentClinically-relevant assessment
– reliablereliable– validvalid– responsive to familiar anchorsresponsive to familiar anchors
Concomitant medicationsConcomitant medications Complete dataComplete data Controls in designControls in design
– QoL assessment pre-disclosureQoL assessment pre-disclosure– Control for pre-study impactControl for pre-study impact– Control for improvements in emotional well-beingControl for improvements in emotional well-being
Evolution of QOL Studies in OncologyEvolution of QOL Studies in Oncology
• Old idea (cytotoxic): “Chemotherapy makes
patients worse in the short run; justified in the
long run.”
• Discovery: Symptomatic patients who respond
to cytotoxic chemotherapy usually improve even
during chemotherapy
• New idea (cytostatic): “Chemotherapy can
make patients better in the short and long run.”
Quality-of-life dimensionsQuality-of-life dimensions
Quality of life
Physical wellbeingPhysical wellbeing– – disease symptomsdisease symptoms– – treatment side effectstreatment side effects
Functional wellbeingFunctional wellbeing– – ADLsADLs– – role performancerole performance
EmotionalEmotionalwellbeingwellbeing– – copingcoping– – distressdistress
– – enjoymentenjoyment
Social wellbeingSocial wellbeing– – social activity/supportsocial activity/support– – relationship qualityrelationship quality– – family wellbeingfamily wellbeing
FACIT measurement systemFACIT measurement system
FFunctional unctional AAssessment of ssessment of CChronic hronic
IIllness llness TTherapyherapy
An array of multidimensional self-reportAn array of multidimensional self-reportquality-of-life questionnairesquality-of-life questionnaires
Over 400 itemsOver 400 items
Over 40 languages (selected scales)Over 40 languages (selected scales)
FACT includes:FACT includes:
FACT-G:FACT-G: Physical wellbeing (7 items)Physical wellbeing (7 items) Social/family wellbeing (7 items)Social/family wellbeing (7 items) Emotional wellbeing (6 items)Emotional wellbeing (6 items) Functional wellbeing (7 items)Functional wellbeing (7 items)
Plus...Plus... Additional questions specific to the disease, Additional questions specific to the disease,
treatment or condition treatment or condition
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 well-beingPhysical well-being
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
BreastBreast
EsophagealEsophageal
Head and neckHead and neck
FACIT disease-specific subscalesFACIT disease-specific subscales
OvarianOvarian
HepatobiliaryHepatobiliary
LungLung
CervicalCervical
BrainBrain
CNSCNS ProstateProstate
ColonColon
BladderBladder
Fatigue subscale Fatigue 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
Anorexia/Cachexia subscale - 12Anorexia/Cachexia subscale - 12
AppetiteAppetite Ability to eat a sufficient quantityAbility to eat a sufficient quantity Worry over weightWorry over weight Unpleasantness of foodUnpleasantness of food Body image concernBody image concern Loss of interest in foodLoss of interest in food Difficulty with “heavy” foodsDifficulty with “heavy” foods Pressure to eat from familyPressure to eat from family VomitingVomiting Early satietyEarly satiety Stomach painStomach pain General health ratingGeneral health rating
Lung Cancer Subscale QuestionsLung Cancer Subscale Questions
I have been short of breathI have been short of breath I have been coughingI have been coughing I feel tightness in my chestI feel tightness in my chest Breathing is easy for meBreathing is easy for me I am losing weightI am losing weight My thinking is clearMy thinking is clear I have a good appetiteI have a good appetite
Overall score range is 0-28 (severe to asymptomatic).
Phase III Trial of 5-FU vs Gemcitabine in Advanced Phase III Trial of 5-FU vs Gemcitabine in Advanced Pancreatic cancerPancreatic cancer
• Randomized clinical trial of 126 patientsRandomized clinical trial of 126 patients• End-pointsEnd-points
Clinical benefitClinical benefit PainPain Performance statusPerformance status• WeightWeight
SurvivalSurvivalBurris, H.A., et al, (1997). J Clinical Oncology. 15 (6), 2403-2413.
5-FU vs Gemcitabine Results5-FU vs Gemcitabine Results
Improvement in clinical benefit indexImprovement in clinical benefit index
5-FU5-FU 4.8% 4.8%GemcitabineGemcitabine 23.8% (p=.0022)23.8% (p=.0022)
SurvivalSurvival5-FU5-FU 4.4 mos.4.4 mos.GemcitabineGemcitabine 5.6 mos.5.6 mos. (p=.0025)(p=.0025)
Burris, H.A., et al, (1997). Burris, H.A., et al, (1997). J Clinical Oncology J Clinical Oncology 6), 2403-24136), 2403-2413
Baseline to 12-week change in Lung Cancer Subscale score Baseline to 12-week change in Lung Cancer Subscale score (best overall response)(best overall response)
2.4
1.1
-0.03
-2
-1
0
1
2
3
CR/PR (n = 95) SD (n = 82) PD (n = 102)
Best Response to Treatment
LC
S c
han
ge
CR/PR > PD
<58, no
<58, yes
>58, no
>58, yes
Initial, improved?
Proportion surviving
1.0
0.8
0.6
0.4
0.2
0.00 1 2 3 4 5 6 7 8 9 10 11 12
Initial TOI and improvement at Initial TOI and improvement at 6 weeks* (n=352)6 weeks* (n=352)
*Patients with missing QoL excluded
What is a (clinically) meaningful change?What is a (clinically) meaningful change?
Meaningful change: A difference or change in score Meaningful change: A difference or change in score on a health-related quality of life (HRQoL) on a health-related quality of life (HRQoL) questionnaire that is important to the involved person questionnaire that is important to the involved person or peopleor people
““Clinically” meaningful corresponds to a clinically Clinically” meaningful corresponds to a clinically important difference or change in patient status.important difference or change in patient status.
E5592 - Lung Cancer SubscaleE5592 - Lung Cancer SubscaleBest overall response to treatmentBest overall response to treatment
12
14
16
18
20
22
24
26
base. 6 wk 12 wk
CR/PR
SD
PD
(Range: 0-28)
E5592 - Lung Cancer SubscaleE5592 - Lung Cancer SubscaleProgression statusProgression status
10
12
14
16
18
20
22
24
base. 6 wk 12 wk
Laterprogressors
Earlyprogressors
(Range: 0-28)
E5592 - Shortness of BreathE5592 - Shortness of Breath
0
1
2
3
4
Baseline 6 weeks 12 weeks
Earlyprogressors
Laterprogressors
Notat all
Verymuch
E5592 - Weight lossE5592 - Weight loss
0
1
2
3
4
Baseline 6 weeks 12 weeks
Earlyprogressors
Laterprogressors
Notat all
Verymuch
E5592 - CoughE5592 - Cough
0
1
2
3
4
Baseline 6 weeks 12 weeks
Earlyprogressors
Laterprogressors
Notat all
Verymuch
Tumor SitesTumor Sites AdvancedAdvanced– BladderBladder– BrainBrain– BreastBreast– ColorectalColorectal– Head & NeckHead & Neck– HepatobiliaryHepatobiliary– LungLung– OvarianOvarian– ProstateProstate
SummarySummaryRevisedRevised
Number of times symptom is in “top 5%?”Number of times symptom is in “top 5%?”lack of energy (fatigue)lack of energy (fatigue) 9/99/9
painpain 8/98/9
nauseanausea 7/97/9
losing weightlosing weight 5/95/9
worry condition worseworry condition worse 5/95/9
content w/ QOLcontent w/ QOL 4/94/9
certain areas experience paincertain areas experience pain 3/93/9
swelling/cramps in stomachswelling/cramps in stomach 3/93/9
able to enjoy lifeable to enjoy life 2/92/9
short of breathshort of breath 2/92/9
trouble meeting needs of familytrouble meeting needs of family 2/92/9
Colorectal 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)
Item
s
% Endorsed (top 5)
(chance probability=20.8%)
HepatobiliaryHepatobiliary
Distribution of Items (n=61)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
feel ill
bothered by constipation
able to do usual activities
spend time in bed
content w/ QOL
have/had fever
losing hope
diarrhea
good appetite
pain in back
have/had itching
swelling/cramps in stomach
bothered by jaundice
discomfort/pain stomach
nausea
feel fatigued
lack of energy (fatigue)
losing weight
pain
Ite
ms
% Endorsed (top 5)
(chance probability=14.3%)
FACT Hepatobiliary FACT Hepatobiliary Symptom IndexSymptom Index
(FHSI)(FHSI)
FACT Hepatobiliary Symptom Index - 8 FACT Hepatobiliary Symptom Index - 8 item (FHSI-8)item (FHSI-8)
painpain weight lossweight loss fatigue (I feel fatigued)fatigue (I feel fatigued) nauseanausea jaundicejaundice back painback pain stomach pain/discomfortstomach pain/discomfort fatigue (I lack energy)fatigue (I lack energy)
Performance Comparison Performance Comparison FHSI-8 versus FACT-HepFHSI-8 versus FACT-Hep
0
20
40
60
80
100
120
Sca
le R
espo
nse
(0-1
00)
ECOG PSR 0, n=16
ECOG PSR 1, n=12
ECOG PSR 2/3, n=23
** [1]
* ** [1]** [1]
** [2] ** [2] ** [3]
Scale*p<.05, **p<.0001
[1] discrimination between (PSR=0) v (PSR=1 or 2/3); [2] discrimination between (PSR=0) v (PSR=1) v (PSR=2/3) [3] discrimination between (PSR=0 or 1) v (PSR=2/3)
Yount et al, 2002
Performance Comparison Performance Comparison FHSI-8 versus FACT-HepFHSI-8 versus FACT-Hep
0
20
40
60
80
100
120
Scal
e R
espo
nse
(0-1
00)
Not on treatment, n=18
On treatment, n=33
** * *
Scale
*
*p<.05, **p<.01
Colorectal and Hepatobiliary Cancer Colorectal and Hepatobiliary Cancer QOL studies: What to evaluate?QOL studies: What to evaluate?
DefinitelyDefinitely– General pain and abdominal crampingGeneral pain and abdominal cramping– FatigueFatigue– Appetite and weight lossAppetite and weight loss– DiarrheaDiarrhea– NauseaNausea
ProbablyProbably– Other bowel concerns (e.g., constipation)Other bowel concerns (e.g., constipation)– Other side effects (e.g., mucositis, fever, alopecia) Other side effects (e.g., mucositis, fever, alopecia) – Activity limitation; Life enjoymentActivity limitation; Life enjoyment– Worry, Distress, HopeWorry, Distress, Hope– Overall (global) quality of lifeOverall (global) quality of life
MaybeMaybe– Multidimensional health statusMultidimensional health status
Internal Consistency Reliability and 2 Week Reproducibility of the GCSI Total Internal Consistency Reliability and 2 Week Reproducibility of the GCSI Total and and
Subscale ScoresSubscale Scores
0.10 (0.82)0.10 (0.82)0.810.810.850.8533Nausea/VomitingNausea/Vomiting
-0.05 (0.94)-0.05 (0.94)0.680.680.830.8344Post-prandial fullness/Early satietyPost-prandial fullness/Early satiety
-0.14 (1.29)-0.14 (1.29)0.690.690.840.8422BloatingBloating
-0.02 (0.72)-0.02 (0.72)0.76b0.76b0.840.8499GCSI TotalGCSI Total
Mean ScoreMean Score
Difference (SD)Difference (SD)ICCICC
Cronbach’sCronbach’s
AlphaaAlphaaNumber Number
Of ItemsOf ItemsSubscaleSubscale
ReproducibilityReproducibilitybb
aN=159-166, with variation due to missing databN=23 stable patients over 2 week periodSource: Revicki et al. (2002)
ReferencesReferences
Cella, D.F., Bonomi, A.E., Lloyd S.R., Tulsky, D.S., Kaplan, E., Bonomi, P. (1995). Reliability and validity of the Functional Assessment of Cancer Therapy - Lung (FACT-L) quality of life instrument. Lung Cancer, 12, 199-220.
Yellen, S.B., Cella, D.F., Webster, K.A., Blendowski, C., & Kaplan, E. (1997). Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) Measurement System. Journal of Pain and Symptom Management, 13 (2), 63-74.
Ribaudo, J.M., Cella, D., Hahn, EA, Lloyd, S.R., Tchekmedyian, N.S., Von Roenn, J., & Leslie, W. (2001). Re-Validation and Shortening of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Quality of Life Research, 9, 1137-1146.
Cella, D., Lai, J-S., Chang, C-H., Peterman, A., & Slavin, M. (2002). Fatigue in Cancer Patients Compared with Fatigue in the General United States Population. Cancer, 94(2), 528-538.
Cella, D., Hahn, E., & Dineen, K. (2002). Meaningful change in cancer-specific quality of life scores: Differences between improvement and worsening. Quality of Life Research, 11 (3), 207-21.