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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.

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Presentation on theme: "NON-TRADITIONAL ENDPOINTS IN LUNG CANCER - Patient Reported Outcomes - Richard J. Gralla, MD New York Lung Cancer Alliance New York, New York."— Presentation transcript:

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

2 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

3 NON-SMALL CELL LUNG CANCER - Quality of Life at Baseline: Influence on Survival - - Prospective Analysis of 673 Patients at 30 Centers - * p = , using the LCSS quality of life instrument MONTHS PERCENT SURVIVING* LOWER QLHIGHER QL

4 NON-SMALL CELL LUNG CANCER - Survival: Supportive Care and Chemotherapy (N = 10,995 / 9361) 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) - 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

7 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%

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 - 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

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 - DISEASE-SPECIFIC: SITE-SPECIFIC: TREATMENT-SPECIFIC: GENERAL HEALTH: All Populations Cancer Diabetes Arthritis Lymphoma Lung Cancer Clinical Trials Post - Op Clinical Trials 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) - PSYCHOMETRICSCHARACTERISTICS 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 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

17 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

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 OUTCOME INSTRUMENTS 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.

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 - 1) Lack of investigator commitment 2) Cumbersome instruments 3) Patient deterioration

25 PROSPECTIVE CLINICAL TRIAL IN NSCLC - Causes of Patient Attrition - Causes for attrition Death Disease progression Unknown Patients entered Remaining on study after 3 cycles % 19% 2% 64% 100%

26 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

27 NON-SMALL CELL LUNG CANCER - Quality of Life at Baseline: Influence on Survival - - Prospective Analysis of 673 Patients at 30 Centers - * p = , using the LCSS quality of life instrument MONTHS PERCENT SURVIVING* LOWER QLHIGHER QL

28 QUALITY OF LIFE - Baseline Values for Age and LCSS (p = ) (p = ) Percent of Patients Age Average Symptom Burden QL Item (p = NS) Patients remaining on study (n=431); attrition group (n=242) (N = 673 Patients with NSCLC) On Study Attrition Group

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.

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34 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

35 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

36 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:

37 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

38 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

39 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:

40 LUNG CANCER SYMPTOM SCALE (LCSS): Directions: 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;

41 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: ?

42 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 On Study Attrition Group

43 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 = CHEMOTHERAPY REGIMEN MEDIAN SURVIVAL IN MONTHS: VinorelbineSupportive Care

44 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

45 NON-SMALL CELL LUNG CANCER - SWOG Randomized Trial in 410 Patients - Kelly J Clin Oncol 2001; Survival: 1 YR 36%/38%, 2 YR 15%/16%; Resp Rate: 28%/25% CHEMOTHERAPY REGIMEN MEDIAN SURVIVAL IN MONTHS: Vinorelbine + DDPPaclitaxel + Carbo

46 NON-SMALL CELL LUNG CANCER - SWOG Randomized Trial: Quality of Life - Kelly J Clin Oncol (N = 410). Baseline Compared with Week 25 (Using FACT-L) Vinorelbine + CisplatinPaclitaxel + Carboplatin PERCENT OF PATIENTS: QL: ImpovedQL: Stable

47 STUDY DESIGN: Tax 326 RANDOMIZERANDOMIZE Stratification factors: Stage of disease IIIB vs IV Region US/Canada Latin America Europe/Lebanon Israel South Africa/Australia New Zealand Docetaxel 75 mg/m 2 IV Carboplatin AUC 6 IV Q 3 wks Vinorelbine 25 mg/m 2 IV D 1, 8, 15 & 22 Cisplatin 100 mg/m 2 IV D 1Q 4 wks Docetaxel 75 mg/m 2 IV Cisplatin 75 mg/m 2 IV Q 3 wks vs

48 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 = CHEMOTHERAPY REGIMEN MEDIAN SURVIVAL IN MONTHS: Cisplatin 100 mg/M2Vinorelbine + Cisplatin

49 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 ( mg/M 2 ) BSC N = 209; Updated, latest analysis of all patients Reference: Shepherd et al, JCO 2000,

50 STUDY DESIGN: Tax 326 – First Line RANDOMIZERANDOMIZE Stratification factors: Stage of disease IIIB vs IV Region US/Canada Latin America Europe/Lebanon Israel South Africa/Australia New Zealand Docetaxel 75 mg/m 2 IV Carboplatin AUC 6 IV Q 3 wks Vinorelbine 25 mg/m 2 IV D 1, 8, 15 & 22 Cisplatin 100 mg/m 2 IV D 1Q 4 wks Docetaxel 75 mg/m 2 IV Cisplatin 75 mg/m 2 IV Q 3 wks vs

51 TAX 326: Survival for DOCETAXEL + CISPLATIN vs. VINORELBINE + CISPLATIN DOC + CIS Median (months) year survival (%) year survival (%)2114 V + CIS P = Probability of Survival Survival Time (months)

52 TAX 326: Survival for DOCETAXEL + CARBO vs. VINORELBINE + CISPLATIN Survival (%) Time (months) Docetaxel Carboplatin Vinorelbine Cisplatin P = (adjusted log-rank) N = 812

53 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

54 LCSS – Global QoL Weeks Mean Change from Baseline P = * Bars represent +/- a unit of standard error. Better Worse D + CISV + CIS Baseline score ~ 68 * Longitudinal analysis (logistic regression)

55 EuroQoL Global Health Status Weeks Mean Change from Baseline *Bars represent +/- a unit of standard error. P = * Better Worse D + CISV + CIS Baseline score ~ 72 * Longitudinal analysis (logistic regression)

56 LCSS – Patient-Rated Pain Assessment Weeks Mean Change from Baseline 20 TAX + CISV + CIS 0 P = 0.033* * Longitudinal analysis Bars represent +/- a unit of standard error. Better Worse Baseline score ~ 77

57 Weight Change (Kg) from Baseline to Last On-Treatment Assessment Mean Weight Change (Kg) from Baseline TAX + CIS V + CIS All Subjects Subjects with signs of fluid retention Subjects with no signs of fluid retention P  P  0.001

58 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

59 QUALITY OF LIFE - Conclusions from TAX 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

60 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

61 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

62 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

63 NON-SMALL CELL LUNG CANCER - Treatment Approaches - Less Aggressive in Advanced Disease More Aggressive in Earlier Stages Trends in Treatment

64 WEIGHT LOSS DURING TREATMENT Percent of Patients with Weight Loss > 10% 5% 8% 0% 5% 10% 15% 20% 25% T75V/I TAX317TAX320 2% 25% 0% 5% 10% 15% 20% 25% T75BSC75 p<0.001p=ns

65 NSCLC: SECOND-LINE TRIAL (TAX 317B) - Opioid Analgesic Use: Change from Baseline - p=nsp< % 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

66 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 317BTAX 320 Better for BSC75 Better for T75 Better for V/I Better for T

67 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 < (for both DC vs VC and DCb vs VC) 7 % VC

68 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 SURVIVALPrimary endpoint for most Large randomized trials* RESPONSEPrimary endpoint for Phase II exploratory trials QUALITY OF LIFEPrimary endpoint for trials in special populations**

69 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

70 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

71 QUALITY OF LIFE INSTRUMENTS - Instrument Focus - DISEASE-SPECIFIC: SITE-SPECIFIC: TREATMENT-SPECIFIC: GENERAL HEALTH: All Populations Cancer Diabetes Arthritis Breast Cancer Lung Cancer Clinical Trials Radiation Therapy Clinical Trials BMT


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