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NON-SMALL CELL LUNG CANCER - Issues -

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NON-SMALL CELL LUNG CANCER - Issues - Powered By Docstoc
					NON-TRADITIONAL ENDPOINTS IN
       LUNG CANCER
   - Patient Reported Outcomes -



         Richard J. Gralla, MD
     New York Lung Cancer Alliance
         New York, New York
ENDPOINTS IN DECISION-MAKING
- Clinical Trials and Patient Management -

                TRIALS            MANAGEMENT

SURVIVAL     Appropriate if        Not relevant for
           Survival Difference    individual patients
                is likely
RESPONSE    Considered to be      The most commonly
               Unreliable           used parameter

QoL           Appropriate if      Should become the
           Survival Differences   most used parameter
                Unlikely
        NON-SMALL CELL LUNG CANCER
  - Quality of Life at Baseline: Influence on Survival -
       - Prospective Analysis of 673 Patients at 30 Centers -

                                 100
            PERCENT SURVIVING*




                                 80

                                 60

                                 40

                                 20

                                  0
                                       0   2   4   6   8   10 12 14 16 18 20 22 24
                                                           MONTHS
                                                   LOWER QL      HIGHER QL
* p = 0.0001, using the LCSS quality of life instrument
                  NON-SMALL CELL LUNG CANCER
        - Survival: Supportive Care and Chemotherapy 1991- 2001
                          (N = 10,995 / 9361) -
                                                                              9.17
                                                                   +10,2%               -11,4%
                                                           8.66                                    8.6
                                                  +17,9%
                                         7.77
                                 +11%
                        7.22


              +45,5%


       4.96




  BSC 1995-2001        P alone           PE           Old Cis + no PE       New Cis +            Carbo +
     718 pts           783 pts          509 pts            1103 pts          4648 pts             1600 pts
Refs: Proc ASCO 2002: Raftopoulos, Bria, Gralla, Eid
PATIENT REPORTED OUTCOMES (“PROs”)
         - Rationale and Need -
PROs can create an accurate picture of the disease course that is
unavailable from the review of other endpoints

Health care professionals are not accurate in evaluating subjective or
palliative benefits associated with anti-cancer treatments, when compared
with patient self-reports


PROs are often reported by patients as improved with less than major
responses to treatment - even with only stable disease…response rates
underestimate patient reported benefit

The balance between symptom improvement and toxicity, or the effects of
delayed progression summarized in many PRO measures, cannot be
consistently predicted by other biomedical endpoints
   SYMPTOMS OF LUNG CANCER
    - By Patient Reports (N = 121) -
              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
    NON-SMALL CELL LUNG CANCER
 - Number of Presenting Symptoms at Baseline -
          (N = 673 Stage III and IV Patients)


Three or more                               80%


        Two         12%


         One        5%


        None        3%


                0    20    40      60      80     100

                           Percentage
PATIENT REPORTED OUTCOMES (“PROs”)
 - Clinical Benefit and Quality of Life -
 • Quality of Life
    – Multidimensional
    – Includes areas not likely to be affected by chemo


• Clinical Benefit
   - Subjective or Palliative Control of Common Problems
   - Previously Defined to Evaluate:
          - Pain Control
          - Weight Loss
          - Performance Status
QUALITY OF LIFE INSTRUMENTS
        - Dimensions -

          Physical
         Functional
        Psychological
           Social
          Spiritual
      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
      •Appetite            Global             Global
      •Fatigue             Activity           Quality
      •Cough               Status
      •Dyspnea                                of Life
      •Hemoptysis
      •Pain
  Symptomatic Distress    Dimensions         Dimensions
                          Captured:          Captured:
   Global symptomatic     •Physical         •Cognitive
                          •Cognitive
      distress from
                          •Social           •Psychological
      lung cancer                           •Social
                           (Role)           •Spiritual
                                            •All others
       QUALITY OF LIFE
          - Questions -
1) Can we DEFINE quality of life?

2) Can we MEASURE quality of life?
3) Can we agree on how to ANALYZE quality of
   life results?
4) Can we PRESENT quality of life findings in a
   clear and useful way?
QUALITY OF LIFE INSTRUMENTS
      - Instrument Focus -

GENERAL HEALTH:                      All Populations


DISEASE-SPECIFIC:          Cancer      Diabetes Arthritis


                          Lymphoma
                                      Lung
SITE-SPECIFIC:                        Cancer


TREATMENT-SPECIFIC:       Clinical         Clinical
                      BMT Trials Post - Op Trials
QUALITY OF LIFE INSTRUMENTS
     - Lung Cancer Specific -

1. Lung Cancer Symptom Scale (LCSS)
   - Patient (9 items) & Observer (6 items) Forms
   - Developed Specifically for Clinical Trials

2. EORTC
   - General and Lung Cancer Modules (30-40 items)
   - Developed for General Use

3. FACT-L
   - General and Lung Cancer Modules (30-40 items)
   - Developed for General Use
LUNG CANCER SPECIFIC INSTRUMENTS
           - Psychometrics (1) -
   PSYCHOMETRICS       CHARACTERISTICS
   FEASIBILITY:         Short administration time
                        Low reading level required
                        Easily understood
                        Multi-center utility

   CONTENT VALIDITY:    Oncology expert agreement
                        Patient agreement

   RELIABILITY:         Items internally consistent
                        Intra / interrater agreement
                        Patient reproducibility
 QUALITY OF LIFE INSTRUMENTS
  - Good reliability features include: -


• Internal consistency = Cronbach’s alpha > 0.70
                        for new measures

• Stability =             Reliability coefficient > 0.70

• Equivalence = Kappa statistic > 0.61

  Ref: Nunnally & Bernstein, 1994; Landis & Koch, 1977
QOL MEASURES FOR LUNG CANCER
  - Example: Reliability Coefficients -
       FACT-L                         LCSS

 Total core measure           Total patient scale
   (alpha, 0.89)                (alpha 0.82) for
   for 116 patients             207 patients

 Lung cancer module           Observer scale
  (alpha 0.68) for             (alpha 0.75) for
  116 patients                 21 observers

  Cronbach’s alpha of 0.70 for new measures
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         Compares well to
(CONCURRENT) VALIDITY:     "gold standards"

CLINICAL SIGNIFICANCE:    KPS and LCSS Observer
                           scales used as anchors

NORMATIVE DATA:           673 LC patients from two
                           North American cancer trials
                           (30 centers)
QUALITY OF LIFE INSTRUMENTS
    - Additional Information -

• Clinically meaningful difference
   – Often subject to “risk-benefit” considerations
   – Difficult to determine for the survival endpoint too
• Normative data for subgroups


Ref: Mayo Proceedings, 2002
    PATIENT RESPONSE OUTCOME
INSTRUMENTS IN LUNG CANCER TRIALS
        - Other Questionnaires -
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.
NON-SMALL CELL LUNG CANCER
- Clinical Benefit and Quality of Life –


        Assessment in Patients
          In Phase II Trials
  RANDOMIZED PHASE II TRIAL OF IRESSA AT 2
         DOSE LEVELS – “IDEAL 2”
  Quality of Life / Clinical Benefit: ASCO 2002 Abstract #1167

• A subscale of the FACT-L instrument was used (the
  LCS)

• Palliation was noted rapidly when it occurred:
  generally within 7 to 10 days

• Responding patients had greater symptom relief than
  those with stable disease or progressive NSCLC
   – 43% with symptom improvement
   – 34% with quality of life improvement
        QUALITY OF LIFE EVALUATION
                IN CLINICAL TRIALS
- Difficulties with Results Analysis: Phase II Trials -
   Appropriate Standard Palliation Confounds Analysis:
   – Complicates benefit assessment when there is no control group
   – Leads to overestimate of benefit with study agent when
     patients are receiving standard approaches as well
   Response and Palliation:
   – Likely that major response leads to QoL or Clinical Benefit
   – Major response underestimates benefit: Lesser responses may
     give symptom relief
   – Benefit in patients with stable disease may be due to either the
     study agent or to standard palliation: can lead to overestimation
NON-SMALL CELL LUNG CANCER
- Clinical Benefit and Quality of Life –


        Assessment in Patients
          In Phase III Trials
 PATIENT REPORTED OUTCOMES IN
        CLINICAL TRIALS
- Problems in Evaluation and Analysis -


 1) Lack of investigator commitment
 2) Cumbersome instruments
 3) Patient deterioration
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       431    64%
    after 3 cycles
 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
        NON-SMALL CELL LUNG CANCER
  - Quality of Life at Baseline: Influence on Survival -
       - Prospective Analysis of 673 Patients at 30 Centers -

                                 100
            PERCENT SURVIVING*




                                 80

                                 60

                                 40

                                 20

                                  0
                                       0   2   4   6   8   10 12 14 16 18 20 22 24
                                                           MONTHS
                                                   LOWER QL      HIGHER QL
* p = 0.0001, using the LCSS quality of life instrument
                      QUALITY OF LIFE
      - Baseline Values for Age and LCSS -
                        (N = 673 Patients with NSCLC)
Percent of
Patients
    90                        79
                                                76
    80                             72
    70        60 62                                  60
    60
    50                                                        On Study
    40                                                        Attrition Group
    30
    20
    10
     0         Age      Average Symptom          QL Item
             (p = NS)       Burden           (p = 0.0002)
                          (p = 0.0001)
     Patients remaining on study (n=431); attrition group (n=242)
 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
        QUALITY OF LIFE EVALUATION
                IN CLINICAL TRIALS
- Difficulties with Results Analysis: Phase III Trials -
 No standard statistical approach is used:
– Simply evaluating averages of patient scores at subsequent time points is
  problematic:
    • In Single Arm evaluation: Overestimates QoL and Clinical Benefit
    • In Comparison trials: Underestimates QoL differences between study arms
      IF survival differences also are found

 Survival differences complicate QoL analysis
– Patient attrition (due to death or progression) is not random
    • The most symptomatic patients drop out of the analysis first
    • Patients with the poorer prognostic factors drop out first
    • Thus, a regimen with poorer survival loses more lower QoL patients earlier and
      paradoxically - but incorrectly - appears to gain in QoL

 Results from all patients on trial need to be Analyzed
PATIENT REPORTED OUTCOMES (“PROs”)
            - Conclusions -
•       Use valid, feasible, reliable and sensitive instruments
        appropriate for the disease stage which yields consistent results
        across socioeconomic status, literacy, and culture or language
        differences in the study population

•       Specify clearly defined primary and secondary endpoints

    –      In that different features of available validated instruments can be found,
           care in the selection of the instrument is advised

    –      Attention to prospectively defined analyses, including primary and
           secondary endpoints, and methods for handling (or more importantly,
           avoiding) missing data is necessary
PATIENT REPORTED OUTCOMES (“PROs”)
            - Conclusions -
•    Use an appropriate control group for comparison of
     outcomes
    –   concomitant interventions affecting these outcomes must be
        collected and when possible controlled

•    Emphasize compliance with protocol specified PRO
     assessments
    –   Enrollment of patients, with adequate follow-up, must be
        considered as mandatory for the study
    –   This point must be made to individual investigators, and
        must be clear to patients as part of the consenting process.
•    Blinding of interventions when feasible to minimize
     bias.
QUALITY OF LIFE AND LUNG CANCER
          - Conclusions -
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
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
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
 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
  Ref: Anastasi, 1988
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
 Ref: Anastasi, 1988
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
  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.
     0   Severe; narcotic oral medications required but pain control
         not satisfactory or parenteral narcotics are required.
 PSYCHOMETRICS
        "The Jargon"
FEASIBILITY: Can the instrument
             be used efficiently?

RELIABILITY: Does the instrument
             consistentlymeasure the
             characteristic of interest?

VALIDITY:     Does the instrument
              measure what it is
              supposed to measure?
                   QUALITY OF LIFE
   - Baseline Values of Prognostic Factors -
                   (N = 673 Patients with NSCLC)
Percent of
Patients
                                               85%
      90                76%              78%
      80
      70          64%
      60
      50                                                     On Study
      40                                                     Attrition Group
      30
      20
      10
       0           Males                 Stage IV
                (p = 0.001)            (p = 0.029)
    Patients remaining on study (n = 431); attrition group (n = 242)
    NON-SMALL CELL LUNG CANCER
        - Single Agent Vinorelbine vs Supportive Care -
  - In Patients > Age 70: A Prospective Randomized Trial -
        MEDIAN SURVIVAL IN MONTHS:



                                     12

                                     10

                                     8
                                            6.2
                                     6                          4.7
                                     4

                                     2

                                     0
                                           CHEMOTHERAPY REGIMEN

                                          Vinorelbine   Supportive Care

Gridelli et al JNCI 1999, p = 0.04
  NON-SMALL CELL LUNG CANCER
       - Single Agent Vinorelbine vs Supportive Care -
 - In Patients > Age 70: A Prospective Randomized Trial -

     Quality of Life and Clinical Benefit
• QoL Endpoints favored the vinorelbine arm

• Palliation was more frequent with the chemotherapy
• While the analysis was logical, a validated instrument
  was not used:
   – Not a true criticism of the study design, since validated
     instruments in NSCLC were only beginning to be used at
     the start of this trial
   NON-SMALL CELL LUNG CANCER
   - SWOG 95-09 Randomized Trial in 410 Patients -
         MEDIAN SURVIVAL IN MONTHS:

                                      12

                                      10
                                                   8                 8
                                      8

                                      6

                                      4

                                      2

                                      0
                                                CHEMOTHERAPY REGIMEN

                                           Vinorelbine + DDP   Paclitaxel + Carbo
Kelly J Clin Oncol 2001; Survival: 1 YR 36%/38%, 2 YR 15%/16%; Resp Rate: 28%/25%
                                  NON-SMALL CELL LUNG CANCER
                                  - SWOG Randomized Trial: Quality of Life -


                                  100
                                   90
           PERCENT OF PATIENTS:




                                   80
                                   70
                                   60
                                   50
                                   40
                                   30
                                   20
                                   10
                                    0
                                         Vinorelbine + Cisplatin         Paclitaxel + Carboplatin

                                                    QL: Impoved          QL: Stable
Kelly J Clin Oncol 2001. (N = 410).             Baseline Compared with Week 25 (Using FACT-L)
                  STUDY DESIGN: Tax 326


Stratification factors:       Docetaxel 75 mg/m2 IV
                          R   Cisplatin 75 mg/m2 IV Q 3 wks
 Stage of disease
     IIIB vs IV
                          A
                          N
      Region              D
     US/Canada                Docetaxel 75 mg/m2 IV
                          O
                              Carboplatin AUC 6 IV Q 3 wks
    Latin America         M
                          I
  Europe/Lebanon
                          Z                      vs
       Israel
                          E   Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22
South Africa/Australia        Cisplatin 100 mg/m2 IV D 1Q 4 wks
   New Zealand
  NON-SMALL CELL LUNG CANCER
  - SWOG Randomized Trial in 415 Patients -
         MEDIAN SURVIVAL IN MONTHS:

                                      12

                                      10
                                                                         8
                                      8
                                                     6
                                      6

                                      4

                                      2

                                      0
                                                   CHEMOTHERAPY REGIMEN

                                           Cisplatin 100 mg/M2   Vinorelbine + Cisplatin

Wozniak et al J Clin Oncol 1999; Survival: 1 YR 36%/20% 2 YR 12%/6% p = 0.0018
NSCLC: SECOND-LINE TRIAL (TAX 317)
     Survival: Docetaxel vs BSC - Intention to Treat
               1.0
               0.9                                                 Docetaxel (75 + 100 mg/M2)
               0.8                                                 BSC

               0.7                                         Median Survival 7.4 vs 4.6 Months
               0.6                                         Log-Rank P = .047
Cumulative
               0.5
Probability
               0.4
               0.3
               0.2
               0.1
               0.0
                     0         3           6           9         12         15        18         21
                                                    Survival in Months
N = 209; Updated, latest analysis of all patients     Reference: Shepherd et al, JCO 2000, 2095-2103
        STUDY DESIGN: Tax 326 – First Line


Stratification factors:       Docetaxel 75 mg/m2 IV
                          R   Cisplatin 75 mg/m2 IV Q 3 wks
 Stage of disease
     IIIB vs IV
                          A
                          N
      Region              D
     US/Canada                Docetaxel 75 mg/m2 IV
                          O
                              Carboplatin AUC 6 IV Q 3 wks
    Latin America         M
                          I
  Europe/Lebanon
                          Z                      vs
       Israel
                          E   Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22
South Africa/Australia        Cisplatin 100 mg/m2 IV D 1Q 4 wks
   New Zealand
                          TAX 326: Survival for DOCETAXEL + CISPLATIN
                                 vs. VINORELBINE + CISPLATIN
                          1.0

                          0.9                                         DOC + CIS V + CIS
                          0.8
                                                      Median (months)        11.3        10.1
Probability of Survival




                          0.7                         1-year survival (%)     46         41
                          0.6                         2-year survival (%)     21         14
                          0.5

                          0.4
                                                                            P = 0.044
                          0.3

                          0.2

                          0.1

                          0.0
                                0   3   6   9    12      15   18     21     24      27    30    33
                                                Survival Time (months)
TAX 326: Survival for DOCETAXEL + CARBO
     vs. VINORELBINE + CISPLATIN
                   100
                                                               Docetaxel
                   90
                                                               Carboplatin
                   80                                          Vinorelbine
                                                               Cisplatin
                   70
    Survival (%)




                                                             P = 0.657
                   60                                   (adjusted log-rank)

                   50

                   40
                                                                  N = 812
                   30

                   20

                   10

                    0
                         0   3   6   9   12   15   18   21   24   27    30    33
                                         Time (months)
NON-SMALL CELL LUNG CANCER
- Clinical Benefit and Quality of Life -
• Quality of Life
   – Multidimensional
   – Includes areas not likely to be affected by chemo


• Clinical Benefit
  - Subjective or Palliative Control of Common Problems
  - Previously Defined to Evaluate:
         - Pain Control
         - Weight Loss
         - Performance Status
                                                    LCSS – Global QoL
                              20
Mean Change from Baseline




                                                                           D + CIS         V + CIS
                              10
                                            Better


                                0



                             -10            Worse
                                                                 Baseline score ~ 68             P = 0.064 *


                             -20
                                              0              3             6           9   12        15        18
                      * Longitudinal analysis (logistic regression)              Weeks
                            Bars represent +/- a unit of standard error.
                                    EuroQoL Global Health Status
                            10
                                                                        D + CIS          V + CIS
Mean Change from Baseline




                              5          Better


                              0


                             -5
                                         Worse
                                                               Baseline score ~ 72                 P = 0.016 *
                            -10
                                            0              3            6            9   12        15        18
                                                                                Weeks
            *Bars represent +/- a unit of standard error.

                        * Longitudinal analysis (logistic regression)
LCSS – Patient-Rated Pain Assessment
                              20
                                                       TAX + CIS       V + CIS
  Mean Change from Baseline




                              10    Better



                               0


                                                 Baseline score ~ 77              P = 0.033*
                                    Worse
                              -10

                                      0      3           6        9    12        15      18
  * Longitudinal analysis
  Bars represent +/- a unit of standard error.
                                                               Weeks
Weight Change (Kg) from Baseline to
  Last On-Treatment Assessment
                                                TAX + CIS        V + CIS

                          1.0                   Subjects with       Subjects with
                                                signs of fluid        no signs of
                          0.5
Mean Weight Change (Kg)




                                 All Subjects     retention         fluid retention
                            0
     from Baseline




                          -0.5                                        0.05
                                 -0.29
                          -1.0
                                                  -0.65
                          -1.5
                          -2.0
                          -2.5
                                                                             -2.2
                          -3.0           -2.4
                                                          -2.6
                          -3.5
                                  P  0.0001      P  0.0001           P  0.001
 KARNOFSKY PERFORMANCE STATUS
- Difference in Treatment Group Means -

                                  Better for       Better for
KPS Change from Baseline           V+CIS           TAX+CIS


Cycle 1

Cycle 2

Cycle 3

Mean Across Cycles 1-3

Last Assessment on Trt


                           -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7
                      QUALITY OF LIFE
               - Conclusions from TAX 326 -

• Quality of life (QoL) can be assessed efficiently,
  during large multinational prospective trials.

• QoL differences can be found among treatment
  regimens with small but meaningful differences
  indicated by patients using validated instruments.

• Differences in clinical benefit parameters (pain,
  performance status, and major weight change) can
  also be found in areas important to patients and
  families.
* Reference: Gralla, Rodrigues, Von Pawel et al Proc ASCO 2002
QUALITY OF LIFE MEASUREMENT
         - Uses in Lung Cancer -

     •    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
      QUALITY OF LIFE EVALUATION
           IN CLINICAL PRACTICE
      - Use in Routine Patient Evaluation -


• Patients who Respond to chemotherapy
  typically have better survival and
  improved clinical benefit / Quality of Life

• Is the opposite true?:
 Does clinical benefit coupled with QoL benefit
 predict objective response?
  • Sensitivity / Specificity Issues
  • Ease of Measurement: Hand-held Computer Technology
     QUALITY OF LIFE EVALUATION
       USE IN CLINICAL PRACTICE
     - Other Strategies for Improvement -

• Determine the lowest fully effective dose
  of agents:
– Or, find the dose at which “diminishing returns”
  occurs
– Is this the same as the “MTD?”

• Address major patient concerns:
– Concerns beyond the effectiveness of chemotherapy
– When survival / response / toxicity results are similar,
  it is not surprising that QoL differences are not large
NON-SMALL CELL LUNG CANCER
     - Treatment Approaches -



                 Trends in
                 Treatment



   Less Aggressive in   More Aggressive in

   Advanced Disease       Earlier Stages
WEIGHT LOSS DURING TREATMENT
 Percent of Patients with Weight Loss > 10%
            TAX317                    TAX320
                      25%
25%                           25%




20%                           20%




15%                           15%




10%                           10%
                                                 8%


                                    5%
 5%                           5%
      2%


 0%                           0%
      T75             BSC75         T75          V/I

            p<0.001                       p=ns
 NSCLC: SECOND-LINE TRIAL (TAX 317B)
- Opioid Analgesic Use: Change from Baseline -
                              60%
                                                         49%
                              50%
     Percentage of Patients




                              40%                                           35%
                                                                                        T75
                              30%
                                                                                        BSC75
                                    20% 18%
                              20%
                                                 13%

                              10%                                    5%

                              0%
                                    Ongoing at   Additional Opioid    Newly-started
                                     Baseline       Analgesic        Opioid Analgesic




                                     p=ns        p<0.001             p<0.001
   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

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
CLINICAL BENEFIT: PATIENTS WITH WEIGHT LOSS
          >10% DURING TREATMENT
           (DC vs VC and DCb vs VC)

      25%


      20%

                                                           15 %
      15%


      10%
                   7%                    7%

       5%


       0%
                 DC                     DCb                  VC
       Fisher’s Exact Test, P < 0.001 (for both DC vs VC and DCb vs VC)
      NON-SMALL CELL LUNG CANCER
  - Primary Endpoints for Determining Study Size -
 ENDPOINTS                                    STUDY TYPE

 SURVIVAL                            Primary endpoint for most
                                     Large randomized trials*

 RESPONSE                            Primary endpoint for
                                     Phase II exploratory trials

 QUALITY OF LIFE                     Primary endpoint for trials in
                                     special populations**
* First-line Comparison Trials
** Survival differences small or unlikely (2nd line, Infirm)
    KARNOFSKY PERFORMANCE STATUS
        CHANGE DURING TREATMENT
   Difference in Treatment Group Means: N = 812

                                 Better for       Better for
KPS Change from Baseline            VC               DC


Cycle 1

Cycle 2

Cycle 3

Mean Across Cycles 1-3

Last Assessment on Trt

                           -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7
                 LCSS BACKGROUND
• Practical
     – Designed for clinical trials, especially for serial quality of life
       and symptom measurement
     – Administered in 2 to 5 minutes with high patient and staff
       acceptance

• Patient form: 100 mm visual analogue scale (9 questions)
• Observer form*: 5-point categorical scale (6 questions)
• Well-tested; good psychometric properties for lung
  cancer (Hollen et al. Cancer 1994.)
• Available in more than 40 languages
     – Standard methodology involving multiple bilingual translators
       for forward - backward translations; then patient pilot-testing
* optional
QUALITY OF LIFE INSTRUMENTS
      - Instrument Focus -

GENERAL HEALTH:                     All Populations


DISEASE-SPECIFIC:          Cancer     Diabetes Arthritis


                           Breast    Lung
SITE-SPECIFIC:             Cancer    Cancer


TREATMENT-SPECIFIC:       Clinical Radiation Clinical
                      BMT Trials   Therapy Trials

				
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