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 -

Should become the most used parameter

Appropriate if Survival Differences

Unlikely

QoL

The most commonly used parameter

Considered to be Unreliable

RESPONSE

Not relevant for individual patients

Appropriate if Survival Difference

is likely

SURVIVAL

MANAGEMENTTRIALS

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

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

MONTHS

PE

RC

EN

T S

UR

VIV

ING

*

LOWER QL HIGHER QL

4.96

7.22

7.77

8.66

9.17

8.6

BSC 1995-2001 P alone PE Old Cis + no PE New Cis + Carbo +

+45,5%

+11%

+17,9%

+10,2% -11,4%

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

(N = 10,995 / 9361) -

718 pts718 pts 783 pts783 pts 509 pts509 pts 1103 pts1103 pts 4648 pts4648 pts 1600 pts1600 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

ANOREXIAPAINHEMOPTYSIS

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%

0 20 40 60 80 100

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

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

PHYSICALDIMENSION

Symptoms

Symptomatic Distress

distress from

FUNCTIONALDIMENSION

ActivityStatus

QUALITY OF LIFEFOR THE LUNG

CANCER EXPERIENCE

Qualityof Life

Global

QUALITY OF LIFE IN LUNG CANCER

Global

Global symptomatic

lung cancer

DimensionsCaptured: 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

LymphomaLungCancer

Clinical Trials Post - Op

Clinical TrialsBMT

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

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

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

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 OUTCOMEINSTRUMENTS 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 -

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 -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 -

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

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

MONTHS

PE

RC

EN

T S

UR

VIV

ING

*

LOWER QL HIGHER QL

QUALITY OF LIFE- Baseline Values for Age and LCSS -

7972

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)

0

10

20

30

40

50

60

70

80

90

On StudyAttrition Group

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 -

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 -

• Self-reporting style

• Short administration time

• Low reading level

• Patient / staff acceptance

• Multi-site utility

Characteristics of good feasibility include:

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

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

Directions: 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?

LCSS: Patient Scale: Example:

LUNG CANCER SYMPTOM SCALE (LCSS):

Directions:

100

75

50

None

Observer Scale: Example:

6. PAIN [Score: ]

Mild;

Moderate;

present but either no medications required oronly 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; paincontrol satisfactory, or reasonable.

0 narcotic oral medications required but pain controlnot 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 instrumentconsistentlymeasure the

characteristic of interest?

Does the instrumentmeasure what it issupposed to measure?

FEASIBILITY:

RELIABILITY:

VALIDITY:

?

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 IV0

10

20

30

40

50

60

70

80

90

On Study

Attrition Group

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

6.2

4.7

0

2

4

6

8

10

12

CHEMOTHERAPY REGIMENME

DIA

N S

UR

VIV

AL

IN M

ON

TH

S:

Vinorelbine Supportive Care

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 -

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

8 8

0

2

4

6

8

10

12

CHEMOTHERAPY REGIMEN

ME

DIA

N S

UR

VIV

AL

IN M

ON

TH

S:

Vinorelbine + DDP Paclitaxel + Carbo

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)

0

10

20

30

40

50

60

70

80

90

100

Vinorelbine + Cisplatin Paclitaxel + Carboplatin

PE

RC

EN

T O

F P

AT

IEN

TS

:

QL: Impoved QL: Stable

STUDY DESIGN: Tax 326

RANDOMIZE

Stratification factors:

Stage of diseaseIIIB vs IV

Region

US/Canada

Latin America

Europe/LebanonIsrael

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

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

6

8

0

2

4

6

8

10

12

CHEMOTHERAPY REGIMEN

ME

DIA

N S

UR

VIV

AL

IN M

ON

TH

S:

Cisplatin 100 mg/M2 Vinorelbine + Cisplatin

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21

Survival in Months

Cumulative Probability

Median Survival 7.4 vs 4.6 MonthsLog-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

RANDOMIZE

Stratification factors:

Stage of diseaseIIIB vs IV

Region

US/Canada

Latin America

Europe/LebanonIsrael

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

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

DOC + CIS

Median (months) 11.310.1

1-year survival (%) 46 41

2-year survival (%) 21 14

V + CIS

P = 0.044

Pro

bab

ilit

y o

f S

urv

ival

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

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

Su

rviv

al (

%)

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

DocetaxelCarboplatin

VinorelbineCisplatin

P = 0.657(adjusted log-rank)

N = 812

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

Weeks0 3 6 9 12 15 18

0

-20

Mea

n C

han

ge f

rom

Bas

elin

e

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)

EuroQoL Global Health Status

0 3 6 9 12 15 18

Weeks

10

5

0

-5

-10

Mea

n C

han

ge f

rom

Bas

elin

e

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

P = 0.016 *

Better

Worse

D + CIS V + CIS

Baseline score ~ 72

* Longitudinal analysis (logistic regression)

LCSS – Patient-Rated Pain Assessment

0 3 6 9 12 15 18

Weeks

10

-10

Mea

n C

han

ge

fro

m B

asel

ine

20

TAX + CIS V + CIS

0

P = 0.033*

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

Better

WorseBaseline score ~ 77

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

Mea

n W

eig

ht

Ch

ang

e (K

g)

fro

m B

asel

ine

-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

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 forV+CIS

Better forTAX+CIS

-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 -

- 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 -

• 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 -

Less Aggressive in

Advanced Disease

More Aggressive in

Earlier Stages

Trends in

Treatment

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

5%

8%

0%

5%

10%

15%

20%

25%

T75 V/I

TAX317 TAX320

2%

25%

0%

5%

10%

15%

20%

25%

T75 BSC75

p<0.001 p=ns

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 atBaseline

Additional Opioid Analgesic

Newly-started Opioid Analgesic

Per

cen

tag

e o

f P

atie

nts

T75BSC75

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 forBSC75

Better forT75

Better forV/I

Better forT75

-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)

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

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

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

ENDPOINTS STUDY TYPE

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**

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 forVC

Better forDC

-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 -

DISEASE-SPECIFIC:

SITE-SPECIFIC:

TREATMENT-SPECIFIC:

GENERAL HEALTH: All Populations

Cancer Diabetes Arthritis

BreastCancer

LungCancer

Clinical Trials

Radiation Therapy

Clinical TrialsBMT