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

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Presentation on theme: "NON-TRADITIONAL ENDPOINTS IN LUNG CANCER - Patient Reported Outcomes -"— Presentation transcript:

1 NON-TRADITIONAL ENDPOINTS IN LUNG CANCER - Patient Reported Outcomes -
Calif / epidem Pg 1 History of regimen comparison with cav Tox Meta with DDP New agent list 3 drugs better than 2? Incl rand Replace agents: Carbo ** - Equivalency vs >…granis examples Nsc examples: Gatz / (next) 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 MANAGEMENT TRIALS

3 NON-SMALL CELL LUNG CANCER - Quality of Life at Baseline: Influence on Survival - - Prospective Analysis of 673 Patients at 30 Centers - 20 40 60 80 100 2 4 6 8 10 12 14 16 18 22 24 MONTHS PERCENT SURVIVING* LOWER QL HIGHER QL * p = , using the LCSS quality of life instrument

4 NON-SMALL CELL LUNG CANCER - Survival: Supportive Care and Chemotherapy 1991- 2001
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) FATIGUE 84% 79% COUGH 71% 62% DYSPNEA 59% 56% ANOREXIA 57% 60% PAIN 48% 54% HEMOPTYSIS 25% 14% Ref: Hollen et al. (1993). Eur J Cancer, 29A, S51-S58

7 (N = 673 Stage III and IV Patients)
NON-SMALL CELL LUNG CANCER - Number of Presenting Symptoms at Baseline - (N = 673 Stage III and IV Patients) 20 40 60 80 100 Three or more 80% Two 12% One 5% 3% None Percentage

8 PATIENT REPORTED OUTCOMES (“PROs”) - Clinical Benefit and 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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

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” - PHYSICAL OVERALL FUNCTIONAL DIMENSION DIMENSION QUALITY OF LIFE FOR THE LUNG CANCER EXPERIENCE Symptoms Global •Appetite Global •Fatigue Activity Quality •Cough Status of Life •Dyspnea •Hemoptysis •Pain Dimensions Symptomatic Distress Dimensions Captured: Captured: •Physical Global symptomatic •Cognitive •Cognitive distress from •Psychological •Social lung cancer •Social (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 Cancer Diabetes DISEASE-SPECIFIC: Arthritis Lung Cancer SITE-SPECIFIC: Lymphoma TREATMENT-SPECIFIC: Clinical Trials Clinical Trials BMT Post - Op

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)

14 LUNG CANCER SPECIFIC INSTRUMENTS - Psychometrics (1) -
CHARACTERISTICS FEASIBILITY: Short administration time Low reading level required Easily understood Multi-center utility CONTENT VALIDITY: Oncology expert agreement Here you can see that making a list or chart of the psychometric properties as well as the presence of clinical significance and norms is important when choosing a QL measure. Many developers have done this for you to help you in your decision making. 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 The third step in comparing measures is to evaluate reliability. There are three common forms of reliability: internal consistency (which is an indicator of how the items relate to each other; most developers use Cronbach's alpha) stability (which estimates reproducibility, using the test-retest method with a short timeframe to assess the state of symptoms); and equivalence (one generally sees: - interrater reliability - when rater judgment is being used between or among two or more raters; - or intrarater reliability, which compares the rater to self at one or more times and is needed for longitudinal studies; - Last is parallel forms which is generally not used for quality of life measures. Most use Nunnally and Bernstein's 1994 guideline of a coefficient of 0.70 or greater as an acceptable reliability coefficient for new instruments. Benchmarks for interrater agreement use the Kappa statistic of .61 or greater as representing substantial agreement. 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 As examples of reliability coefficients, the initial reporting of reliability for the FACIT-L and LCSS met Nunnally’s and Bernstein’s for new measures. Nunnally first published his guidelines in his book Psychometric Theory back in the 70s, and these have not change over time and are universally used. When possible, it is important to obtain alpha coefficients for subsequent testing to see if they also meet the higher suggested standard of 0.80 for established measures. Cronbach’s alpha of 0.70 for new measures

17 LUNG CANCER SPECIFIC INSTRUMENTS - Psychometrics (2) -
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" If the reliability and validity properties are acceptable for several measures, then one generally goes back to the key features and feasibility in relation to the chosen population and purpose of assessment. Using the progressive disease of lung cancer as an example, patient burden is critical for trials with serial measurement. Thus, the format of the measure may be the deciding factor. There is no gold standard for QL measures, and that is as it should be. CLINICAL SIGNIFICANCE: KPS and LCSS Observer scales used as anchors NORMATIVE DATA: 673 LC patients from two North American cancer trials (30 centers)

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 In addition to feasibility, reliability, and validity testing, determining the clinical significance of a measure is the responsibility of the developers. Knowing what difference is clinically meaningful for the scale helps with trial planning and interpreting outcomes. Published norms provide comparability for an individual or small group through a defined reference group.

19 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.

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

21 A subscale of the FACT-L instrument was used (the LCS)
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 In both the TAX 317 and the TAX 320 trials, important clinical benefit and quality of life advantages were found for the patients randomly assigned to the Taxotere arms. Patients receiving Taxotere used fewer pain medications and achieved better pain control, experienced less weight loss, and had better performance status, than patients on the comparison arms. In several instances these quality of life and clinical benefit improvements were statistically significant, even though these trials were powered to examine survival rather than quality of life differences. This was particularly notable when contrasted to the results of the patients assigned to best supportive care in the TAX 317 study. While potential difficulties of chemotherapy could produce detrimental effects on overall quality of life, there was no evidence of this, using both the LCSS and the EORTC quality of life instruments. The results were consistent with all three analysis methods that were used. Whichever term is used: Quality of life, clinical benefit, or palliation - benefit was consistently associated with taxotere treatment, in both trials and with all evaluation instruments.

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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

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

24 Lack of investigator commitment Cumbersome instruments
PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS - Problems in Evaluation and Analysis - Lack of investigator commitment Cumbersome instruments Patient deterioration Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

25 PROSPECTIVE CLINICAL TRIAL IN NSCLC - Causes of Patient Attrition -
Patients entered 673 100% Causes for attrition Death 97 14% Disease progression 131 19% Unknown 14 2% Remaining on study after 3 cycles 431 64%

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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

27 NON-SMALL CELL LUNG CANCER - Quality of Life at Baseline: Influence on Survival - - Prospective Analysis of 673 Patients at 30 Centers - 20 40 60 80 100 2 4 6 8 10 12 14 16 18 22 24 MONTHS PERCENT SURVIVING* LOWER QL HIGHER QL * p = , using the LCSS quality of life instrument

28 QUALITY OF LIFE - Baseline Values for Age and LCSS -
(N = 673 Patients with NSCLC) Percent of Patients 10 20 30 40 50 60 70 80 90 On Study Attrition Group 79 76 72 62 60 60 Age Average Symptom Burden QL Item (p = NS) (p = ) (p = ) Patients remaining on study (n=431); attrition group (n=242)

29 QUALITY OF LIFE IN LUNG CANCER - Evaluation Problems in Advanced Disease –
SERIAL MEASUREMENT IN CLINCAL TRIALS: 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

30 No standard statistical approach is used:
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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

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. Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

33

34 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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

35 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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

36 QUALITY OF LIFE INSTRUMENTS - Step #2: Compare Feasibility -
Characteristics of good feasibility include: Self-reporting style Short administration time Low reading level Patient / staff acceptance Multi-site utility Step #2 when choosing a measure is to compare the feasibility of the measures of interest. Good feasibility, is a term used to sum up how easy it is to use. This means that one should look for: - a self-reporting style for accurate assessment - a short administration time, especially if the patient has a progressive disease or is elderly - a low reported readability index suitable for clinic patients - reported patient and staff acceptance - and, reported multi-site use, if a clinical trial is being planned

37 QUALITY OF LIFE INSTRUMENTS - Step #4: Examine Support for Validity -
Results indicating good support for validity include: Use of multiple procedures Sequential use of these procedures Assessment of validity at various stages of development The last step in comparing measures is to examine support for validity. Although not everyone agrees, one generally see textbooks describing three basic types of validity: Content validity – which is validation of content usually by a patient panel and a panel of experts. Construct validity – which addresses how well the measure captures the construct or theoretical conceptualization. Criterion-related validity – which is used when one compares the new instrument to some a gold standard; thus, the new measure must be justifiably better in some way (e.g., more specific, shorter, etc.). These are all outlined in the abstract. The important point to remember for validity is that it is best when - multiple procedures have been used, - which are usually obtained in a certain sequential order, and - obtained at various stages during instrument development. Ref: Anastasi, 1988

38 QUALITY OF LIFE INSTRUMENTS - Step #4: Support for Validity (Cont.) -
Characteristics of good support for validity include: Question of degree, with no absolute standard for magnitude of coefficient Validity coefficient lower than reliability Coefficient of .30 to .40 is considered high According to Anastasi, good support for validity should take into consideration the magnitude of the validity coefficient, but there is no absolute standard. One expects validity coefficients to be lower than those for reliability because reliability is like correlation with itself; however, validity is correlation with an external criterion that may not measure the construct in the same way. Thus, validity coefficients of 0.30 to 0.40 are usually considered high and one rarely sees one greater than 0.60. Ref: Anastasi, 1988

39 LCSS: Patient Scale: Example:
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 pain do you have? None As much as it could be

40 LUNG CANCER SYMPTOM SCALE (LCSS):
Observer Scale: Example: Directions: Direct the interview to separate lung cancer symptoms using the time frame of during the past day (last 24 hours). 6. PAIN [Score: ] 100 None 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. Severe; narcotic oral medications required but pain control not satisfactory or parenteral narcotics are required.

41 PSYCHOMETRICS "The Jargon"
FEASIBILITY: RELIABILITY: VALIDITY: 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?

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

43 NON-SMALL CELL LUNG CANCER - Single Agent Vinorelbine vs Supportive Care - - In Patients > Age 70: A Prospective Randomized Trial - 6.2 4.7 2 4 6 8 10 12 CHEMOTHERAPY REGIMEN MEDIAN SURVIVAL IN MONTHS: Vinorelbine Supportive Care Gridelli et al JNCI 1999, p = 0.04

44 Quality of Life and Clinical Benefit
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 In both the TAX 317 and the TAX 320 trials, important clinical benefit and quality of life advantages were found for the patients randomly assigned to the Taxotere arms. Patients receiving Taxotere used fewer pain medications and achieved better pain control, experienced less weight loss, and had better performance status, than patients on the comparison arms. In several instances these quality of life and clinical benefit improvements were statistically significant, even though these trials were powered to examine survival rather than quality of life differences. This was particularly notable when contrasted to the results of the patients assigned to best supportive care in the TAX 317 study. While potential difficulties of chemotherapy could produce detrimental effects on overall quality of life, there was no evidence of this, using both the LCSS and the EORTC quality of life instruments. The results were consistent with all three analysis methods that were used. Whichever term is used: Quality of life, clinical benefit, or palliation - benefit was consistently associated with taxotere treatment, in both trials and with all evaluation instruments.

45 NON-SMALL CELL LUNG CANCER - SWOG 95-09 Randomized Trial in 410 Patients -
8 2 4 6 10 12 CHEMOTHERAPY REGIMEN MEDIAN SURVIVAL IN MONTHS: Vinorelbine + DDP Paclitaxel + Carbo Kelly J Clin Oncol 2001; Survival: 1 YR 36%/38%, 2 YR 15%/16%; Resp Rate: 28%/25%

46 NON-SMALL CELL LUNG CANCER - SWOG Randomized Trial: Quality of Life -
10 20 30 40 50 60 70 80 90 100 Vinorelbine + Cisplatin Paclitaxel + Carboplatin PERCENT OF PATIENTS: QL: Impoved QL: Stable Kelly J Clin Oncol (N = 410). Baseline Compared with Week 25 (Using FACT-L)

47 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 R A N D O M I Z E Docetaxel 75 mg/m2 IV Cisplatin 75 mg/m2 IV Q 3 wks Docetaxel 75 mg/m2 IV Carboplatin AUC 6 IV Q 3 wks Eligible pts were stratified by stage of diseae (i.e. IIIb or IV) and Region, and then randomized to 1 of 3 treatment groups: doctaxel 75 mg/m2 + cisplatin 75 mg/m2 Q 3 wks docetaxel 75 mg/m2 + carboplatin AUC 6 Q 3 wks or a control regimen of vinorelbine 25 mg/m2 weekly + cisplatin 100 mg/m2 Q 4 wks vs Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22 Cisplatin 100 mg/m2 IV D 1Q 4 wks

48 NON-SMALL CELL LUNG CANCER - SWOG Randomized Trial in 415 Patients -
6 8 2 4 10 12 CHEMOTHERAPY REGIMEN MEDIAN SURVIVAL IN MONTHS: Cisplatin 100 mg/M2 Vinorelbine + Cisplatin Wozniak et al J Clin Oncol 1999; Survival: 1 YR 36%/20% 2 YR 12%/6% p =

49 Reference: Shepherd et al, JCO 2000, 2095-2103
NSCLC: SECOND-LINE TRIAL (TAX 317) Survival: Docetaxel vs BSC - Intention to Treat Docetaxel ( 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, 16

50 STUDY DESIGN: Tax 326 – First Line
Stratification factors: Stage of disease IIIB vs IV Region US/Canada Latin America Europe/Lebanon Israel South Africa/Australia New Zealand R A N D O M I Z E Docetaxel 75 mg/m2 IV Cisplatin 75 mg/m2 IV Q 3 wks Docetaxel 75 mg/m2 IV Carboplatin AUC 6 IV Q 3 wks Eligible pts were stratified by stage of diseae (i.e. IIIb or IV) and Region, and then randomized to 1 of 3 treatment groups: doctaxel 75 mg/m2 + cisplatin 75 mg/m2 Q 3 wks docetaxel 75 mg/m2 + carboplatin AUC 6 Q 3 wks or a control regimen of vinorelbine 25 mg/m2 weekly + cisplatin 100 mg/m2 Q 4 wks vs Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22 Cisplatin 100 mg/m2 IV D 1Q 4 wks

51 Probability of Survival Survival Time (months)
TAX 326: Survival for DOCETAXEL + CISPLATIN vs. VINORELBINE + CISPLATIN 1.0 DOC + CIS V + CIS 0.9 0.8 Median (months) 1-year survival (%) 46 41 2-year survival (%) 21 14 0.7 0.6 Probability of Survival 0.5 0.4 P = 0.044 0.3 Having established non-inferiority for Taxotere plus cisplatin, as specified in the statistical plan, we went on to test for superiority. Here we have again the survival curves, this time with the survival estimates. The median survival for Taxotere plus cisplatin is 11.3 months, and 10.1 months for the control arm. At 2 years, 21% of the patients assigned to the Taxotere arm are alive, compared to 14% for the vinorelbine arm. The p-value for the stratified covariate-adjusted log-rank test for superiority is 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 Survival Time (months)

52 TAX 326: Survival for DOCETAXEL + CARBO vs. VINORELBINE + CISPLATIN
100 90 80 70 60 50 40 30 20 10 Docetaxel Carboplatin Vinorelbine Cisplatin P = (adjusted log-rank) Survival (%) N = 812 Now we look at the second pair-wise survival comparison, between docetaxel/carboplatin vs the vinorelbine/;cisplatin control. This analysis shows that the 2 survival curves are comparable, with equivalent median, 1-year, and 2-year survivals. Time (months)

53 NON-SMALL CELL LUNG CANCER - Clinical Benefit and 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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

54 LCSS – Global QoL 20 D + CIS V + CIS 10 Better
Mean Change from Baseline -10 We now move from clinical benefit to the multidimensional endpoint, quality of life, examining the results from the two quality of life instruments used in this prospective trial. This graph shows the changes from baseline using the validated lung cancer specific instrument, the LCSS. Shown here is the patient rated global quality of life score comparing the two treatment arms. The positive changes indicate improvement and the negative changes represent worsening. Again, the differences between the two arms are small, but are consistently positive for the docetaxel+cisplatin arm over the 18 weeks of chemotherapy and the follow-up period, when compared with changes in the vinorelbine + cisplatin arm. Worse P = * Baseline score ~ 68 -20 3 6 9 12 15 18 * Longitudinal analysis (logistic regression) Weeks Bars represent +/- a unit of standard error.

55 EuroQoL Global Health Status
10 D + CIS V + CIS 5 Better Mean Change from Baseline -5 Worse The EQ5D or Euroqol is another validated scale used to measure patient determined perception of health. Again, as with the LCSS, a consistent pattern at all time points was found, favoring the docetaxel arm. The overall difference between the two groups by a longitudinal analysis, showed p-value=0.016. Baseline score ~ 72 P = * -10 3 6 9 12 15 18 Weeks *Bars represent +/- a unit of standard error. * Longitudinal analysis (logistic regression)

56 LCSS – Patient-Rated Pain Assessment
20 TAX + CIS V + CIS 10 Better Mean Change from Baseline This graph demonstrates the patient-rated pain control over time for the first 6 evaluations of pain, for each regimen. It continues to be challenging to define what are clinically meaningful differences to patients? Three thoughtful investigators in the area of quality of life have recently published helpful papers addressing this very question: they are David Osoba (the President of ISOQoL – the international society of quality of life)…Patricia Hollen – the primary developer of the LCSS instrument…and David Cella – the primary developer of the FACT-L instrument. They independently have found that changes in the 7% to 10% range are of importance – specifically in instruments which have been validated in patients with lung cancer. As seen here, the mean changes in pain scores are modest, but favor the docetaxel arm at all evaluation periods, are in the positive direction at all times, and approach the 10% improvement rate. These differences over time, analyzed by a longitudinal analysis, accounting for all available assessments, showed the two group comparison p-value= to Baseline score ~ 77 P = 0.033* Worse -10 3 6 9 12 15 18 * Longitudinal analysis Bars represent +/- a unit of standard error. Weeks

57 Weight Change (Kg) from Baseline to Last On-Treatment Assessment
TAX + CIS V + CIS Subjects with signs of fluid retention Subjects with no signs of fluid retention 1.0 0.5 All Subjects -0.5 0.05 Mean Weight Change (Kg) from Baseline -0.29 -1.0 -0.65 -1.5 Weight loss with cancer is a source of great concern for families and patients, and is easily and accurately evaluated. As seen in this graph, patients randomly assigned to the docetaxel + cisplatin regimen – the red bars - had significant less weight loss. These patients had nearly no weight loss, while those on the vinorelbine arm lost an average of 2.4 kilos – over 5 pounds. [THE BAR NEEDS FIXING: .03 KG SHOULD BE MUCH SMALLER] Even though significant edema is an unusual side effect with docetaxel these days, if one examines the weight loss data by whether or not there was fluid retention, the results remain the same. -2.0 -2.5 -2.2 -3.0 -2.4 -2.6 -3.5 P  P  P  0.001

58 KARNOFSKY PERFORMANCE STATUS - Difference in Treatment Group Means -
Better for Better for V+CIS TAX+CIS KPS Change from Baseline Cycle 1 Cycle 2 Cycle 3 The third parameter in the clinical benefit profile is the commonly used measure of performance status. In this plot, the tick marks demonstrate the mean changes in Karnofsky performance status from baseline through several treatment cycles, as well as at the time of last assessment. When the mark is plotted to the right of the midline, it indicates improved results for the docetaxel treatment arm. The changes are small, but are consistent at all time points showing better results for those randomly assigned to docetaxel+cisplatin. Mean Across Cycles 1-3 Last Assessment on Trt

59 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

60 QUALITY OF LIFE MEASUREMENT - Uses in Lung Cancer -
CLINICAL TRIALS - Comparison of treatments PATIENT MONITORING - Effectiveness of intervention - Change over time PROGRAM EVALUATION - Usefulness of plan - 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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

62 Determine the lowest fully effective dose of agents:
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 Two terms have become common when evaluating palliative or subjective benefits of chemotherapy in patients with cancer. Both terms can be useful, and it may be helpful to review briefly the advantages or limitations of each. “Clinical Benefit” refers to control of common cancer-related problems. This has previously been defined in new agent testing to include specifically the 3 areas of pain control, weight loss, and performance status. Quality of life evaluation differs in that it is multidimensional. It includes clinical benefit aspects as part of the physical and functional domains or dimensions…but it also includes social, psychological and spiritual dimensions. While all are important considerations, many of these dimensions are unlikely to be affected by the chemotherapy agents being tested. A new agent is less likely to affect, for example social relationships within a family, than it is to help control pain. Thus, while all dimensions of quality of life are important, to evaluate a new treatment it may be relevant to concentrate on those aspects most likely to be influenced by the intervention. Without consensus in this area, these trials examined both quality of life and clinical benefit.

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% 10% 15% 20% 25% T75 V/I TAX317 TAX320 2% BSC75 p<0.001 p=ns This presentation will focus on the Taxotere 75 mg / M2 comparisons in both trials. First, examining clinical benefit; this graph looks at a degree of weight loss generally considered to be of importance, that is, the percentage of patients in each trial with 10% or greater weight loss, displayed by treatment assignment. As is seen in the graph, less major weight loss occurred in patients randomly assigned to receive Taxotere in each trial. The difference was marked in the 317 trial, comparing Taxotere with best supportive care, and only minor in the 320 study. Perhaps most important is the consistency of less weight loss and the degree of less weight loss in the Taxotere groups in both trials. That is, there is an average of fewer than 4% of the patients treated with Taxotere experiencing major weight loss during treatment. Weight loss is not only an important factor as related by patients and families, but it also represents a parameter that can be objectively measured, and it indicates a consistent benefit over the entire course of treatment.

65 Additional Opioid Analgesic Newly-started Opioid Analgesic
NSCLC: SECOND-LINE TRIAL (TAX 317B) - Opioid Analgesic Use: Change from Baseline - 60% 49% 50% 40% 35% T75 Percentage of Patients 30% BSC75 20% 18% 20% 13% Still focusing on study 317, the comparison of Taxotere with best supportive care, it is interesting to see that the trend toward better pain scores, is achieved with less additional use of pain medications, when viewed against the comparison group. Significantly less additional opiate based pain medication was required for those patients randomly assigned to receive Taxotere. At pretreatment baseline, there was similar use of opiates by both assignment groups; however, those given best supportive care more frequently required additional opiates or required initiation of opiate medications. Also, the significant differences demonstrating less additional pain medication initiation or additional use was also found when one examines all pain medication use…not just opiate based medications. No significant differences in pain medication use was seen in the TAX 320 comparison study. Of interest is the finding that patients on best supportive care more frequently required supplemental radiation therapy (41% vs only 16% for the Taxotere group). The difference was statistically significant with a p value of < Palliative RT was allowed in the protocol for any assignment group, if needed. 10% 5% 0% Ongoing at Baseline Additional Opioid Analgesic Newly-started Opioid Analgesic p=ns p<0.001 p<0.001

66 NSCLC: SECOND-LINE TRIAL (TAX 317B) - PERFORMANCE STATUS EVALUATION - Change from Baseline: Difference in Treatment Group Means TAX 317B TAX 320 Better for Better for Better for Better for BSC75 T75 V/I T75 Performance Status (ECOG) Cycle 1 Cycle 2 Performance status, often viewed as an activity scale, but relating also to functioning in the physical, social and psychological dimensions in quality of life evaluation, represents one of the most frequently measured areas in new agent testing for palliative benefit. To examine all time points for assessment, performance status was analyzed after each treatment cycle, at the last assessment, and as a mean across all cycles. No matter which time point is used, consistent results demonstrating performance status benefits associated with taxotere treatment, are reported in both trials. Using the ECOG performance status scale, in both trials better performance status ratings are reported with Taxotere treatment, at all of the time points. The degree of benefit reaches statistical improvement for most of the time points, and in both trials. Cycle 3 Mean Across Cycles 1-3 Last Assessment -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

67 CLINICAL BENEFIT: PATIENTS WITH WEIGHT LOSS >10% DURING TREATMENT (DC vs VC and DCb vs VC)
25% 20% 15 % 15% 10% 7 % This bar graph looks at weight loss during treatment, which occurred with greater frequency in the control group than in the docetaxel/cisplatin cohort. This difference in weight loss was significant, with a P-value of <0.001. 7 % 5% 0% VC DC DCb Fisher’s Exact Test, P < (for both DC vs VC and DCb vs VC)

68 NON-SMALL CELL LUNG CANCER - Primary Endpoints for Determining Study Size -
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** * First-line Comparison Trials ** Survival differences small or unlikely (2nd line, Infirm)

69 KARNOFSKY PERFORMANCE STATUS CHANGE DURING TREATMENT Difference in Treatment Group Means: N = 812
Better for Better for VC DC KPS Change from Baseline Cycle 1 Cycle 2 Cycle 3 And here, looking at change in performance status during treatment, we see consistent improvement in PS in the docetaxel/cisplatin group compared with the control. Mean Across Cycles 1-3 Last Assessment on Trt

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 -
GENERAL HEALTH: All Populations Cancer Diabetes DISEASE-SPECIFIC: Arthritis Breast Cancer Lung Cancer SITE-SPECIFIC: TREATMENT-SPECIFIC: Clinical Trials Radiation Therapy Clinical Trials BMT


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