# Presentation: 512612

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

- Richard J. Gralla, MD
- New York Lung Cancer Alliance
- New York, New York

**Notes:**
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 / 1594  (next)        

## ENDPOINTS IN DECISION-MAKING- Clinical Trials and Patient Management -

## NON-SMALL CELL LUNG CANCER- Quality of Life at Baseline:  Influence on Survival -- Prospective Analysis of 673 Patients at 30 Centers -

- * p = 0.0001,  using the LCSS quality of life instrument

## NON-SMALL CELL LUNG CANCER- Survival:  Supportive Care and Chemotherapy 1991- 2001

- NON-SMALL CELL LUNG CANCER- Survival:  Supportive Care and Chemotherapy 1991- 2001
- (N = 10,995 / 9361) -

- 718 pts

- 783 pts

- 509 pts

- 1103 pts

- 4648 pts

- 1600 pts

- Refs:  Proc ASCO 2002: Raftopoulos, Bria, Gralla, Eid

## PATIENT REPORTED OUTCOMES (“PROs”)- Rationale and Need -

-     PROs can create an accurate picture of the disease course that is unavailable from the review of other endpoints
-    Health care professionals are not accurate in evaluating subjective or palliative benefits associated with anti-cancer treatments, when compared with patient self-reports
-    PROs are often reported by patients as improved with less than major responses to treatment - even with only stable disease...response rates underestimate patient reported benefit
-    The balance between symptom improvement and toxicity, or the effects of delayed progression summarized in many PRO measures, cannot be consistently predicted by other biomedical endpoints

## SYMPTOMS  OF  LUNG  CANCER- By  Patient  Reports  (N = 121) -

-      Ref:  Hollen et al. (1993). _Eur J Cancer_, _29A_, S51-S58

- 84%

- 79%

- 71%

- 62%

- 59%

- 56%

- 57%

- 60%

- 48%

- 25%

- 14%

- 54%

- (n = 69)

- (n = 52)

- NON-SMALL CELL

- SMALL CELL

- FATIGUE

- COUGH

- DYSPNEA

- ANOREXIA

- PAIN

- HEMOPTYSIS

## NON-SMALL CELL LUNG CANCER	- Number of Presenting Symptoms at Baseline -

- Percentage

- (N = 673 Stage III and IV Patients)

- 80%

-  12%

- 5%

-  Three or more

- Two

-   One

-   None

- 3%

## PATIENT REPORTED OUTCOMES (“PROs”) - Clinical Benefit and Quality of Life -

- 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

**Notes:**
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.

## QUALITY  OF  LIFE  INSTRUMENTS- Dimensions -

- Physical
- Functional
- Psychological
- Social
- Spiritual

## QUALITY OF LIFE IN LUNG CANCER 

- PHYSICAL

- DIMENSION

- _Symptoms_

- _Symptomatic Distress_

- distress from

- FUNCTIONAL

- DIMENSION

- Activity

- Status

***QUALITY OF LIFE***

- FOR THE LUNG

- CANCER EXPERIENCE

- Quality

- of Life

- Global

**QUALITY OF LIFE IN LUNG CANCER **

- Global

- Global symptomatic

- lung cancer

- Dimensions

- _Captured:_

- Dimensions

- _Captured:_

***OVERALL***

- •Cognitive

- •Physical

- •Social

- (Role)

- •Cognitive

- •Psychological

- •Spiritual

- •All others

- •Appetite

- •Fatigue

- •Cough

- •Dyspnea

- •Hemoptysis

- •Pain

- •Social

## QUALITY  OF  LIFE - Questions -

- 1)  Can we ***DEFINE*** quality of life?
- 2)  Can we ***MEASURE*** quality of life?
- 3)  Can we agree on how to ***ANALYZE*** quality of life results?
- 4)  Can we ***PRESENT*** quality of life findings in a clear and useful way?

## QUALITY  OF  LIFE  INSTRUMENTS- Instrument  Focus -

- DISEASE-SPECIFIC:

- SITE-SPECIFIC:

- TREATMENT-SPECIFIC:

- GENERAL HEALTH:

- All Populations

- Cancer

- Diabetes

- Arthritis

-  Lymphoma

- LungCancer

- Clinical Trials

- Post - Op

- Clinical Trials

- BMT

## QUALITY  OF  LIFE  INSTRUMENTS- Lung Cancer Specific -

-      1.  Lung Cancer Symptom Scale (LCSS)         - Patient (9 items) & Observer (6 items) Forms
-               - Developed Specifically for Clinical Trials
-      2.  EORTC         - General and Lung Cancer Modules (30-40 items)
-               - Developed for General Use
-      3.  FACT-L         - General and Lung Cancer Modules (30-40 items)
-               - Developed for General Use

## LUNG  CANCER  SPECIFIC INSTRUMENTS- Psychometrics (1) -

- _PSYCHOMETRICS_

- _CHARACTERISTICS_

- FEASIBILITY:

-  Short administration time

-  Low reading level required

-  Easily understood

-  Multi-center utility

- CONTENT  VALIDITY:

-  Oncology expert agreement

-  Patient agreement

- RELIABILITY:

-  Items internally consistent

-  Intra / interrater agreement

-  Patient reproducibility

**Notes:**

 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.

## 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

**Notes:**
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.  

## 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**

**Notes:**

 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. 

## 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

**Notes:**

 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.  

## 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

**Notes:**
  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.

## PATIENT RESPONSE OUTCOMEINSTRUMENTS IN LUNG CANCER TRIALS- Other Questionnaires -

- Rotterdam Symptom Checklist (RSCL)
- Hospital Anxiety and Depression scale (HADS)          -   Often used together in British Medical    			Research Council (MRC) studies
-      Note:  These instruments are not lung cancer-specific, and have varying degrees of published psychometric results.

## NON-SMALL CELL LUNG CANCER - Clinical Benefit and Quality of Life –

- Assessment in Patients
- In Phase II Trials

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

- 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

**Notes:**
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.

## QUALITY OF LIFE EVALUATION IN CLINICAL TRIALS- Difficulties with Results Analysis:  Phase II Trials -

- 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_

**  **

**Notes:**
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.

## 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 -

- PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS- Problems in Evaluation and Analysis -

-  Lack of investigator commitment
-  Cumbersome instruments
-  Patient deterioration

**  **

**Notes:**
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.

## PROSPECTIVE  CLINICAL  TRIAL  IN  NSCLC- Causes of Patient Attrition -

- Causes for attrition

- Death

- Disease progression

- Unknown

- Patients entered

- Remaining on studyafter 3 cycles

**673**

- 97

- 131

- 14

**431**

- 14%

- 19%

- 2%

**64%**

**100%**

## PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS- Prospective Emphasis on PRO: A Recent Study -

- 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

**  **

**Notes:**
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.

## NON-SMALL CELL LUNG CANCER- Quality of Life at Baseline:  Influence on Survival -- Prospective Analysis of 673 Patients at 30 Centers -

- * p = 0.0001,  using the LCSS quality of life instrument

## QUALITY  OF  LIFE- Baseline  Values  for  Age  and  LCSS -

- 79

- 72

- 76

- 60

- (p = 0.0001)

- (p = 0.0002)

- Percent of Patients

- 60

- 62

- Age

- Average Symptom      Burden

- QL Item

- (p = NS)

- Patients remaining on study (n=431); attrition group (n=242)

- (N = 673 Patients with NSCLC)

## QUALITY  OF  LIFE  IN  LUNG  CANCER- Evaluation  Problems in Advanced Disease –

- Patient loss or “attrition” in a progressive disease, such as lung cancer
- Patient attrition is not random.  Lost first are:
-  The most symptomatic at presentation
-  Those with the lowest baseline quality of life
-  Patients with poorer prognostic factors

- _SERIAL  MEASUREMENT IN CLINCAL TRIALS: _

## QUALITY OF LIFE EVALUATION IN CLINICAL TRIALS- Difficulties with Results Analysis:  Phase III Trials -

- 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

**  **

**Notes:**
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.

## PATIENT REPORTED OUTCOMES (“PROs”)- Conclusions -

- 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

**  **

**Notes:**
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.

## PATIENT REPORTED OUTCOMES (“PROs”)- Conclusions -

- 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.

**  **

**Notes:**
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.

## Slide 33

## QUALITY OF LIFE AND LUNG CANCER- Conclusions -

- 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

**  **

**Notes:**
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.

## QUALITY OF LIFE AND LUNG CANCER- Conclusions -

- 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

**  **

**Notes:**
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.

## 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:

**Notes:**

 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

## 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

**Notes:**
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.

## 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

**Notes:**

 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.

## LCSS:  Patient  Scale:  Example:

- Please place a mark along the linewhere it would best describe thesymptoms of your lung cancerduring  the  past  day.

- 6.  How much

- None

- As much as it could be

-   pain

-    do you have?

## LUNG  CANCER  SYMPTOM  SCALE  (LCSS):

- _Directions_:

**100**

**75**

**50**

**None**

-  Observer Scale:  Example:

- 6.  **PAIN**  [Score:         ]

**Mild;**

**Moderate;**

-  present but either no medications required or

- only non-narcotic, non-codeine type oral agents;

- pain control satisfactory or reasonable.

-   codeine or codeine-containing oral medications

- needed; pain control satisfactory or reasonable.

**25**

-    narcotic oral agents are required; pain

- control satisfactory, or reasonable.

**0**

-    narcotic oral medications required but pain control

- not satisfactory or parenteral narcotics are required.

- Direct the interview to separate lung cancer symptoms using thetime frame of

- during the past day (last 24 hours).

_**Marked**_**;**

_**Severe**_**;**

## PSYCHOMETRICS"The Jargon"

- Can the instrumentbe used

- _efficiently_

- Does the instrument

- _consistently_

- measure the

- characteristic of interest?

- Does the instrumentmeasure

- _what_

- it is

- supposed to measure?

- ?

## 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

## NON-SMALL CELL LUNG CANCER- Single Agent Vinorelbine vs Supportive Care -- In Patients > Age 70:  A Prospective Randomized Trial -

- Gridelli et al *JNCI *1999,  p = 0.04

## NON-SMALL CELL LUNG CANCER- Single Agent Vinorelbine vs Supportive Care -- In Patients > Age 70:  A Prospective Randomized Trial -

- 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

**Notes:**
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.

## NON-SMALL CELL LUNG CANCER- SWOG 95-09 Randomized Trial in 410 Patients -

- <date/time>

- NON-SMALL CELL LUNG CANCER- SWOG 95-09 Randomized Trial in 410 Patients -

- Kelly *J Clin Oncol* 2001; _Survival_: 1 YR 36%/38%, 2 YR 15%/16%; _Resp Rate:_ 28%/25%

## NON-SMALL CELL LUNG CANCER- SWOG Randomized Trial:  Quality of Life -

- Kelly *J Clin Oncol* 2001. (N = 410).    Baseline Compared with Week 25 (Using FACT-L)

## 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/AustraliaNew Zealand

- Docetaxel 75 mg/m2 IV Carboplatin AUC 6 IV Q 3 wks

- Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22Cisplatin 100 mg/m2 IV D 1Q 4 wks

- Docetaxel 75 mg/m2 IVCisplatin 75 mg/m2 IV Q 3 wks

- vs

**Notes:**
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

## NON-SMALL CELL LUNG CANCER- SWOG Randomized Trial in 415 Patients -

- Wozniak et al *J Clin Oncol *1999; Survival: 1 YR 36%/20%  2 YR 12%/6%  p = 0.0018

## NSCLC:  SECOND-LINE TRIAL (TAX 317) Survival: Docetaxel vs BSC - Intention to Treat                         

- <date/time>

- Median Survival 7.4 vs 4.6 Months
- Log-Rank* P = *.047

- NSCLC:  SECOND-LINE TRIAL (TAX 317) *Survival: Docetaxel vs BSC - Intention to Treat**   *

- Docetaxel  (75 + 100 mg/M2)
- BSC

- N = 209; Updated, latest analysis of all patients

-     Reference:  Shepherd et al, JCO 2000, 2095-2103

## STUDY DESIGN: Tax 326 – First Line

**R****A****N****D****O****M****I****Z****E**

- Stratification factors:
_**Stage of disease**_
- IIIB vs IV
_**Region**_US/Canada
-  Latin America
- Europe/Lebanon
- Israel
- South Africa/AustraliaNew Zealand

- Docetaxel 75 mg/m2 IV Carboplatin AUC 6 IV Q 3 wks

- Vinorelbine 25 mg/m2 IV D 1, 8, 15 & 22Cisplatin 100 mg/m2 IV D 1Q 4 wks

- Docetaxel 75 mg/m2 IVCisplatin 75 mg/m2 IV Q 3 wks

- vs

**Notes:**
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

## TAX 326:  Survival for DOCETAXEL + CISPLATIN           vs. VINORELBINE + CISPLATIN

-  DOC + CIS

- Median (months)	11.3	10.1
- 1-year survival (%)	46	41
- 2-year survival (%)	21	14

- V + CIS

*P *= 0.044

**Probability of Survival**

**1.0**

**0.9**

**0.8**

**0.7**

**0.6**

**0.5**

**0.4**

**0.3**

**0.2**

**0.1**

**0.0**

**Survival Time (months)**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**27**

**30**

**33**

**Notes:**
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 0.044.

## TAX 326: Survival for DOCETAXEL + CARBO vs. VINORELBINE + CISPLATIN

**Survival (%)**

**Time (months)**

- 100
- 90
- 80
- 70
- 60
- 50
- 40
- 30
- 20
- 10
- 0

- 0	3	6	9	12	15	18	21	24	27	30	33

**Docetaxel****Carboplatin**

**Vinorelbine**
**Cisplatin**

- P = 0.657(adjusted log-rank)

- N = 812

**Notes:**
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.

## NON-SMALL CELL LUNG CANCER - Clinical Benefit and Quality of Life -

- 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

**Notes:**
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.

## LCSS – Global QoL

**Weeks**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**0**

**-20**

**Mean Change from Baseline**

**10**

**-10**

**20**

***P***** = 0.064 ***

**Bars represent +/- a unit of standard error.**

**Better**

**Worse**

- D + CIS

- V + CIS

**Baseline score ~ 68**

*** ****Longitudinal analysis (logistic regression)**

**Notes:**
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. 

## EuroQoL Global Health Status  

- EuroQoL Global Health Status

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**Weeks**

**10**

**5**

**0**

**-5**

**-10**

**Mean Change from Baseline**

***Bars represent +/- a unit of standard error.**

***P***** = 0.016 ***

**Better**

**Worse**

- D + CIS

- V + CIS

**Baseline score ~ 72**

*** Longitudinal analysis (logistic regression)**

**Notes:**

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.

## LCSS – Patient-Rated Pain Assessment

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**Weeks**

**10**

**-10**

**Mean Change from Baseline**

**20**

- TAX + CIS

- V + CIS

**0**

***P***** = 0.033***

*** Longitudinal analysis**
**Bars represent +/- a unit of standard error.**

**Better**

**Worse**

**Baseline score ~ 77**

**Notes:**
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 0.033.

## Weight Change (Kg) from Baseline to Last On-Treatment Assessment

- Weight Change (Kg) from Baseline to Last On-Treatment Assessment

**Mean Weight Change (Kg) ****from Baseline**

**-3.5**

**-3.0**

**-2.5**

**-2.0**

**-1.5**

**-1.0**

**-0.5**

**0**

**0.5**

**1.0**

**TAX + CIS**

**V + CIS**

**-0.29**

**-2.4**

**-0.65**

**-2.6**

**0.05**

**-2.2**

**All Subjects**

**Subjects with signs of fluid retention**

**Subjects with no signs of fluid retention**

**P ******** 0.0001**

**P ******** 0.0001**

**P ******** 0.001**

**Notes:**
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. 

## KARNOFSKY PERFORMANCE STATUS- Difference in Treatment Group Means -

_**KPS Change from Baseline**_

**Cycle 1**

**Cycle 2**

**Cycle 3**

**Mean Across Cycles 1-3**

**Last  Assessment on Trt**

**Better for**

**V+CIS**

**Better for**

**TAX+CIS**

**-****7  -6  -5  -4  -3  -2  -1   0   1   2   3   4   5   6   7**

**Notes:**
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.  

## QUALITY OF LIFE- Conclusions from TAX 326 -

- Quality of life (QoL) can be assessed efficiently, during large multinational prospective trials.
- QoL differences can be found among treatment regimens with small but meaningful differences indicated by patients using validated instruments.
- Differences in clinical benefit parameters (pain, performance status, and major weight change) can also be found in areas important to patients and families.

- * Reference:  Gralla, Rodrigues, Von Pawel et al Proc ASCO 2002

## QUALITY  OF  LIFE  MEASUREMENT- Uses  in  Lung  Cancer -

- - Comparison of treatments

-       CLINICAL  TRIALS

- - Effectiveness of intervention

- - Change over time

-       PATIENT  MONITORING

- •

- - Usefulness of plan

-       PROGRAM EVALUATION

- •

- •

- - Benefit of approach: such as oral regimens

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

- 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

**  **

**Notes:**
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.

## QUALITY OF LIFE EVALUATION USE IN CLINICAL PRACTICE- Other Strategies for Improvement - 

- 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

**  **

**Notes:**
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.

## NON-SMALL CELL LUNG CANCER- Treatment Approaches -

## WEIGHT LOSS DURING TREATMENTPercent of Patients with Weight Loss > 10%

**Notes:**
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.

## NSCLC:  SECOND-LINE TRIAL (TAX 317B) - Opioid Analgesic Use:  Change from Baseline -

- <date/time>

- NSCLC:  SECOND-LINE TRIAL (TAX 317B) - Opioid Analgesic Use:  Change from Baseline -

**p=ns**

**p<0.001**

**p<0.001**

**20%**

**13%**

**5%**

**49%**

**35%**

**18%**

**0%**

**10%**

**20%**

**30%**

**40%**

**50%**

**60%**

**Ongoing at**
**Baseline**

**Additional Opioid Analgesic**

**Newly-started Opioid Analgesic**

**Percentage of Patients**

**T75**

**BSC75**

**Notes:**
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 < 0.01.  Palliative RT was allowed in the protocol for any assignment group, if needed.

## NSCLC:  SECOND-LINE TRIAL (TAX 317B) - PERFORMANCE STATUS EVALUATION - Change from Baseline:  Difference in Treatment Group Means

- <date/time>

- NSCLC:  SECOND-LINE TRIAL (TAX 317B) - PERFORMANCE STATUS EVALUATION - Change from Baseline:  Difference in Treatment Group Means

_**Performance Status (ECOG)**_

**Cycle 1**

**Cycle 2**

**Cycle 3**

**Mean Across Cycles 1-3**

**Last  Assessment**

_**TAX 317B**_

_**TAX 320**_

**Better for**

**BSC75**

**Better for**

**T75**

**Better for**

**V/I**

**Better for**

**T75**

**Notes:**
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.

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

**7 %**

**     ****15 %**

**0%**

**5%**

**10%**

**15%**

**20%**

**25%**

**DC**** **

**DCb**

**Fisher’s Exact Test, P < 0.001 (for both DC vs VC and DCb vs VC****)**

**7 %**

**  ****VC**

**Notes:**

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.

## NON-SMALL CELL LUNG CANCER- Primary Endpoints for Determining Study Size -

- *   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

_**KPS Change from Baseline**_

**Cycle 1**

**Cycle 2**

**Cycle 3**

**Mean Across Cycles 1-3**

**Last  Assessment on Trt**

**Better for**

**VC**

**Better for**

**DC**

**-7  -6  -5  -4  -3  -2  -1   0   1   2   3   4   5   6   7**

**Notes:**
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.

## 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 -

- DISEASE-SPECIFIC:

- SITE-SPECIFIC:

- TREATMENT-SPECIFIC:

- GENERAL HEALTH:

- All Populations

- Cancer

- Diabetes

- Arthritis

- BreastCancer

- LungCancer

- Clinical Trials

- Radiation Therapy

- Clinical Trials

- BMT