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NON-TRADITIONAL ENDPOINTS IN LUNG CANCER
- Patient Reported Outcomes -
Richard J. Gralla, MD
New York Lung Cancer Alliance
New York, New York
ENDPOINTS IN DECISION-MAKING- Clinical Trials and Patient Management -
Should become the most used parameter
Appropriate if Survival Differences
Unlikely
QoL
The most commonly used parameter
Considered to be Unreliable
RESPONSE
Not relevant for individual patients
Appropriate if Survival Difference
is likely
SURVIVAL
MANAGEMENTTRIALS
NON-SMALL CELL LUNG CANCER- Quality of Life at Baseline: Influence on Survival -
- Prospective Analysis of 673 Patients at 30 Centers -
* p = 0.0001, using the LCSS quality of life instrument
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24
MONTHS
PE
RC
EN
T S
UR
VIV
ING
*
LOWER QL HIGHER QL
4.96
7.22
7.77
8.66
9.17
8.6
BSC 1995-2001 P alone PE Old Cis + no PE New Cis + Carbo +
+45,5%
+11%
+17,9%
+10,2% -11,4%
NON-SMALL CELL LUNG CANCER- Survival: Supportive Care and Chemotherapy 1991- 2001
(N = 10,995 / 9361) -
718 pts718 pts 783 pts783 pts 509 pts509 pts 1103 pts1103 pts 4648 pts4648 pts 1600 pts1600 pts
Refs: Proc ASCO 2002: Raftopoulos, Bria, Gralla, Eid
PATIENT REPORTED OUTCOMES (“PROs”)
- Rationale and Need - PROs can create an accurate picture of the disease course that is
unavailable from the review of other endpoints
Health care professionals are not accurate in evaluating subjective or palliative benefits associated with anti-cancer treatments, when compared with patient self-reports
PROs are often reported by patients as improved with less than major responses to treatment - even with only stable disease…response rates underestimate patient reported benefit
The balance between symptom improvement and toxicity, or the effects of delayed progression summarized in many PRO measures, cannot be consistently predicted by other biomedical endpoints
SYMPTOMS OF LUNG CANCER- By Patient Reports (N = 121) -
Ref: Hollen et al. (1993). Eur J Cancer, 29A, S51-S58
84% 79%71% 62%59% 56%57% 60%48%25% 14%
54%
(n = 69) (n = 52)NON-SMALL CELL SMALL CELL
FATIGUE
COUGH
DYSPNEA
ANOREXIAPAINHEMOPTYSIS
NON-SMALL CELL LUNG CANCER- Number of Presenting Symptoms at Baseline -
Percentage
(N = 673 Stage III and IV Patients)
80%
12%
5%
Three or more
Two
One
None 3%
0 20 40 60 80 100
PATIENT REPORTED OUTCOMES
(“PROs”) - Clinical Benefit and Quality of Life -• Quality of Life
– Multidimensional
– Includes areas not likely to be affected by chemo
• Clinical Benefit
- Subjective or Palliative Control of Common Problems - Previously Defined to Evaluate:
- Pain Control- Weight Loss- Performance Status
QUALITY OF LIFE INSTRUMENTS- Dimensions -
Physical
Functional
Psychological
Social
Spiritual
- Conceptual Model for Clinical Trials: THE “LCSS” -
PHYSICALDIMENSION
Symptoms
Symptomatic Distress
distress from
FUNCTIONALDIMENSION
ActivityStatus
QUALITY OF LIFEFOR THE LUNG
CANCER EXPERIENCE
Qualityof Life
Global
QUALITY OF LIFE IN LUNG CANCER
Global
Global symptomatic
lung cancer
DimensionsCaptured: Dimensions
Captured:
OVERALL
•Cognitive•Physical
•Social(Role)
•Cognitive•Psychological
•Spiritual•All others
•Appetite•Fatigue•Cough•Dyspnea•Hemoptysis•Pain
•Social
QUALITY OF LIFE - Questions -
1) Can we DEFINE quality of life?
2) Can we MEASURE quality of life?
3) Can we agree on how to ANALYZE quality of life results?
4) Can we PRESENT quality of life findings in a clear and useful way?
QUALITY OF LIFE INSTRUMENTS
- Instrument Focus -
DISEASE-SPECIFIC:
SITE-SPECIFIC:
TREATMENT-SPECIFIC:
GENERAL HEALTH: All Populations
Cancer Diabetes Arthritis
LymphomaLungCancer
Clinical Trials Post - Op
Clinical TrialsBMT
QUALITY OF LIFE INSTRUMENTS- Lung Cancer Specific -
1. Lung Cancer Symptom Scale (LCSS) - Patient (9 items) & Observer (6 items) Forms
- Developed Specifically for Clinical Trials
2. EORTC - General and Lung Cancer Modules (30-40 items)
- Developed for General Use
3. FACT-L - General and Lung Cancer Modules (30-40 items)
- Developed for General Use
LUNG CANCER SPECIFIC INSTRUMENTS
- Psychometrics (1) -PSYCHOMETRICS CHARACTERISTICS
FEASIBILITY: Short administration time Low reading level required Easily understood Multi-center utility
CONTENT VALIDITY: Oncology expert agreement Patient agreement
RELIABILITY: Items internally consistent Intra / interrater agreement Patient reproducibility
QUALITY OF LIFE INSTRUMENTS
- Good reliability features include: -
• Internal consistency = Cronbach’s alpha > 0.70
for new measures
• Stability = Reliability coefficient > 0.70
• Equivalence = Kappa statistic > 0.61
Ref: Nunnally & Bernstein, 1994; Landis & Koch, 1977
QOL MEASURES FOR LUNG CANCER
- Example: Reliability Coefficients -FACT-L
Total core measure
(alpha, 0.89) for 116 patients
Lung cancer module (alpha 0.68) for 116 patients
LCSS
Total patient scale
(alpha 0.82) for 207 patients
Observer scale (alpha 0.75) for 21 observers
Cronbach’s alpha of 0.70 for new measures
LUNG CANCER SPECIFIC INSTRUMENTS
- Psychometrics (2) -PSYCHOMETRICS CHARACTERISTICS
Based on conceptual model Valid for LC patients with different extents of disease
Compares well to "gold standards"
673 LC patients from two North American cancer trials (30 centers)
CONSTRUCT VALIDITY:
CRITERION-RELATED(CONCURRENT) VALIDITY:
NORMATIVE DATA:
CLINICAL SIGNIFICANCE: KPS and LCSS Observer scales used as anchors
QUALITY OF LIFE INSTRUMENTS - Additional Information -
• Clinically meaningful difference
– Often subject to “risk-benefit” considerations
– Difficult to determine for the survival endpoint too
• Normative data for subgroups
Ref: Mayo Proceedings, 2002
PATIENT RESPONSE OUTCOMEINSTRUMENTS IN LUNG CANCER
TRIALS- Other Questionnaires -
1. Rotterdam Symptom Checklist (RSCL)
2. Hospital Anxiety and Depression scale (HADS) - Often used together in British Medical
Research Council (MRC) studies
Note: These instruments are not lung cancer-specific, and have varying degrees of published psychometric results.
NON-SMALL CELL LUNG CANCER
- Clinical Benefit and Quality of Life –
Assessment in Patients
In Phase II Trials
RANDOMIZED PHASE II TRIAL OF IRESSA AT 2 DOSE LEVELS – “IDEAL 2”
Quality of Life / Clinical Benefit: ASCO 2002 Abstract #1167
• A subscale of the FACT-L instrument was used (the LCS)
• Palliation was noted rapidly when it occurred: generally within 7 to 10 days
• Responding patients had greater symptom relief than those with stable disease or progressive NSCLC– 43% with symptom improvement
– 34% with quality of life improvement
QUALITY OF LIFE EVALUATION IN CLINICAL TRIALS
- Difficulties with Results Analysis: Phase II Trials -
Appropriate Standard Palliation Confounds Analysis:
– Complicates benefit assessment when there is no control group
– Leads to overestimate of benefit with study agent when patients are receiving standard approaches as well
Response and Palliation:
– Likely that major response leads to QoL or Clinical Benefit
– Major response underestimates benefit: Lesser responses may give symptom relief
– Benefit in patients with stable disease may be due to either the study agent or to standard palliation: can lead to overestimation
NON-SMALL CELL LUNG CANCER
- Clinical Benefit and Quality of Life –
Assessment in Patients
In Phase III Trials
PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS
- Problems in Evaluation and Analysis -
1) Lack of investigator commitment
2) Cumbersome instruments
3) Patient deterioration
PROSPECTIVE CLINICAL TRIAL IN NSCLC
- Causes of Patient Attrition -
Causes for attrition
Death
Disease progression
Unknown
Patients entered
Remaining on studyafter 3 cycles
673
97
131
14
431
14%
19%
2%
64%
100%
PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS
- Prospective Emphasis on PRO: A Recent Study -1) A brief training session for all investigative and
data management personnel on the methods and role of HRQOL evaluation
2) Inclusion of baseline QoL data as part of eligibility for randomization
3) Continued emphasis during the trial for vigilance in assessing PRO endpoints
4) As a result, more than 90% of the planned weekly assessments occurred over the initial 6 cycles of the trial, despite the difficult and progressive nature of mesothelioma
NON-SMALL CELL LUNG CANCER- Quality of Life at Baseline: Influence on Survival -
- Prospective Analysis of 673 Patients at 30 Centers -
* p = 0.0001, using the LCSS quality of life instrument
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24
MONTHS
PE
RC
EN
T S
UR
VIV
ING
*
LOWER QL HIGHER QL
QUALITY OF LIFE- Baseline Values for Age and LCSS -
7972
76
60
(p = 0.0001)(p = 0.0002)
Percent of Patients
60 62
Age Average Symptom Burden
QL Item(p = NS)
Patients remaining on study (n=431); attrition group (n=242)
(N = 673 Patients with NSCLC)
0
10
20
30
40
50
60
70
80
90
On StudyAttrition Group
QUALITY OF LIFE IN LUNG CANCER- Evaluation Problems in Advanced Disease
–
• Patient loss or “attrition” in a progressive disease, such as lung cancer
• Patient attrition is not random. Lost first are:
– The most symptomatic at presentation
– Those with the lowest baseline quality of life
– Patients with poorer prognostic factors
SERIAL MEASUREMENT IN CLINCAL TRIALS:
QUALITY OF LIFE EVALUATION IN CLINICAL TRIALS
- Difficulties with Results Analysis: Phase III Trials -
No standard statistical approach is used:– Simply evaluating averages of patient scores at subsequent time points is
problematic:• In Single Arm evaluation: Overestimates QoL and Clinical Benefit
• In Comparison trials: Underestimates QoL differences between study arms IF survival differences also are found
Survival differences complicate QoL analysis– Patient attrition (due to death or progression) is not random
• The most symptomatic patients drop out of the analysis first
• Patients with the poorer prognostic factors drop out first
• Thus, a regimen with poorer survival loses more lower QoL patients earlier and paradoxically - but incorrectly - appears to gain in QoL
Results from all patients on trial need to be Analyzed
PATIENT REPORTED OUTCOMES (“PROs”)- Conclusions -
• Use valid, feasible, reliable and sensitive instruments appropriate for the disease stage which yields consistent results across socioeconomic status, literacy, and culture or language differences in the study population
• Specify clearly defined primary and secondary endpoints
– In that different features of available validated instruments can be found, care in the selection of the instrument is advised
– Attention to prospectively defined analyses, including primary and secondary endpoints, and methods for handling (or more importantly, avoiding) missing data is necessary
PATIENT REPORTED OUTCOMES (“PROs”)- Conclusions -
• Use an appropriate control group for comparison of outcomes
– concomitant interventions affecting these outcomes must be collected and when possible controlled
• Emphasize compliance with protocol specified PRO assessments
– Enrollment of patients, with adequate follow-up, must be considered as mandatory for the study
– This point must be made to individual investigators, and must be clear to patients as part of the consenting process.
• Blinding of interventions when feasible to minimize bias.
QUALITY OF LIFE AND LUNG CANCER- Conclusions -
1) QoL can be defined and accurately measured
2) Analysis problems persist:– Trials generally not powered for QoL endpoints– Survival differences present analysis problems
3) Need to address issues beyond efficacy / toxicity:– Patient and family burden– Administration route
– Continued re-assessment over the course of the cancer
QUALITY OF LIFE AND LUNG CANCER- Conclusions -
4) QoL needs to be evaluated in all clinical care– Not only in clinical trials
– Evaluation needs to be easy for patients and staff
– Instruments need to be straight-forward and easy to analyze
– Electronic technology may simplify the process
5) Patient care decisions should be based on QoL and traditional results
QUALITY OF LIFE INSTRUMENTS
- Step #2: Compare Feasibility -
• Self-reporting style
• Short administration time
• Low reading level
• Patient / staff acceptance
• Multi-site utility
Characteristics of good feasibility include:
QUALITY OF LIFE INSTRUMENTS
- Step #4: Examine Support for Validity -
• Use of multiple procedures• Sequential use of these procedures • Assessment of validity at various stages of development
Results indicating good support for validity include:
Ref: Anastasi, 1988
QUALITY OF LIFE INSTRUMENTS
- Step #4: Support for Validity (Cont.) -
• Question of degree, with no absolute standard for magnitude of coefficient
• Validity coefficient lower than reliability
• Coefficient of .30 to .40 is considered high
Characteristics of good support for validity include:
Ref: Anastasi, 1988
Directions: Please place a mark along the linewhere it would best describe thesymptoms of your lung cancerduring the past day.
6. How much
None As much as it could be
pain do you have?
LCSS: Patient Scale: Example:
LUNG CANCER SYMPTOM SCALE (LCSS):
Directions:
100
75
50
None
Observer Scale: Example:
6. PAIN [Score: ]
Mild;
Moderate;
present but either no medications required oronly non-narcotic, non-codeine type oral agents;
pain control satisfactory or reasonable. codeine or codeine-containing oral medications
needed; pain control satisfactory or reasonable.
25 narcotic oral agents are required; paincontrol satisfactory, or reasonable.
0 narcotic oral medications required but pain controlnot satisfactory or parenteral narcotics are required.
Direct the interview to separate lung cancer symptoms using thetime frame of during the past day (last 24 hours).
Marked;
Severe;
PSYCHOMETRICS
"The Jargon"Can the instrumentbe used efficiently
Does the instrumentconsistentlymeasure the
characteristic of interest?
Does the instrumentmeasure what it issupposed to measure?
FEASIBILITY:
RELIABILITY:
VALIDITY:
?
QUALITY OF LIFE- Baseline Values of Prognostic Factors -
(N = 673 Patients with NSCLC)
(p = 0.001) (p = 0.029)
Percent of Patients
64%
76% 78%85%
Patients remaining on study (n = 431); attrition group (n = 242)
Males Stage IV0
10
20
30
40
50
60
70
80
90
On Study
Attrition Group
NON-SMALL CELL LUNG CANCER- Single Agent Vinorelbine vs Supportive Care -
- In Patients > Age 70: A Prospective Randomized Trial -
Gridelli et al JNCI 1999, p = 0.04
6.2
4.7
0
2
4
6
8
10
12
CHEMOTHERAPY REGIMENME
DIA
N S
UR
VIV
AL
IN M
ON
TH
S:
Vinorelbine Supportive Care
NON-SMALL CELL LUNG CANCER- Single Agent Vinorelbine vs Supportive Care -
- In Patients > Age 70: A Prospective Randomized Trial -
Quality of Life and Clinical Benefit
• QoL Endpoints favored the vinorelbine arm
• Palliation was more frequent with the chemotherapy
• While the analysis was logical, a validated instrument was not used:– Not a true criticism of the study design, since validated
instruments in NSCLC were only beginning to be used at the start of this trial
NON-SMALL CELL LUNG CANCER- SWOG 95-09 Randomized Trial in 410 Patients -
Kelly J Clin Oncol 2001; Survival: 1 YR 36%/38%, 2 YR 15%/16%; Resp Rate: 28%/25%
8 8
0
2
4
6
8
10
12
CHEMOTHERAPY REGIMEN
ME
DIA
N S
UR
VIV
AL
IN M
ON
TH
S:
Vinorelbine + DDP Paclitaxel + Carbo
NON-SMALL CELL LUNG CANCER- SWOG Randomized Trial: Quality of Life -
Kelly J Clin Oncol 2001. (N = 410). Baseline Compared with Week 25 (Using FACT-L)
0
10
20
30
40
50
60
70
80
90
100
Vinorelbine + Cisplatin Paclitaxel + Carboplatin
PE
RC
EN
T O
F P
AT
IEN
TS
:
QL: Impoved QL: Stable
STUDY DESIGN: Tax 326
RANDOMIZE
Stratification factors:
Stage of diseaseIIIB vs IV
Region
US/Canada
Latin America
Europe/LebanonIsrael
South Africa/AustraliaNew Zealand
Docetaxel 75 mg/m2 IV
Carboplatin AUC 6 IV Q 3 wks
Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22Cisplatin 100 mg/m2 IV D 1Q 4 wks
Docetaxel 75 mg/m2 IVCisplatin 75 mg/m2 IV Q 3 wks
vs
NON-SMALL CELL LUNG CANCER- SWOG Randomized Trial in 415 Patients -
Wozniak et al J Clin Oncol 1999; Survival: 1 YR 36%/20% 2 YR 12%/6% p = 0.0018
6
8
0
2
4
6
8
10
12
CHEMOTHERAPY REGIMEN
ME
DIA
N S
UR
VIV
AL
IN M
ON
TH
S:
Cisplatin 100 mg/M2 Vinorelbine + Cisplatin
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21
Survival in Months
Cumulative Probability
Median Survival 7.4 vs 4.6 MonthsLog-Rank P = .047
NSCLC: SECOND-LINE TRIAL (TAX 317)
Survival: Docetaxel vs BSC - Intention to Treat
Docetaxel (75 + 100 mg/M2)
BSC
N = 209; Updated, latest analysis of all patients Reference: Shepherd et al, JCO 2000, 2095-2103
STUDY DESIGN: Tax 326 – First Line
RANDOMIZE
Stratification factors:
Stage of diseaseIIIB vs IV
Region
US/Canada
Latin America
Europe/LebanonIsrael
South Africa/AustraliaNew Zealand
Docetaxel 75 mg/m2 IV
Carboplatin AUC 6 IV Q 3 wks
Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22Cisplatin 100 mg/m2 IV D 1Q 4 wks
Docetaxel 75 mg/m2 IVCisplatin 75 mg/m2 IV Q 3 wks
vs
TAX 326: Survival for DOCETAXEL + CISPLATIN vs. VINORELBINE + CISPLATIN
DOC + CIS
Median (months) 11.310.1
1-year survival (%) 46 41
2-year survival (%) 21 14
V + CIS
P = 0.044
Pro
bab
ilit
y o
f S
urv
ival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Survival Time (months)
0 3 6 9 12 15 18 21 24 27 30 33
TAX 326: Survival for DOCETAXEL + CARBO vs. VINORELBINE + CISPLATIN
Su
rviv
al (
%)
Time (months)
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33
DocetaxelCarboplatin
VinorelbineCisplatin
P = 0.657(adjusted log-rank)
N = 812
NON-SMALL CELL LUNG CANCER - Clinical Benefit and Quality of Life -
• Quality of Life– Multidimensional
– Includes areas not likely to be affected by chemo
• Clinical Benefit
- Subjective or Palliative Control of Common Problems - Previously Defined to Evaluate:
- Pain Control- Weight Loss- Performance Status
LCSS – Global QoL
Weeks0 3 6 9 12 15 18
0
-20
Mea
n C
han
ge f
rom
Bas
elin
e
10
-10
20
P = 0.064 *
Bars represent +/- a unit of standard error.
Better
Worse
D + CIS V + CIS
Baseline score ~ 68
* Longitudinal analysis (logistic regression)
EuroQoL Global Health Status
0 3 6 9 12 15 18
Weeks
10
5
0
-5
-10
Mea
n C
han
ge f
rom
Bas
elin
e
*Bars represent +/- a unit of standard error.
P = 0.016 *
Better
Worse
D + CIS V + CIS
Baseline score ~ 72
* Longitudinal analysis (logistic regression)
LCSS – Patient-Rated Pain Assessment
0 3 6 9 12 15 18
Weeks
10
-10
Mea
n C
han
ge
fro
m B
asel
ine
20
TAX + CIS V + CIS
0
P = 0.033*
* Longitudinal analysisBars represent +/- a unit of standard error.
Better
WorseBaseline score ~ 77
Weight Change (Kg) from Baseline to Last On-Treatment Assessment
Mea
n W
eig
ht
Ch
ang
e (K
g)
fro
m B
asel
ine
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0
0.5
1.0
TAX + CIS V + CIS
-0.29
-2.4
-0.65
-2.6
0.05
-2.2
All Subjects
Subjects with signs of fluid
retention
Subjects with no signs of
fluid retention
P 0.0001 P 0.0001 P 0.001
KARNOFSKY PERFORMANCE STATUS- Difference in Treatment Group Means -
KPS Change from Baseline
Cycle 1
Cycle 2
Cycle 3
Mean Across Cycles 1-3
Last Assessment on Trt
Better forV+CIS
Better forTAX+CIS
-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7
QUALITY OF LIFE- Conclusions from TAX 326 -
• Quality of life (QoL) can be assessed efficiently, during large multinational prospective trials.
• QoL differences can be found among treatment regimens with small but meaningful differences indicated by patients using validated instruments.
• Differences in clinical benefit parameters (pain, performance status, and major weight change) can also be found in areas important to patients and families.
* Reference: Gralla, Rodrigues, Von Pawel et al Proc ASCO 2002
QUALITY OF LIFE MEASUREMENT
- Uses in Lung Cancer -
- Comparison of treatments
CLINICAL TRIALS
- Effectiveness of intervention
- Change over time
PATIENT MONITORING•
- Usefulness of plan
PROGRAM EVALUATION•
•
- Benefit of approach: such as oral regimens
QUALITY OF LIFE EVALUATION IN CLINICAL PRACTICE
- Use in Routine Patient Evaluation -
• Patients who Respond to chemotherapy typically have better survival and improved clinical benefit / Quality of Life
• Is the opposite true?:
Does clinical benefit coupled with QoL benefit predict objective response?
• Sensitivity / Specificity Issues
• Ease of Measurement: Hand-held Computer Technology
QUALITY OF LIFE EVALUATION USE IN CLINICAL PRACTICE
- Other Strategies for Improvement -
• Determine the lowest fully effective dose of agents:
– Or, find the dose at which “diminishing returns” occurs
– Is this the same as the “MTD?”
• Address major patient concerns: – Concerns beyond the effectiveness of chemotherapy
– When survival / response / toxicity results are similar, it is not surprising that QoL differences are not large
NON-SMALL CELL LUNG CANCER- Treatment Approaches -
Less Aggressive in
Advanced Disease
More Aggressive in
Earlier Stages
Trends in
Treatment
WEIGHT LOSS DURING TREATMENTPercent of Patients with Weight Loss > 10%
5%
8%
0%
5%
10%
15%
20%
25%
T75 V/I
TAX317 TAX320
2%
25%
0%
5%
10%
15%
20%
25%
T75 BSC75
p<0.001 p=ns
NSCLC: SECOND-LINE TRIAL (TAX 317B) - Opioid Analgesic Use: Change from Baseline -
p=ns p<0.001 p<0.001
20%
13%
5%
49%
35%
18%
0%
10%
20%
30%
40%
50%
60%
Ongoing atBaseline
Additional Opioid Analgesic
Newly-started Opioid Analgesic
Per
cen
tag
e o
f P
atie
nts
T75BSC75
NSCLC: SECOND-LINE TRIAL (TAX 317B)
- PERFORMANCE STATUS EVALUATION - Change from Baseline: Difference in Treatment Group Means
Performance Status (ECOG)
Cycle 1
Cycle 2
Cycle 3
Mean Across Cycles 1-3
Last Assessment
TAX 317B TAX 320
Better forBSC75
Better forT75
Better forV/I
Better forT75
-1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6
CLINICAL BENEFIT: PATIENTS WITH WEIGHT LOSS >10% DURING TREATMENT (DC vs VC and DCb vs VC)
7 %
15 %
0%
5%
10%
15%
20%
25%
DC DCb
Fisher’s Exact Test, P < 0.001 (for both DC vs VC and DCb vs VC)
7 %
VC
NON-SMALL CELL LUNG CANCER- Primary Endpoints for Determining Study Size -
* First-line Comparison Trials** Survival differences small or unlikely (2nd line, Infirm)
ENDPOINTS STUDY TYPE
SURVIVAL Primary endpoint for most
Large randomized trials*
RESPONSE Primary endpoint for
Phase II exploratory trials
QUALITY OF LIFE Primary endpoint for trials in
special populations**
KARNOFSKY PERFORMANCE STATUS CHANGE DURING TREATMENT
Difference in Treatment Group Means: N = 812
KPS Change from Baseline
Cycle 1
Cycle 2
Cycle 3
Mean Across Cycles 1-3
Last Assessment on Trt
Better forVC
Better forDC
-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7
LCSS BACKGROUND• Practical
– Designed for clinical trials, especially for serial quality of life and symptom measurement
– Administered in 2 to 5 minutes with high patient and staff acceptance
• Patient form: 100 mm visual analogue scale (9 questions)
• Observer form*: 5-point categorical scale (6 questions)
• Well-tested; good psychometric properties for lung cancer (Hollen et al. Cancer 1994.)
• Available in more than 40 languages– Standard methodology involving multiple bilingual translators for
forward - backward translations; then patient pilot-testing
* optional
QUALITY OF LIFE INSTRUMENTS
- Instrument Focus -
DISEASE-SPECIFIC:
SITE-SPECIFIC:
TREATMENT-SPECIFIC:
GENERAL HEALTH: All Populations
Cancer Diabetes Arthritis
BreastCancer
LungCancer
Clinical Trials
Radiation Therapy
Clinical TrialsBMT