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Treatments and Agents Vary in their Side- Effects and Risk Profiles ... benefits associated with anti-cancer treatments, when compared with patient self-reports ...

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patient reported outcomes as endpoints in lung cancer and thoracic malignancies
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

patient reported outcomes pros clinical benefit and quality of life
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
quality of life and pro evaluation is there a need in studies of anticancer treatments
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
symptoms of lung cancer by patient reports n 121
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

non small cell lung cancer number of presenting symptoms at baseline

0

20

40

60

80

100

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

slide6

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

patient reported outcomes pros rationale and need in testing anticancer agents
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 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

quality of life and pro s questions
QUALITY OF LIFE AND PRO’s - 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 dimensions
QUALITY OF LIFE INSTRUMENTS- Dimensions -

Physical

Functional

Psychological

Social

Spiritual

slide10

QUALITY OF LIFE AND PRO’S 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

quality of life instruments instrument focus
QUALITY OF LIFE INSTRUMENTS- Instrument Focus -

GENERAL HEALTH:

All Populations

Diabetes

Arthritis

Cancer

DISEASE-SPECIFIC:

LungCancer

Lymphoma

SITE-SPECIFIC:

TREATMENT-SPECIFIC:

Clinical Trials

Clinical Trials

Post - Op

BMT

quality of life instruments lung cancer specific
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
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
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
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

  • Cronbach’s alpha of 0.70 for new measures
lung cancer specific instruments psychometrics 2
LUNG CANCER SPECIFIC INSTRUMENTS- Psychometrics (2) -

PSYCHOMETRICS

CHARACTERISTICS

CONSTRUCT VALIDITY:

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

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:

quality of life and pro evaluation additional information
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

non small cell lung cancer clinical benefit and quality of life

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

Assessment in Patients

In Phase II Trials

slide19
RANDOMIZED PHASE II TRIAL OF GEFITINIB AT TWO 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 and pro evaluation difficulties with analysis phase ii trials
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
non small cell lung cancer clinical benefit and quality of life21

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
PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS- Problems in Evaluation and Analysis -
  • Cumbersome instruments
  • Patient deterioration
  • Lack of investigator commitment
prospective clinical trial in nsclc causes of patient attrition
PROSPECTIVE CLINICAL TRIAL IN NSCLC- Causes of Patient Attrition -

100%

673

Patients entered

Causes for attrition

Death

97

14%

Disease progression

131

19%

Unknown

14

2%

431

64%

Remaining on studyafter 3 cycles

quality of life and pro evaluation baseline values for age and lcss

90

80

70

60

50

On Study

Attrition Group

40

30

20

10

0

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 = NS)

(p = 0.0002)

(p = 0.0001)

Patients remaining on study (n=431); attrition group (n=242)

patient reported outcomes in clinical trials prospective emphasis on pro a recent study
PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS- Prospective Emphasis on PRO: A Recent Study *-
  • A brief training session for all investigative and data management personnel on the methods and role of PRO evaluation
  • Inclusion of baseline QoL data as part of eligibility for randomization
  • Continued emphasis during the trial for vigilance in assessing PRO endpoints
  • 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.

slide26

ENDPOINTS AND TREATMENT

Relationships and Role of Patient Reported Outcomes (“PROs”)

Malignancy

Survival

Quality of Life

Tumor

Response &

Side Effects

Treatment

slide27

100

80

60

PERCENT SURVIVING*

40

20

0

0

2

4

6

8

10

12

14

16

18

20

22

24

MONTHS

LOWER QL

HIGHER QL

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

quality of life evaluation in clinical trials difficulties with results analysis phase iii trials
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
slide29

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

N=92

N=41

N=77

N=37

N=87

N=94

Worsening

* Greater benefit reported by patients in 8 of 8 PRO parameters (p <0.05), validated LCSS-meso

(Model-based means.)

slide30

92%

86%

92%

82%

AUC

47%

43%

45%

38%

p = 0.167

p = 0.012

AUC

53%

50%

51%

44%

p = 0.162

p = 0.009

Survival and PRO Outcomes in a Random Assignment Trial: Added Value from Patient Determined Outcome Data

Week 12 Week 18

Pem+cis Cis Pem+cis 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.