Patient Reported Outcomes as Endpoints in Lung Cancer and Thoracic Malignancies

1
Patient Reported Outcomes as Endpoints in Lung
Cancer and Thoracic Malignancies

• Richard J. Gralla, MD
• New York Lung Cancer Alliance
• For the ASCO and FDA Working Group

2
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 Include such
  considerations as
• Pain Control
• Weight Loss
• Performance Status

3
QUALITY OF LIFE AND PRO EVALUATION- Is there
a Need in Studies of Anticancer Treatments? -

• Highly Symptomatic Disease
• Survival and Response data reveal only part of
  the results that are important to patients,
  families, and health care professionals
• Treatments and Agents Vary in their Side-
  Effects and Risk Profiles
• Balancing patient experienced benefit and risk
  is needed
• Meaningful Survival Differences are Uncommon

4
SYMPTOMS OF LUNG CANCER- By Patient Reports
(N 121) -
NON-SMALL CELL
SMALL CELL
(n 69)
(n 52)
84
FATIGUE
79
71
COUGH
62
59
DYSPNEA
56
57
60
ANOREXIA
48
PAIN
54
HEMOPTYSIS
25
14
Ref Hollen et al. (1993). Eur J Cancer,
29A, S51-S58
5
NON-SMALL CELL LUNG CANCER - Number of
Presenting Symptoms at Baseline -
(N 673 Stage III and IV Patients)
80
Three or more
Two
12
One
5
3
None
Percentage
6
NON-SMALL CELL LUNG CANCER- Survival
Supportive Care and Chemotherapy 1991- 2001 (N
10,995 / 9361) -
718 pts
783 pts
509 pts
1103 pts
4648 pts
1600 pts
Refs Proc ASCO 2002 Raftopoulos, Bria, Gralla,
Eid
7
PATIENT REPORTED OUTCOMES (PROs)- Rationale
and Need in Testing Anticancer Agents -

• 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
  diseaseresponse 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

8
QUALITY OF LIFE AND PROs - 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?

9
QUALITY OF LIFE INSTRUMENTS- Dimensions -

• Physical
• Functional
• Psychological
• Social
• Spiritual

10
QUALITY OF LIFE AND PROS IN LUNG CANCER
- Conceptual Model for Clinical Trials THE
LCSS -
PRO Dimensions
OVERALL
FUNCTIONAL
PHYSICAL
QUALITY OF LIFE
DIMENSION
DIMENSION
FOR THE LUNG
CANCER EXPERIENCE
Symptoms
Global
Appetite
Global
Activity
Fatigue
Quality
Cough
Status
of Life
Dyspnea
Hemoptysis
Pain
Dimensions
Symptomatic Distress
Dimensions
Captured
Captured
Physical
Global symptomatic
Cognitive
Cognitive
distress from
Psychological
Social
Social
lung cancer
(Role)
Spiritual
All others
11
QUALITY OF LIFE INSTRUMENTS- Instrument
Focus -
GENERAL HEALTH
All Populations
Diabetes
Cancer
Arthritis
DISEASE-SPECIFIC
LungCancer
Lymphoma
SITE-SPECIFIC
TREATMENT-SPECIFIC
Clinical Trials
Clinical Trials
Post - Op
BMT
12
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

13
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

14
QUALITY OF LIFE INSTRUMENTS- Good reliability
features include -

• Internal consistency Cronbachs alpha gt 0.70
  
• for new measures
• Stability Reliability coefficient gt
  0.70
• Equivalence Kappa statistic gt 0.61

Ref Nunnally Bernstein, 1994 Landis Koch,
1977
15
QOL MEASURES FOR LUNG CANCER - Example
Reliability Coefficients -
FACT-L
LCSS
Total patient scale (alpha 0.82) for 207
patients Observer scale (alpha 0.75) for
21 observers
Total core measure (alpha, 0.89) for 116
patients Lung cancer module (alpha 0.68) for
116 patients

• Cronbachs alpha of 0.70 for new measures

16
LUNG CANCER SPECIFIC INSTRUMENTS-
Psychometrics (2) -
PSYCHOMETRICS
CHARACTERISTICS

• Based on conceptual model
• Valid for LC patients with different extents
  of disease

CONSTRUCT VALIDITY
CRITERION-RELATED(CONCURRENT) VALIDITY

• Compares well to "gold standards"

CLINICAL SIGNIFICANCE

• KPS and LCSS Observer
• scales used as anchors

• 673 LC patients from two North American
  cancer trials (30 centers)

NORMATIVE DATA
17
QUALITY OF LIFE AND PRO EVALUATION -
Additional Information -

• Clinically meaningful difference
• Often subject to risk-benefit considerations
• Not clearly defined for survival or response
  endpoints too
• Normative data for subgroups
• Ref Mayo Proceedings, 2002

18
NON-SMALL CELL LUNG CANCER - Clinical Benefit
and Quality of Life

• Assessment in Patients
• In Phase II Trials

19
RANDOMIZED PHASE II TRIAL OF GEFITINIB AT TWO
DOSE LEVELS IDEAL 2Quality 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

20
QUALITY OF LIFE AND PRO EVALUATION -
Difficulties with Analysis Phase II Trials -

• Analysis Problem as with Surivial Analysis
  relates to the lack of a Control Group for
  Judging Context
• 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
• 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

21
NON-SMALL CELL LUNG CANCER - Clinical Benefit
and Quality of Life

• Assessment in Patients
• In Phase III Trials

22
PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS-
Problems in Evaluation and Analysis -

1. Cumbersome instruments
2. Patient deterioration
3. Lack of investigator commitment

23
PROSPECTIVE CLINICAL TRIAL IN NSCLC- Causes
of Patient Attrition -
100
Patients entered
673
Causes for attrition
Death
97
14
Disease progression
131
19
Unknown
14
2
431
64
Remaining on studyafter 3 cycles
24
QUALITY OF LIFE AND PRO EVALUATION- Baseline
Values for Age and LCSS -
(N 673 Patients with NSCLC)
Percent of Patients
79
76
72
62
60
60
QL Item
Age
Average Symptom Burden
(p 0.0002)
(p NS)
(p 0.0001)
Patients remaining on study (n431) attrition
group (n242)
25
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 PRO 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

Vogelzang et al, J Clin Oncol 2003 Gralla
et al, Proc ASCO 2003.
26
ENDPOINTS AND TREATMENT Relationships and Role of
Patient Reported Outcomes (PROs)
Malignancy
Quality of Life
Survival
Tumor Response Side Effects



Treatment
27
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
28
QUALITY OF LIFE EVALUATION IN CLINICAL TRIALS-
Difficulties with Results Analysis Phase III
Trials -

• Standards for statistical approaches remain
  controversial
• Simply evaluating averages of 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

29
Response and PRO Outcomes in a Random Assignment
Trial Added Value from Patient Determined
Data- Using Pain Scores within Major Response as
an Example -
Improvement
Change from baseline (mm)
Note y-axis error bars represent SE of the means
N92
N41
N77
N37
N87
N94
Worsening
Greater benefit reported by patients in 8 of 8
PRO parameters (p lt0.05), validated LCSS-meso
(Model-based means.)
30
Survival and PRO Outcomes in a Random Assignment
Trial Added Value from Patient Determined
Outcome Data
Week 12 Week 18 Pemcis
Cis Pemcis Cis
Surviving Quality of Life Symptom
Distress
p 0.797
p 0.247
Vogelzang et al, J Clin Oncol 2003 Gralla
et al, Proc ASCO 2003.