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.