Patient Reported Outcomes

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Patient Reported Outcomes

• Lowell E. Schnipper, M.D.
• Berenson Professor of Medicine
• Harvard Medical School
• Chief, Hematology-Oncology
• Beth Israel Deaconess Medical Center

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Question

• PROs and HRQoL is of diminishing importance in
  the era of emerging targeted therapies?
• True?
• False?

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Patient Reported OutcomesWhy?

• Cancer often an incurable illness
• Improvement in patients HRQoL is an expectation
  of appropriate therapy
• Palliation is often the goal
• HRQoL is the product of Patient Reported Outcomes

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Value to the Clinical Trials Process

• Provide information about toxicity
• Symptom relief
• These often are primary or secondary clinical
  trial endpoints
• In the clinical setting HRQoL assessments can
  have predictive value for survival

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Subjectivity and Objectivity

• HRQoL is not subjective in the usual sense of the
  term
• It can be measured accurately in an individual,
  and in a group
• It is subjective in that it derives from the
  human subject of research or clinical practice

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Health-Related Quality of Life (HRQOL) Assessment
1. What is HRQOL? 2. What Should You Measure? 3.
How Should You Measure it? 4. How is it
incorporated into clinical research
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Health Related Quality of Life (HRQoL)

• Includes a number of domains
• Physical functioning ranges from normal to
  complete impairment
• Psychological well-being (depression, anxiety,
  fear of recurrence)
• Social functioning

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P. Ganz, personal communicationt
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HRQoL Dimensions

• Physical Functioning Spirituality
• Occupational/Role Functioning FutureOrientation
• Social Functioning Sexuality/Intimacy
• Emotional Well-being
  Health Concerns
• Symptom Status Family Well-Being
• Financial Concerns Satisfaction w/Care
• Global/Overall Perception of Quality of Life

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HRQOL Assessment
What Should You Measure?
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Definitions

• Instrument Questionnaire
• Item Question
• Domain Dimension Area of Behavior or
  Experience
• Cross-Sectional DesignCompares 2 or More
  Populations at One Point in Time
• Longitudinal DesignAssesses Changes in HRQOL
  Over Time in 1 or More Populations

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Types of QOL Instruments

• Health profiles-descriptive questionnaires-measure
  s by a simple metric different aspects of HRQoL
  across multiple domains
• Generic, multi-dimensional
• Disease-specific, multi-dimensional
• Condition-specific, multi-dimensional

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Functional Status

• Measure of Functioning

Focus May be Generic or Disease-Specific
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Domain Specific
Linear Analog Self-Assessment
Place an X at a point on the line that best
represents how you have felt over the past two
weeks.
X
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Aggregated Scores
Simple Average
Sum or Mean of Item or Subscale Scores to Yield a
Global Score This Approach Weights each Item
Proportional to its Variance in the Population
Under Study Example Quality of Life Index
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Quality of Life Index
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Quality of Life Index
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HRQOL
Functional Status
Symptoms
Global Ratings
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Symptoms

• Focus
• Disease (e.g., asthma, CHF, cancer, lung cancer)
• Type of symptom (e.g., pain)
• Dimension(s)
• Frequency
• Severity
• Distress
• Interference with activities

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HRQOL
Functional Status
Symptoms
Global Ratings
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Global Ratings
Single Assessment of Overall Health or HRQOL
Example E-V-G-F-P
How would you describe your overall state of
health CHECK ONE? Excellent Very Good
Good Fair Poor
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HRQOL Assessment
Why Should You Measure It?
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HRQOL Value Added
Operational Definition
HRQOL Assessment Adds Value IF HRQOL Data Can
Influence Overall Conclusions of the Study
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Study Goals
Nature of the Value Added Depends on Overall
Study Goals

• evaluating the effectiveness of interventions
• characterizing treatment-specific outcomes for
  use in shared decision making
• characterizing the burden of illness
• predicting patient outcomes
• quality-adjusting survival for resource
  allocation and other policy decisions

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Question

• HRQoL is relevant to which type(s) of clinical
  trials
• Phase I
• Phase Ib/II
• Randomized phase II trial
• Prospective randomized trial
• All of the above

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Evaluating Effectiveness
Depends On
1. Phase of the Trial 2. Natural History of
Disease
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Type of Clinical Trial and PRO

• Phase I not critical-goal is primarily to define
  MTD or optimal biologic dose
• Phase II can be used but not essential
• An opportunity to collect pilot data for use in
  phase III trial
• Phase III-HRQOL data is essential in this context

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Tailoring study design to the natural history of
the disease

• 3 paradigms
• Chronic and/or recurrent, non-lethal diseases
• Lethal but curable diseases
• Lethal, incurable diseases

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Chronic and/or recurrent, non-lethal diseases

• Effectiveness
• relief of disease-related symptoms
• minimal treatment-related toxicity

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Chronic and/or recurrent, non-lethal diseases

• What outcomes do you need?
• Primary
• Disease-related symptoms
• Secondary
• Treatment-related symptoms
• Global rating
• Functional status
• Utilities (if CEA is planned)

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Lethal but curable diseases

• Effectiveness
• cure rates
• minimize toxicity

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Lethal but curable diseases

• What outcomes do you need?
• Primary
• Survival
• Secondary
• Utilities (if CEA analysis is planned)
• treatment-related symptoms, functional status

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Lethal, incurable diseases

• Effectiveness
• palliation
• prolongation of survival

J. Weeks July 2006
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Lethal, incurable diseases

• What outcomes do you need?
• Primary
• Survival
• Functional status
• Disease-related symptoms
• Global rating
• Secondary
• Utilities (if CEA is planned)

J. Weeks July 2006
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Supporting SharedDecision Making
Information Patients Need
Nature of Alternative TreatmentsLikely Outcomes
from Treatments Descriptive Information forEach
of the Possible Outcomes simple, transparent
measures
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Characterizing theBurden of Illness
To Benchmark Study Population generic health
status measures To Identify Patient
Needs domain-specific measuressymptom-specific
measures
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Predicting Outcomes
Baseline HRQoL has been Shown to be an
Independent Predictor for survival response to
therapy Breast Cancer Lung Cancer functional
status resource use (chronic illness)
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HRQoL Assessment
How Should You Measure It?
Identify the Respondent patientsurrogateprovider
(MD, RN, other)
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HRQoL Assessment
How Should You Measure It?

• Identify the Respondent

Choose the Domains to be Measured disease or
domain-specific instrumentgeneric
instrumentglobal assessment of QoL
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HRQoL Assessment
How Should You Measure It?

• Identify the Respondent
• Choose the Domains to be Measured

Consider the Need for Interpretability health
state descriptionstranslating numeric into
clinical differences
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HRQoL Assessment
How Should You Measure It?

• Identify the Respondent
• Choose the Domains to be Measured
• Consider Need for Interpretability

Choose a Mode of Administration in person, by
phone, mailedcomputer assisted (in person or
phone)self-administered (forms, computer)
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HRQoL Instruments

• Multi-dimensional HRQoL instruments are available
  that cover the basic HRQoL domains
• Generic
• Cancer-specific
• Domain-specific

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HRQoL Instruments

• Generic types
• Intended for use across broad chronic disease
  populations
• Allow comparisons across these groups
• Disadvantage may not permit adequate
  cancer-specific focus
• Disease caused symptoms
• Treated related symptoms

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HRQoL Instruments

• Generic types-examples
• Medical Outcome Study Short Form Health Survey
  (SF-36) Ware, JE, Med Care (1992)30473-83.
• EuroQoL (EQ-5D) Health Policy (1990)16199-208.

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HRQoL Instruments

• Cancer-specific instruments
• Responsive to disease-related changes
• Cannot be used across populations with chronic
  disease
• Several are in common use because they are
  reliable and have been validated
• Functional Living Index-Cancer ShipperJCO
  (1984) 2427-483
• Modular instruments combine a generic or core
  instrument applicable to a broad range of cancer
  patients with cancer-type specific questions
• FACT-C Gunnars, Acta Oncologica (2001)40175-84.
• EORTC QLQ-C30, Aaronson JNCI (1993)85365-367.

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HRQoL Instruments

• Domain Specific Instruments
• Designed to address one specific aspect of HRQoL
• Examples
• Multi-dimensional Fatigue Inventory (MFI)
• McGill Pain Questionnaire

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Uses of HRQoL Instruments

• Outcome measure
• RCT evaluating treatment outcomes
• To qualify quantity of survival
  (e.g.,cost-effectiveness)
• Assess late physical/psychological problems
• Predictor
• Intervention

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HRQOL Assessment
Other Considerations

• Is the proposed analysis too taxing for the
  subject?
• must questionnaire be completed serially in light
  of possible attrition
• Is a proxy needed?
• will population include children, low literacy,
  non-English speaking, visually impaired, or
  cognitively impaired adults?

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HRQOL Assessment
Other Considerations (contd)

• timing of assessments
• consistency across patients/groups critical
• responses influenced by recent experiences
• missing data
• avoid at all costs
• generally cannot be assumed to be at random
• specify methods for dealing in advance!
• multiple comparisons
• specify primary endpoints in advance

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HRQOL Assessment
Make Your Final Choice

• Psychometric (responsive, valid, reproducible)
  properties
• validated in your population
• known and used in your field

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Patient Reported Outcomes Methodological
Challenges

• The variety of questionnaires available
• Choice of time points
• Incomplete data (data attrition)
• Lack of pre-defined endpoints
• Response-shift over time of patient perceptions
  of HRQoL
• Psychological defenses tend to conserve
  perception of good HRQoL

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Question

• In a longitudinal study the best way to deal
  with response shift is to
• Increase the sample size to dilute this effect
• Anticipate it by changing the scales used at
  longitudinal time points when making HRQoL
  measurements
• Use a pre-test (then test) and post-test set of
  questions at a follow-up visit to assess the
  degree of change (shift) in baseline attitude of
  HRQoL
• None of the above

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Examples from Completed Trials
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Developing a HRQoL instrument PrinciplesPhase
III Breast Ca Trial

• 1. Dimensions Physical, emotional and social
  well-being
• 2. Importance items (questions) must reflect
  importance to patients
• 3. Quantifiable summary scores must be amenable
  to statistical analysis
• 4. Validity the instrument should be a true
  measurement of HRQoL
• 5. Reproducibility the instrument should yield
  similar results in comparable patients
• 6. Responsiveness the instrument should detect
  clinically important changes
• 7. Simplicity the questionnaire should be short
• JCO 61798-1810, 1988

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Developing a HRQoL instrument Principles

• Item selection
• Interview patients and determine what issues are
  important
• Winnow redundancies
• Breast cancer Questionnaire (BCQ) hair loss,
  emotional dysfunction, physical symptoms, trouble
  and inconvenience associated with treatment,
  fatigue, nausea, positive well-being
• BCQ contained 30 questions,
• Likert scale administered by an interviewer, and
  took 10-15 minutes 7 points-patients asked to
  recall how they had been feeling over a defined
  period (2 weeks in this case). Maximum score on
  scale equates with most minimal deficit
• Final score expressed as mean of the score on the
  30 questions
• JCO 61798-1810, 1988

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Developing a HRQoL instrument Principles

• Co-administration of several additional
  questionnaires, e.g., Spitzer QoL, Rand Physical
  and Emotional Status, Karnofsky score (by
  physician)
• Each questionnaire was administered at intervals
  throughout study treatment period and up to 72
  weeks.
• JCO 61798-1810, 1988

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Developing a HRQoL instrument Principles

• BCQ had the best correlations with the Rand
  Physical and Emotional surveys and the Spitzer
  QoL instrument (Correlation coefficients approx.
  0.6)
• Not surprisingly the prolonged treatment
  demonstrated a significant dip in QoL using the
  BCQ and Karnofsky scores during the extended
  treatment period. The BCQ correlated better with
  the patients assessments of her QoL.
• JCO 61798-1810, 1988

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Prednisone /- Mitoxantrone in Hormone Resistant
Prostate Cancer

• Randomized controlled trial
• Palliation as an end points 2 point reduction in
  the McGill-Melazak Pain questionnaire
• Approval of Mitoxantrone for this indication
  based upon positive QoL findings

Tannock, JCO (1996)141756-64
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Prednisone /- Mitoxantrone in Hormone Resistant
Prostate Cancer

• Instruments employed
• Prostate Cancer-Specific QoL Instrument with 9
  linear self-assessment scales (pain, physical
  activity, appetite, constipation, etc.)
• EORTC/QLQ-C30 contains multi-item domains for
  physical function, emotional function, pain,
  global QoL

Tannock, JCO (1996)141756-64
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Prednisone /- Mitoxantrone in Hormone Resistant
Prostate Cancer

• Results
• Favored MP for pain (38 reduction), physical
  activity, constipation and mood
• QoL parameters (PS, pain intensity and serum alk
  Phos) significant predictors of OS---PSA was not!
• Could be expanded to include cost effectiveness
  (cost per quality adjusted life year gained)

Tannock, JCO (1996)141756-64
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Question

• In the mitoxantrone/Prednisone trial just
  discussed, how would do you account for missing
  data?

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Question

• a. Anticipate attrition, identify a proxy at the
  point at which the patient is unavailable b. the
  sample size should be large enough to dilute the
  effect of missing data
• c. anticipate loss of patient availability and
  identify proxies at the start of the study
• d. use of a proxy will never provide validated
  data in a study in which HRQoL is an important
  endpoint

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SWOG 8894 Hormonal Therapy of Advanced
Metastatic Prostate Cancer
Bilateral Orchiectomy Flutamide
Bilateral Orchiectomy Placebo
Within one week of registration.
JNCI 1998 90 1537-44
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SWOG 9039 QOL Companion to S8894Activation
History

• Therapeutic trial, S8894, opened 12/89
• QOL Companion study, S9039, opened 10/90
• 290/1387 patients registered to therapeutic
  trial
• QOL sample size 500 patients
• Both studies closed to accrual 9/94

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S9039 Primary Quality of Life Endpoints

• Treatment-specific symptoms
• Diarrhea
• Gas Pain
• Body Image
• Emotional Functioning
• Physical Functioning

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HRQOL Results

• Placebo arm significantly better
• Emotional status
• Less diarrhea
• Consistent picture
• Placebo arm patients reported better HRQOL
• Flutamide not palliative
• Appears to worsen HRQOL relative to placebo
• Could have missed an important outcome if just
  measured symptoms

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Median Emotional Well-Being Scores
100
90
Minor Med Cond
Orch Placebo
CHF
80
Orch Flutamide
COPD Hyperten
70
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///
General Population Patientswith Medical
Conditions
0
S9039 Patients at 6 Months
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CONCLUSIONS
1. Integration of QOL outcomes in cancer clinical
trials is challenging 2. Anticipation of design,
data collection, and analysis will decrease some
problems 3. Additional resources are required to
incorporate QOL outcomes successfully-budget for
them!
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Despite the Uphill Climbwere getting there
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Acknowledgements

• Dr. Jane Weeks
• Dr. Patricia Ganz