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NON-TRADITIONAL ENDPOINTS IN LUNG CANCER - Patient Reported Outcomes -

NON-TRADITIONAL ENDPOINTS IN LUNG CANCER - Patient Reported Outcomes -. Richard J. Gralla, MD New York Lung Cancer Alliance New York, New York. TRIALS. MANAGEMENT. SURVIVAL. Appropriate if Survival Difference is likely. Not relevant for individual patients. RESPONSE.

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NON-TRADITIONAL ENDPOINTS IN LUNG CANCER - Patient Reported Outcomes -

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  1. NON-TRADITIONAL ENDPOINTS IN LUNG CANCER- Patient Reported Outcomes - Richard J. Gralla, MD New York Lung Cancer Alliance New York, New York

  2. TRIALS MANAGEMENT SURVIVAL Appropriate if Survival Difference is likely Not relevant for individual patients RESPONSE Considered to be Unreliable The most commonly used parameter QoL Appropriate if Survival Differences Unlikely Should become the most used parameter ENDPOINTS IN DECISION-MAKING- Clinical Trials and Patient Management -

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. QUALITY OF LIFE INSTRUMENTS- Dimensions - Physical Functional Psychological Social Spiritual

  10. QUALITY OF LIFE IN LUNG CANCER - Conceptual Model for Clinical Trials: THE “LCSS” - OVERALL PHYSICAL FUNCTIONAL 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 - 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?

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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:

  18. 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

  19. PATIENT RESPONSE OUTCOMEINSTRUMENTS 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.

  20. NON-SMALL CELL LUNG CANCER- Clinical Benefit and Quality of Life – Assessment in Patients In Phase II Trials

  21. 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

  22. 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

  23. NON-SMALL CELL LUNG CANCER- Clinical Benefit and Quality of Life – Assessment in Patients In Phase III Trials

  24. PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS- Problems in Evaluation and Analysis - • Lack of investigator commitment • Cumbersome instruments • Patient deterioration

  25. 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

  26. 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

  27. 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

  28. 90 80 70 60 50 On Study Attrition Group 40 30 20 10 0 QUALITY OF LIFE- 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)

  29. 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:

  30. 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

  31. 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

  32. 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.

  33. 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

  34. 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

  35. 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:

  36. 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

  37. 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

  38. LCSS: Patient Scale: Example: Please place a mark along the linewhere it would best describe thesymptoms of your lung cancerduring the past day. Directions: 6. How much pain do you have? As much as it could be None

  39. LUNG CANCER SYMPTOM SCALE (LCSS): Observer Scale: Example: Directions: Direct the interview to separate lung cancer symptoms using thetime frame of during the past day (last 24 hours). 6. PAIN [Score: ] None 100 75 Mild; present but either no medications required or only non-narcotic, non-codeine type oral agents; pain control satisfactory or reasonable. 50 Moderate; codeine or codeine-containing oral medications needed; pain control satisfactory or reasonable. 25 Marked; narcotic oral agents are required; pain control satisfactory, or reasonable. 0 Severe; narcotic oral medications required but pain control not satisfactory or parenteral narcotics are required.

  40. FEASIBILITY: RELIABILITY: VALIDITY: PSYCHOMETRICS"The Jargon" Can the instrumentbe used ? efficiently Does the instrument consistently measure the characteristic of interest? Does the instrumentmeasure what it is supposed to measure?

  41. 90 80 70 60 50 On Study Attrition Group 40 30 20 10 0 QUALITY OF LIFE- Baseline Values of Prognostic Factors - (N = 673 Patients with NSCLC) Percent of Patients 85% 76% 78% 64% Males Stage IV (p = 0.001) (p = 0.029) Patients remaining on study (n = 431); attrition group (n = 242)

  42. 12 10 8 6.2 MEDIAN SURVIVAL IN MONTHS: 6 4.7 4 2 0 CHEMOTHERAPY REGIMEN Vinorelbine Supportive Care 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

  43. 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

  44. 12 10 8 8 8 MEDIAN SURVIVAL IN MONTHS: 6 4 2 0 CHEMOTHERAPY REGIMEN Vinorelbine + DDP Paclitaxel + Carbo 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%

  45. 100 90 80 70 60 PERCENT OF PATIENTS: 50 40 30 20 10 0 Vinorelbine + Cisplatin Paclitaxel + Carboplatin QL: Impoved QL: Stable 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)

  46. STUDY DESIGN: Tax 326 Stratification factors: Stage of disease IIIB vs IV RegionUS/Canada Latin America Europe/Lebanon Israel South Africa/AustraliaNew Zealand RANDOMIZE Docetaxel 75 mg/m2 IVCisplatin 75 mg/m2 IVQ 3 wks Docetaxel 75 mg/m2 IVCarboplatin AUC 6IVQ 3 wks vs Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22Cisplatin 100 mg/m2 IVD 1Q 4 wks

  47. 12 10 8 8 6 MEDIAN SURVIVAL IN MONTHS: 6 4 2 0 CHEMOTHERAPY REGIMEN Cisplatin 100 mg/M2 Vinorelbine + Cisplatin 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

  48. NSCLC: SECOND-LINE TRIAL (TAX 317)Survival: Docetaxel vs BSC - Intention to Treat Docetaxel (75 + 100 mg/M2) BSC Median Survival 7.4 vs 4.6 Months Log-Rank P = .047 N = 209; Updated, latest analysis of all patients Reference: Shepherd et al, JCO 2000, 2095-2103

  49. STUDY DESIGN: Tax 326 – First Line Stratification factors: Stage of disease IIIB vs IV RegionUS/Canada Latin America Europe/Lebanon Israel South Africa/AustraliaNew Zealand RANDOMIZE Docetaxel 75 mg/m2 IVCisplatin 75 mg/m2 IVQ 3 wks Docetaxel 75 mg/m2 IVCarboplatin AUC 6IVQ 3 wks vs Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22Cisplatin 100 mg/m2 IVD 1Q 4 wks

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