Applications of Quality of Life Outcomes in Cancer ...
Transcript of 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%
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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
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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