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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 - 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 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 - 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 ANOREXIA PAIN HEMOPTYSIS 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%
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” - PHYSICAL DIMENSION Symptoms Symptomatic Distress distress from FUNCTIONAL DIMENSION Activity Status QUALITY OF LIFE FOR THE LUNG CANCER EXPERIENCE Quality of Life Global QUALITY OF LIFE IN LUNG CANCER Global Global symptomatic lung cancer Dimensions Captured: 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 Lymphoma Lung Cancer Clinical Trials Post - Op Clinical Trials BMT 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 OUTCOME INSTRUMENTS IN LUNG CANCER TRIALS - Other Questionnaires - Rotterdam Symptom Checklist (RSCL)
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 - Lack of investigator commitment
Cumbersome instruments
Patient deterioration PROSPECTIVE CLINICAL TRIAL IN NSCLC - Causes of Patient Attrition - Causes for attrition Death Disease progression Unknown Patients entered Remaining on study after 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 - A brief training session for all investigative and data management personnel on the methods and role of HRQOL 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, 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 QUALITY OF LIFE - Baseline Values for Age and LCSS - 79 72 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) 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 - QoL can be defined and accurately measured
Analysis problems persist:
Trials generally not powered for QoL endpoints
Survival differences present analysis problems
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 - 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
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 line where it would best describe the symptoms of your lung cancer during 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 or only 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; pain control satisfactory, or reasonable. 0 narcotic oral medications required but pain control not satisfactory or parenteral narcotics are required. Direct the interview to separate lung cancer symptoms using the time frame of during the past day (last 24 hours). Marked; Severe; PSYCHOMETRICS "The Jargon" Can the instrument be used efficiently Does the instrument consistently measure the characteristic of interest? Does the instrument measure what it is supposed 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 IV 0 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 REGIMEN MEDIAN SURVIVAL IN MONTHS: 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 MEDIAN SURVIVAL IN MONTHS: 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 PERCENT OF PATIENTS: QL: Impoved QL: Stable STUDY DESIGN: Tax 326 R A N D O M I Z E Stratification factors:
Stage of disease
IIIB vs IV
Region US/Canada
Latin America
Europe/Lebanon
Israel
South Africa/Australia New Zealand Docetaxel 75 mg/m2 IV Carboplatin AUC 6 IV Q 3 wks Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22 Cisplatin 100 mg/m2 IV D 1Q 4 wks Docetaxel 75 mg/m2 IV Cisplatin 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 MEDIAN SURVIVAL IN MONTHS: Cisplatin 100 mg/M2 Vinorelbine + Cisplatin Median Survival 7.4 vs 4.6 Months
Log-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 R A N D O M I Z E Stratification factors:
Stage of disease
IIIB vs IV
Region US/Canada
Latin America
Europe/Lebanon
Israel
South Africa/Australia New Zealand Docetaxel 75 mg/m2 IV Carboplatin AUC 6 IV Q 3 wks Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22 Cisplatin 100 mg/m2 IV D 1Q 4 wks Docetaxel 75 mg/m2 IV Cisplatin 75 mg/m2 IV Q 3 wks vs TAX 326: Survival for DOCETAXEL + CISPLATIN vs. VINORELBINE + CISPLATIN DOC + CIS Median (months) 11.3 10.1
1-year survival (%) 46 41
2-year survival (%) 21 14 V + CIS P = 0.044 Probability of Survival 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 Survival (%) 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 Docetaxel Carboplatin Vinorelbine
Cisplatin 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 Weeks 0 3 6 9 12 15 18 0 -20 Mean Change from Baseline 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 Mean Change from Baseline *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 Mean Change from Baseline 20 TAX + CIS V + CIS 0 P = 0.033* * Longitudinal analysis
Bars represent +/- a unit of standard error. Better Worse Baseline score ~ 77 Weight Change (Kg) from Baseline to Last On-Treatment Assessment Mean Weight Change (Kg) from Baseline -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 for V+CIS Better for TAX+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 - WEIGHT LOSS DURING TREATMENT Percent of Patients with Weight Loss > 10% 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 at
Baseline Additional Opioid Analgesic Newly-started Opioid Analgesic Percentage of Patients T75 BSC75 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 for BSC75 Better for T75 Better for V/I Better for T75 -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 for VC Better for DC -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
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