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

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Non traditional endpoints in lung cancer patient reported outcomes l.jpg
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 l.jpg

TRIALS

MANAGEMENT

SURVIVAL

Appropriate if Survival Difference is likely

Not relevant for individual patients

RESPONSE

Considered to be Unreliable

The most commonly used parameter

QoL

Appropriate if Survival Differences Unlikely

Should become the most used parameter

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


Slide3 l.jpg

100

80

60

PERCENT SURVIVING*

40

20

0

0

2

4

6

8

10

12

14

16

18

20

22

24

MONTHS

LOWER QL

HIGHER QL

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

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


Slide4 l.jpg

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 l.jpg
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 l.jpg
SYMPTOMS OF LUNG CANCER- By Patient Reports (N = 121) -

NON-SMALL CELL

SMALL CELL

(n = 69)

(n = 52)

84%

FATIGUE

79%

71%

COUGH

62%

59%

DYSPNEA

56%

57%

60%

ANOREXIA

48%

PAIN

54%

HEMOPTYSIS

25%

14%

Ref: Hollen et al. (1993). Eur J Cancer, 29A, S51-S58


Non small cell lung cancer number of presenting symptoms at baseline l.jpg

0

20

40

60

80

100

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

(N = 673 Stage III and IV Patients)

80%

Three or more

Two

12%

One

5%

3%

None

Percentage


Patient reported outcomes pros clinical benefit and quality of life l.jpg
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 l.jpg
QUALITY OF LIFE INSTRUMENTS- Dimensions -

Physical

Functional

Psychological

Social

Spiritual


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QUALITY OF LIFE IN LUNG CANCER

- Conceptual Model for Clinical Trials: THE “LCSS” -

OVERALL

PHYSICAL

FUNCTIONAL

QUALITY OF LIFE

DIMENSION

DIMENSION

FOR THE LUNG

CANCER EXPERIENCE

Symptoms

Global

•Appetite

Global

Activity

•Fatigue

Quality

•Cough

Status

of Life

•Dyspnea

•Hemoptysis

•Pain

Dimensions

Symptomatic Distress

Dimensions

Captured:

Captured:

•Physical

Global symptomatic

•Cognitive

•Cognitive

distress from

•Psychological

•Social

•Social

lung cancer

(Role)

•Spiritual

•All others


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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 l.jpg
QUALITY OF LIFE INSTRUMENTS- Instrument Focus -

GENERAL HEALTH:

All Populations

Diabetes

Arthritis

Cancer

DISEASE-SPECIFIC:

LungCancer

Lymphoma

SITE-SPECIFIC:

TREATMENT-SPECIFIC:

Clinical Trials

Clinical Trials

Post - Op

BMT


Quality of life instruments lung cancer specific l.jpg
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


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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


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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 l.jpg
QOL MEASURES FOR LUNG CANCER - Example: Reliability Coefficients -

FACT-L

LCSS

Total patient scale

(alpha 0.82) for

207 patients

Observer scale

(alpha 0.75) for

21 observers

Total core measure

(alpha, 0.89)

for 116 patients

Lung cancer module

(alpha 0.68) for

116 patients

  • Cronbach’s alpha of 0.70 for new measures


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LUNG CANCER SPECIFIC INSTRUMENTS- Psychometrics (2) -

PSYCHOMETRICS

CHARACTERISTICS

CONSTRUCT VALIDITY:

  • Based on conceptual model

  • Valid for LC patients with different extents of disease

CRITERION-RELATED(CONCURRENT) VALIDITY:

  • Compares well to "gold standards"

CLINICAL SIGNIFICANCE:

  • KPS and LCSS Observer

  • scales used as anchors

  • 673 LC patients from two North American cancer trials (30 centers)

NORMATIVE DATA:


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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


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PATIENT RESPONSE OUTCOMEINSTRUMENTS IN LUNG CANCER TRIALS- Other Questionnaires -

  • Rotterdam Symptom Checklist (RSCL)

  • Hospital Anxiety and Depression scale (HADS) - Often used together in British Medical Research Council (MRC) studies

    Note: These instruments are not lung cancer-specific, and have varying degrees of published psychometric results.


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

Assessment in Patients

In Phase II Trials


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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


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QUALITY OF LIFE EVALUATION “IDEAL 2” 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


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NON-SMALL CELL LUNG CANCER “IDEAL 2”- Clinical Benefit and Quality of Life –

Assessment in Patients

In Phase III Trials


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PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS “IDEAL 2”- Problems in Evaluation and Analysis -

  • Lack of investigator commitment

  • Cumbersome instruments

  • Patient deterioration


Prospective clinical trial in nsclc causes of patient attrition l.jpg
PROSPECTIVE CLINICAL TRIAL IN NSCLC “IDEAL 2”- Causes of Patient Attrition -

100%

673

Patients entered

Causes for attrition

Death

97

14%

Disease progression

131

19%

Unknown

14

2%

431

64%

Remaining on studyafter 3 cycles


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PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS “IDEAL 2”- 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


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100 “IDEAL 2”

80

60

PERCENT SURVIVING*

40

20

0

0

2

4

6

8

10

12

14

16

18

20

22

24

MONTHS

LOWER QL

HIGHER QL

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

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


Quality of life baseline values for age and lcss l.jpg

90 “IDEAL 2”

80

70

60

50

On Study

Attrition Group

40

30

20

10

0

QUALITY OF LIFE- Baseline Values for Age and LCSS -

(N = 673 Patients with NSCLC)

Percent of Patients

79

76

72

62

60

60

QL Item

Age

Average Symptom Burden

(p = NS)

(p = 0.0002)

(p = 0.0001)

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


Quality of life in lung cancer evaluation problems in advanced disease l.jpg
QUALITY OF LIFE IN LUNG CANCER “IDEAL 2”- 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 l.jpg
QUALITY OF LIFE EVALUATION “IDEAL 2” 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 l.jpg
PATIENT REPORTED OUTCOMES (“PROs”) “IDEAL 2”- 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


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PATIENT REPORTED OUTCOMES (“PROs”) “IDEAL 2”- 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 l.jpg
QUALITY OF LIFE AND LUNG CANCER “IDEAL 2”- 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


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QUALITY OF LIFE AND LUNG CANCER “IDEAL 2”- 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


Quality of life instruments step 2 compare feasibility l.jpg
QUALITY OF LIFE INSTRUMENTS “IDEAL 2”- Step #2: Compare Feasibility -

  • Self-reporting style

  • Short administration time

  • Low reading level

  • Patient / staff acceptance

  • Multi-site utility

Characteristics of good feasibility include:


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QUALITY OF LIFE INSTRUMENTS “IDEAL 2”- 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


Quality of life instruments step 4 support for validity cont l.jpg
QUALITY OF LIFE INSTRUMENTS “IDEAL 2”- 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


Slide39 l.jpg

LCSS: Patient Scale: Example: “IDEAL 2”

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

Directions:

6. How much

pain

do you have?

As much as it could be

None


Lung cancer symptom scale lcss l.jpg
LUNG CANCER SYMPTOM SCALE (LCSS): “IDEAL 2”

Observer Scale: Example:

Directions:

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

during the past day (last 24 hours).

6. PAIN [Score: ]

None

100

75

Mild;

present but either no medications required or

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

pain control satisfactory or reasonable.

50

Moderate;

codeine or codeine-containing oral medications

needed; pain control satisfactory or reasonable.

25

Marked;

narcotic oral agents are required; pain

control satisfactory, or reasonable.

0

Severe;

narcotic oral medications required but pain control

not satisfactory or parenteral narcotics are required.


Psychometrics the jargon l.jpg

FEASIBILITY: “IDEAL 2”

RELIABILITY:

VALIDITY:

PSYCHOMETRICS"The Jargon"

Can the instrumentbe used

?

efficiently

Does the instrument

consistently

measure the

characteristic of interest?

Does the instrumentmeasure

what

it is

supposed to measure?


Quality of life baseline values of prognostic factors l.jpg

90 “IDEAL 2”

80

70

60

50

On Study

Attrition Group

40

30

20

10

0

QUALITY OF LIFE- Baseline Values of Prognostic Factors -

(N = 673 Patients with NSCLC)

Percent of Patients

85%

76%

78%

64%

Males

Stage IV

(p = 0.001)

(p = 0.029)

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


Slide43 l.jpg

12 “IDEAL 2”

10

8

6.2

MEDIAN SURVIVAL IN MONTHS:

6

4.7

4

2

0

CHEMOTHERAPY REGIMEN

Vinorelbine

Supportive Care

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

Gridelli et al JNCI 1999, p = 0.04


Slide44 l.jpg
NON-SMALL CELL LUNG CANCER “IDEAL 2”- 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


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12 “IDEAL 2”

10

8

8

8

MEDIAN SURVIVAL IN MONTHS:

6

4

2

0

CHEMOTHERAPY REGIMEN

Vinorelbine + DDP

Paclitaxel + Carbo

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

Kelly J Clin Oncol 2001; Survival: 1 YR 36%/38%, 2 YR 15%/16%; Resp Rate: 28%/25%


Non small cell lung cancer swog randomized trial quality of life l.jpg

100 “IDEAL 2”

90

80

70

60

PERCENT OF PATIENTS:

50

40

30

20

10

0

Vinorelbine + Cisplatin

Paclitaxel + Carboplatin

QL: Impoved

QL: Stable

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

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


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STUDY DESIGN: Tax 326 “IDEAL 2”

Stratification factors:

Stage of disease

IIIB vs IV

RegionUS/Canada

Latin America

Europe/Lebanon

Israel

South Africa/AustraliaNew Zealand

RANDOMIZE

Docetaxel 75 mg/m2 IVCisplatin 75 mg/m2 IVQ 3 wks

Docetaxel 75 mg/m2 IVCarboplatin AUC 6IVQ 3 wks

vs

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


Non small cell lung cancer swog randomized trial in 415 patients l.jpg

12 “IDEAL 2”

10

8

8

6

MEDIAN SURVIVAL IN MONTHS:

6

4

2

0

CHEMOTHERAPY REGIMEN

Cisplatin 100 mg/M2

Vinorelbine + Cisplatin

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

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


Nsclc second line trial tax 317 survival docetaxel vs bsc intention to treat l.jpg
NSCLC: SECOND-LINE TRIAL (TAX 317) “IDEAL 2”Survival: Docetaxel vs BSC - Intention to Treat

Docetaxel (75 + 100 mg/M2)

BSC

Median Survival 7.4 vs 4.6 Months

Log-Rank P = .047

N = 209; Updated, latest analysis of all patients

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


Study design tax 326 first line l.jpg
STUDY DESIGN: Tax 326 – First Line “IDEAL 2”

Stratification factors:

Stage of disease

IIIB vs IV

RegionUS/Canada

Latin America

Europe/Lebanon

Israel

South Africa/AustraliaNew Zealand

RANDOMIZE

Docetaxel 75 mg/m2 IVCisplatin 75 mg/m2 IVQ 3 wks

Docetaxel 75 mg/m2 IVCarboplatin AUC 6IVQ 3 wks

vs

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


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

1.0

DOC + CIS

V + CIS

0.9

0.8

Median (months) 11.3 10.1

1-year survival (%) 46 41

2-year survival (%) 21 14

0.7

0.6

Probability of Survival

0.5

0.4

P = 0.044

0.3

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

100

90

80

70

60

50

40

30

20

10

0

DocetaxelCarboplatin

Vinorelbine

Cisplatin

P = 0.657(adjusted log-rank)

Survival (%)

N = 812

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

Time (months)


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NON-SMALL CELL LUNG CANCER CISPLATIN- 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 l.jpg
LCSS – Global QoL CISPLATIN

20

D + CIS

V + CIS

10

Better

Mean Change from Baseline

0

-10

Worse

P = 0.064 *

Baseline score ~ 68

-20

12

15

18

6

0

3

9

Weeks

* Longitudinal analysis (logistic regression)

Bars represent +/- a unit of standard error.


Euroqol global health status l.jpg
EuroQoL Global Health Status CISPLATIN

10

D + CIS

V + CIS

5

Better

Mean Change from Baseline

0

-5

Worse

P = 0.016 *

Baseline score ~ 72

-10

0

3

6

9

12

15

18

Weeks

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

* Longitudinal analysis (logistic regression)


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LCSS – Patient-Rated Pain Assessment CISPLATIN

20

TAX + CIS

V + CIS

10

Better

Mean Change from Baseline

0

Baseline score ~ 77

P = 0.033*

Worse

-10

12

15

18

0

9

3

6

* Longitudinal analysis

Bars represent +/- a unit of standard error.

Weeks


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

TAX + CIS

V + CIS

Subjects with signs of fluid retention

Subjects with no signs of fluid retention

1.0

0.5

All Subjects

0

-0.5

0.05

-0.29

Mean Weight Change (Kg) from Baseline

-1.0

-0.65

-1.5

-2.0

-2.5

-2.2

-2.4

-3.0

-2.6

-3.5

P  0.0001

P  0.0001

P  0.001


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KARNOFSKY PERFORMANCE STATUS CISPLATIN- Difference in Treatment Group Means -

Better for

Better for

V+CIS

TAX+CIS

KPS Change from Baseline

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


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QUALITY OF LIFE CISPLATIN- 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


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QUALITY OF LIFE MEASUREMENT CISPLATIN- 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


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QUALITY OF LIFE EVALUATION CISPLATIN 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


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QUALITY OF LIFE EVALUATION CISPLATIN 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 l.jpg

Trends in CISPLATIN

Treatment

Less Aggressive in

More Aggressive in

Advanced Disease

Earlier Stages

NON-SMALL CELL LUNG CANCER- Treatment Approaches -


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TAX317 CISPLATIN

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

WEIGHT LOSS DURING TREATMENTPercent of Patients with Weight Loss > 10%


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

60%

49%

50%

40%

35%

T75

Percentage of Patients

30%

BSC75

20%

18%

20%

13%

10%

5%

0%

Ongoing at

Baseline

Additional Opioid Analgesic

Newly-started Opioid Analgesic

p=ns

p<0.001

p<0.001


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0.6 CISPLATIN

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

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


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

25%

20%

15 %

15%

10%

7 %

7 %

5%

0%

VC

DC

DCb

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


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ENDPOINTS CISPLATIN

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**

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

* First-line Comparison Trials** Survival differences small or unlikely (2nd line, Infirm)


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KARNOFSKY PERFORMANCE STATUS CHANGE DURING TREATMENT CISPLATIN Difference in Treatment Group Means: N = 812

Better for

Better for

VC

DC

KPS Change from Baseline

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


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LCSS BACKGROUND CISPLATIN

  • 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


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QUALITY OF LIFE INSTRUMENTS CISPLATIN- Instrument Focus -

GENERAL HEALTH:

All Populations

Diabetes

Arthritis

Cancer

DISEASE-SPECIFIC:

BreastCancer

LungCancer

SITE-SPECIFIC:

TREATMENT-SPECIFIC:

Clinical Trials

Clinical Trials

Radiation Therapy

BMT


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