applications of quality of life outcomes in cancer

Workshop

Applications of Quality of Life Outcomes in Cancer Clinical Trials

M. Brundage and Colleagues August 2019

Outline

• Nature of QOL data – a brief review• Application in practice• Three RCT Examples

• Prevention, Curative, Advanced Systemic• Practical Approaches – Formulating a QOL section of a protocol suitable for funding• Informal and interactive

Research Question

I’m interested in comparing two treatments:“R” and “M”

I want to evaluate how each treatment affects patients’ quality of life.

NCIC CTG PR.3/MRC PR07/SWOG JPR3:Study Scheme

Initial PSA Level: < 20 vs 20-50 vs > 50 μg/L Hormonal Therapy: orchiectomy vs LHRH analogue+ anti androgen Method of lymph node staging: clinical vs radiological vs surgical Gleason Score: < 8 vs 8-10 Prior hormonal therapy: yes vs no Centre

Continuous Androgen Deprivation Therapy

+ Radiotherapy

Continuous Androgen Deprivation Therapy

T3/T4 N0/NXor

T2 and PSA > 40 μg/Lor

T2 and PSA > 20 μg/L and GS: 8-10

Tomorrow’s UV Index will be 3.6

The Earthquake measured 4.1 on the Richter scale

• Some scales are familiar to us, some are not

The treatment improved mean HRQL global scoresfrom 74 to 85 (p = 0.03)

• Some scales are familiar to us, some are not

• Graphical Display of Data is becoming commonplace

• EORTC QLQ-C30+3 Instrument• Domain: Global quality of life

How would you rate your overall health during the past week?1 2 3 4 5 6 7Very poor Excellent

How would you rate your overall quality of life during the past week1 2 3 4 5 6 7Very poor Excellent

Not at All

A Little

Quite a Bit

Very Much

1 Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase? 1 2 3 4

2 Do you have any trouble taking a long walk? 1 2 3 4 3 Do you have any trouble taking a short walk outside of the

house? 1 2 3 4

4 Do you need to stay in bed or a chair during the day? 1 2 3 4 5 Do you need help with eating, dressing, washing yourself

or using the toilet? 1 2 3 4

Raw Score (Mean of Component Items)= (3+3+2+2+1)/5=2.2[1-(2.2-1)/3]*100= 60

Example: Physical Function Measure

0

100

Before During After

QOL Score

Treatment Intent: Improve QOL

Mean 60.8Mean 71.2

0

100

Before During After

QOL Score

Treatment Intent: Improve QOL

0

100

Before During After

QOL Score

Treatment Intent: Improve QOL

Mean 60.8Mean 71.2

0

100

Before During After

QOL Score

Treatment Intent: Improve QOL

0

100

Before During After

QOL Score

Treatment Intent: Improve QOL

0

100

Before During After

QOL Score

Treatment Intent: Improve QOL

0

100

Before During After

QOL Score

Treatment Intent: Improve QOL

0%

100%

After

"Improved"

"Unchanged"

"Worse"

Percent of

Patients

Treatment Intent: Improve QOL

0

50

0 50 100 150 200 250 300Weight

Number of People

Treatment Intent: Shed Pounds

0

50

0 50 100 150 200 250 300Weight

Number of People

Treatment Intent: Shed Pounds

NCIC CTG PR.3/MRC PR07/SWOG JPR3:Study Scheme

Initial PSA Level: < 20 vs 20-50 vs > 50 μg/L Hormonal Therapy: orchiectomy vs LHRH analogue+ anti androgen Method of lymph node staging: clinical vs radiological vs surgical Gleason Score: < 8 vs 8-10 Prior hormonal therapy: yes vs no Centre

Continuous Androgen Deprivation Therapy

+ Radiotherapy

Continuous Androgen Deprivation Therapy

T3/T4 N0/NXor

T2 and PSA > 40 μg/Lor

T2 and PSA > 20 μg/L and GS: 8-10

NCIC CTG PR.3/MRC PR07/SWOG JPR3:Study Scheme

Initial PSA Level: < 20 vs 20-50 vs > 50 μg/L Hormonal Therapy: orchiectomy vs LHRH analogue+ anti androgen Method of lymph node staging: clinical vs radiological vs surgical Gleason Score: < 8 vs 8-10 Prior hormonal therapy: yes vs no Centre

Continuous Androgen Deprivation Therapy

+ Radiotherapy

Continuous Androgen Deprivation Therapy

T3/T4 N0/NXor

T2 and PSA > 40 μg/Lor

T2 and PSA > 20 μg/L and GS: 8-10

Planned Treatment

Androgen Deprivation Therapy• Bilateral Orchiectomy

or

• LHRH agonist– Antiandrogen for 2 weeks, optional to continue

Radiotherapy• 45 Gy/25 F/5 weeks to pelvis

• 20-24 Gy/10-12 F/2-2.5 weeks to prostate

• If treating physician felt patient inappropriate for whole pelvis then RT given to prostate only

Locally Advanced Prostate Cancer1990s

Canadian and UK surveys of clinicians revealed substantial uncertainty about the role of radiotherapy“These men all have metastatic disease; adding radiotherapy to hormones is unnecessary and unkind”

Locally Advanced Prostate Cancer1990s

Canadian and UK surveys of clinicians revealed substantial uncertainty about the role of radiotherapy“These men all have metastatic disease; adding radiotherapy to hormones is unnecessary and unkind”

Additional uncertainty about the ‘best’ instrument for evaluating HRQL in prostate cancer Functional Assessment of Cancer Therapy – Prostate (FACT-P)EORTC instrument (EORTC QLQ C-30 and Prostate-specific check list)

Baseline CharacteristicsCharacteristic ADT Alone ADT+RT

Median Age 69.7 years 69.7 years

T Category

< T2c

T3/T4

11%

89%

10%

88%Gleason Score

< 7

8-10

81%

18%

81%

18%PSA ng/ml

<20

20-50

>50

37%

38%

25%

36%

38%

26%

34

Final Analysis - overall survival

HR = 0.70 (95% C.I. 0.57 to 0.85, P = 0.0003)

10 yr OS 55%

10 yr OS 49%

+RT

Perc

enta

ge

0.0

0.2

0.4

0.6

0.8

1.0

Time (Years) # At Risk(ADT)

# At Risk(ADT + RT)

0602603

2571558

4498505

6353381

8185208

107785

122832

ADT ADT + RT

35

Final Analysis: Cumulative Incidence Probability for Disease-Specific Survival

DSS HR=0.46 (95% CI 0.34-0.61)

Estim

ated

Cum

ulat

ive In

ciden

ce

0

20

40

60

80

100

Time (Years)0 2 4 6 8 10 12

Death related to disease ADT ADT + RT

0102030405060708090

100

0 6 12 18 24 30 36

36

Quality of Life:Bowel Domain (EORTC QLQ)

Mea

n Sy

mpt

om S

core

s

Bowel and Rectum

ADT onlyADT + Radiation

Months

Few

er S

ympt

oms

37

Quality of Life:Bowel Domain (EORTC QLQ)

Mea

n Sy

mpt

om S

core

s

010203040

0 6 12 18 24 30 36

0102030

0 6 12 18 24 30 36

Bowel and Rectum

ADT onlyADT + Radiation

Months

Few

er S

ympt

oms

Diarrhea

ADT onlyADT + Radiation

Proportion of Patients Worsening

• Patients deteriorating by 10 points or more at any point up to 3 years

0102030405060708090

100

ADT only ADT + XRT

Not worsenedWorsened

Rectal Symptoms

P < 0.01

01020304050

0 6 12 18 24 30 36

39

Quality of Life:Urinary Domain (FACT-P)

Mea

n Sy

mpt

om S

core

s

ADT onlyADT + Radiation

Months

Few

er S

ympt

oms

Proportion of Patients changing

• Patients changing by 10 points or more at any point up to 3 years

0102030405060708090

100

ADT only ADT + XRT

ImprovedNeitherWorsened

Urinary Symptoms

P > 0.05

0102030405060708090

100

Baseline 1 2 3 4 5

Time from Baseline in Years

PHYS

Sco

re

41

Quality of Life:Physical Domain (EORTC)

ADT onlyADT + Radiation

Menopause-specific and health-related qualities of lifeamong post-menopausal women taking exemestane for

prevention of breast cancer

James N. Ingle, José Alés-Martínez (GEICAM), Rowan T. Chlebowski, Carol J. Fabian, Gloria Sarto, Judy E. Garber, Pascal Pujol (UNICANCER), Andrea Hiltz, Dongsheng Tu

and Paul E. Goss for the NCIC CTG MAP.3 Study Investigators

Quality of life in NCIC CTG MAP.3

Elizabeth Maunsell, Harriet Richardson

NCIC CTG MAP.3 Prevention Trial

EligiblePostmenopausal and ≥ 35 yearsAt least ONE of the following breast cancer risk factors• Age ≥ 60 years• Gail score >1.66%• Prior ADH, ALH, LCIS• Prior DCIS with mastectomy

Ineligible• BRCA 1 and 2 mutation carriers • Prior DCIS with lumpectomy• Women with a history of breast

cancer or other malignancies

n = 4560 February 2004 – March 2010

RANDOMIZE

Exemestane25 mg/day x 5 years

RANDOMIZE

Placebo1 pill/day x 5 years

Double-Blind

StratificationAspirin use Gail score (<2.0, > 2.0)

QOL Objectives

Compare menopause-specific andgeneral quality of life for women whileon treatment

Evaluate extent of any clinically importantdecline in quality of life while on treatment

MENQOL Menopause–Specific QOL

• Four domains: vasomotor, psychosocial, physical, sexual

• Scores can vary between 1 to 8: “symptom absent” to “very bothered by symptom”

• Clinically meaningful worsening in Menopause-specific QOL based on ~ 5% of the scale breadth:

• MENQOL: 0.5 / 8 points higher from baseline

[Hilditch et al. 1996]

Analysis Net effects of exemestane on QOL:

• Difference in mean change score from baseline between exemestane and placebo (Rank-sum test)

Clinically meaningful worsening in QOL defined as:• MENQOL scores increased by > 0.5 points• SF-36 scores decreased by >5 points

Proportion with meaningful decline > 1visit while on study medication (Chi square test)

Proportion with bothersome menopause-specificsymptoms (scores 6-8) (Chi square test)

[Osoba et al. European J Cancer, 2005]

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5

PhysicalPsychosocialVasomotorSexual

No clinically important differences

BL 6 12 24 36 48 60 months

0.5

0.4

0.3

0.2

0.1

0.0

-0.1

-0.2

> 0.5 = Unfavourable change

0

0.5

1 2 3 4

Proportion of women with worsened domains of MENQOL at least once while on treatment

Exe Placebo Exe Placebo Exe PlaceboExe Placebo

* Vasomotor (p<0.001)

* Sexual (p<0.01)

Psychosocial (p=0.73)

Physical (p=0.12)

43%

33%

39% 38%42% 40%

30%

25%

Goss et al. ASCO, 2011

Incidence of *bothersome MENQOL symptoms at 6 months, or ever, while on treatment

MENQOL Domains

Exemestane (n=2015)

Placebo (n=2096)

Vasomotor: 6 monthsEver

184 9.5 %285 14.1 %

104 5.2 %195 9.3 %

Psychosocial: 6 monthsEver

43 2.2 %89 4.4 %

29 1.4 %73 3.5 %

Physical: 6 monthsEver

24 1.2 %61 3.0 %

16 0.8 %40 1.9 %

Sexual: 6 monthsEver

78 4.0 %171 8.5 %

79 3.9 %179 8.5 %

*Bothersome = MENQOL scores 6-8

Proportion of women on exemestane discontinuing early - greatest at 6 months

0

2

4

6

8

10

12

Baseline 6 mths 1 yr 2 yrs 3 yrs 4 yrs 5 yrs6 12 24 36 48 60

%

12

10

8

6

4

2

0

EXE

months

PLAC

MAP.3 QOL ConclusionsExemestane had few clinically important effects on quality of life as measured by either the MENQOL or SF-36

Specifically: No clinically important worsening in symptoms over

time, based on mean change scores

Excess of vasomotor symptoms due to exemestane most pronounced at 6 months

Excess of early discontinuation in the exemestane arm at 6 months only

Small to no differences observed on other dimensions of menopause-specific or general quality of life

• Five (1%) of 471 patients died of treatment-related

causes

• 42% had grade 3 or 4 immune-related toxicities /

adverse events

• Ipilimumab discontinuation in over half (52%) of patients

Mea

n D

iarr

hea

Scor

e

Capturing what

matters

Designing a high quality study

Obtaining data and

protecting patients

Ensuring that data are

analysed and reported

appropriately

Providing high quality evidence to

inform patient-centred

care.

CONSORTSYSAQOL

SPIRIT

JAMA. 2013;309(8):814-822

Original Consort Statement Consort PRO Extension

Thank you for attending!

0 20 40 60 80 100

Rationale Providedfor Instrument

Evidence forInstrument Validity

Statement on WhoCompletedInstrument

HRQL Hypothesis

HRQL Sample SizeCalculation

Flow Chart

Missing DataAddressed

Discussion ofFindings

Percent of Trials

All Trials(N=794)

0 20 40 60 80 100

Rationale Providedfor Instrument

Evidence forInstrument Validity

Statement on WhoCompletedInstrument

HRQL Hypothesis

HRQL Sample SizeCalculation

Flow Chart

Missing DataAddressed

Discussion ofFindings

Percent of Trials

HRQL in MainRCT (N=684)

HRQL in SecondaryReport (N=110)

0102030405060708090

Prefers LineGraph

Prefers BarGraph

Finds BothUseful

Adjuvant Setting

Perc

ent o

f Par

ticip

ants

0102030405060708090

100

Prefers LineGraph

Prefers BarGraph

Finds BothUseful

Adjuvant SettingPalliative Setting

Perc

ent o

f Par

ticip

ants

Overall Quality of Life

0

20

40

60

80

100

0 12 24

Time (Months)

Glo

bal Q

OL

Treatment "A"Treatment "B"

Bette

r QO

L