# Presentation: 517099

## Cognitive Testing and Patient Reported Outcomes in Brain Tumor Clinical Trials

- Christina A. Meyers, Ph.D., ABPP
- Department of Neuro-Oncology
- M. D. Anderson Cancer Center

## Cognitive Dysfunction

- Net clinical benefit of cancer therapy includes “beneficial effects on disease-related symptoms and/or quality of life” (Working group of FDA & NCI members)
- Maintaining function particularly important since long-term remission or cure is unlikely, or accompanied by significant disability

**Notes:**
Is ? chemobrain fatigue or is fatigue one of a constellation of symptoms that comprise chemobrain
DO YOU MENTION SOMETHING ABOUT CHEMO VS XRT VS BOTH....?

## Clinical Benefit to Patient

- Relief of tumor-specific symptoms
- Symptoms of mass lesion in brain
- Progressive disruption of brain function
- Anatomic evidence does not fully map function

## Measurement of Tumor-Specific Symptoms

- Patient subjective report of symptoms (headache, nausea, etc.)
- Objective assessment of symptoms (cognitive function, mood)
- Objective assessment of function (ability to perform ADL’s)

## Evaluation of Cognitive Function:Clinical Research Questions

- What are the cognitive problems prior to treatment
- Do different treatment regimens
- improve neurocognitive function due to better tumor control
- slow expected neurocognitive deterioration due to tumor
- have more or less short and long-term neurotoxicity

## FDA Input in Brain Met Trial of Radiation Sensitizer

- “Radiological response alone is not acceptable for approval.  However, improvement in neurocognitive function or delay in neurocognitive progression are acceptable endpoints”

## Trials Ongoing/Planned

- Radiosurgery +/- WBXRT
- Doses of PCI in SCLC
- +/- PCI in NSCLC
- WBXRT +/- radiation sensitizer
- Avastin for GBM
- Neurogenic agents for XRT injury

## Evaluation of Cognitive Function:Assessment Issues

- Performance status (KPS) has little relation to cognitive function and QOL
- Brief mental status exams only detect delirium or significant dementia
- Self-report of cognitive problems (i.e., questionnaires) correlate poorly with objective test results

## Pre- and Post-Infusion of CI-980

**Notes:**
I DON’T UNDERSTAND THIS SLIDE BUT AM SURE YOU WILL BE EXPLANING IT! Hopkins significantly declined after 72 hour infusion while MMSE didn’t change a bit, memory recovered some before next infusion – slide represents 3 pre- and post-infusion testings – we could perhaps cite this in the editorial!

## Characteristics of Assessment Battery

- Brief (on the order of 30  minutes)
- Repeatable (alternate forms, minimal practice effect)
- Good psychometric properties
- Sensitive to changes in function
- Highly standardized, simple administration
- Able to be completed by most patients
- Measurement of relevant cognitive functions
- Tumor related cortical versus treatment related subcortical patterns of dysfunction
- Oversight by a neuropsychologist

**Notes:**
Why neuropsychologist?  Familiarity with reliability, validity, proper application; interpretation of test findings (e.g., memory tests), issues about test and patient factors that might compromise validity, test security issues.

## Analytic Validity of Cognitive Tests

- Published validity and reliability, and population norms
- A priori established significant change defined
- Standardized in a manner that variations among assessors/sites is minimal (requires formal certification and QA procedures) and battery can be imported into community settings

## Analytic Validity of Cognitive TestsPediatric Brain Tumor Trials

- Tests are developmentally appropriate
- Selection guided in part by longitudinal design during which tests may change
- Consideration of normal versus altered cognitive development after treatment in long-term survivors

## Analytic Validity of Cognitive Tests

- Confounders need to be identified (adjuvant medications, medical complications like seizures)
- Frequency of assessment should parallel other staging evaluations, and be relevant to usual disease course
- Testing cannot stand alone without correlation with anatomic response and neurologic outcome, but cognitive deterioration may occur in advance

## Ideal Characteristics of PRO

- Based on disease and treatment related symptoms, with less emphasis on social function and satisfaction with life
- Sound psychometric properties
- Able to be completed by persons with cognitive deficits
- Sensitive to change over time

## Caveats of PRO

- Patients need to have adequate cognitive function to complete
- Often suboptimal psychometric properties
- Reporting bias
- Proxy assessments problematic for subjective symptoms
- Need buy-in from investigators to reduce missing data
- QOL change does not parallel cognitive change and cannot be used as a proxy

## Standardized Approach to Assessment?

- Ability to compare different agents in different clinical trials
- Recommendation of BTPRG to develop a “practice guideline protocol”
- Core of standard content for investigators to select tools appropriate to evaluate specific drug/hypothesis

## What Trials Need Alternative Endpoints?

- Only RCT (risk/benefit, cost effectiveness, primary vs secondary endpoint)?
- Phase I/II single arm trials (e.g., safety monitoring, comparison to other I/II trials)?