Maintaining Cognitive Function in Patients with CNS Metastases

Receiving Multimodality Treatment

Jeffrey S. Wefel, PhD, ABPPSection Chief and Associate Professor

Section of NeuropsychologyDepartment of Neuro-Oncology and Department of Radiation Oncology

Objectives

• Review cognitive dysfunction in patients with brain mets

• Highlight approaches to the clinical management of cognitive dysfunction

• Introduce emerging preclinical-translational cognitive science

Breast MelanomaNSCLC

Overallincidence

>10-16%(lung,breast,melanoma)

>170,000/yearinUSA

Challengesrelatedtomaintainingcognitivefunction

• Diseaseandtreatment=cognitivedysfunction• Efficacy/Toxicitybalance(‘Therapeuticwindow’)• Limitedtreatmentstoprotectorrestorecognitivefunction

ImprovedOS

Sperduto,JCO,2012;Nayaketal,CurrNeurolRep,2012

BrainMetastasis

• Tumor Effects– patients with brain mets

are cognitively impaired at the time of diagnosis (>90%)

– cognitive function correlates with lesion volume (r=0.2-0.3, p<0.0001) not number of mets

NCFTest

Multiple%Impaired(N=401)

Single%Impaired(N=80)

0Impaired 9 36

>1Impaired 91 64

>4 Impaired 42 10

MEMORYHVLT-RTR 60 41

PROCESSINGSPEEDTMTA 33 18

EXECUTIVEFUNCTIONTMTBCOWA

4432

1617

FINEMOTOR CONTROLDominantHandNondominant Hand

6563

2223

Meyersetal.,JCO,2004;Wefel,unpublished

BrainMets– CognitiveDysfunction

AdaptedfromHardesty&Nakaji,FrontSurg,2016

Multimodality management

TreatmentApproach

Challenges PotentialSolutions

Surgery ResidualdiseaseInaccessibletumor

-Fluorescence-LITT

Radiation Doseconstraints– locationOfftargettox (cognitive decline)

-Brachytherapy,improvedtargeting-SRS,WBRTsparingtechniques-Sensitizers?

Chemotherapy BBB,branchedevolution,chemobrain

-Targetedtherapy

Immunotherapy Neurotoxicity-seizure-inflammation-CRS,AMS

-?symptommanagement?

Optune (TTF) -METIStrial(SRS+/-TTFinNSCLC)

Combinationsoftheabove

-Patienttolerance-Risk adaptedtherapy

MultimodalityTreatmentStrategies

Goal:Controlbraindiseasewithouttoxicity,andextendlifewhilepreservingfunction/QOL

• Prevent cognitive decline– Technological

• SRS +/- WBRT (MDACC ID00-377, NCCTG N0574)• HA-WBRT (RTOG 0933)

– Pharmacological• Neuroprotection (RTOG 0614)• Targeted approaches, immunotherapies

• Manage cognitive deficits– Comorbidities

• Reversible contributors– Maintain Brain Health– Pharmacological

• Stimulants• Pro-cognitive medications

– Behavioral• Neuroplasticity-based training?• Compensatory strategies

• Preclinical-Translational ‘Next Gen’ Frontier

MaximizingCognitiveFunction

• Technological– SRS +/- WBRT for 1-3 mets (MDACC ID00-377, NCCTG N0574)

Changetal.,LancetOncol,2009

PreventingCognitiveDecline

• Technological– SRS +/- WBRT for 1-3 mets (MDACC ID00-377, NCCTG N0574)

Changetal.,LancetOncol,2009;Brownetal.,JAMA2017

PreventingCognitiveDecline

• Technological– SRS +/- WBRT for 1-3 mets (MDACC ID00-377, NCCTG N0574)

Changetal.,LancetOncol,2009;Brownetal.,JAMA2017;Gondietal.,JCO,2014

PreventingCognitiveDecline

• HA-WBRTdeclineat4months=7%vs 30%(hxl cntl)

– HA-WBRT (RTOG 0933)

• Pharmacological– Neuroprotection (RTOG 0614)

Cog

nitiv

e F

unct

ion

Fai

lure

(%

)

0

25

50

75

100

Months from Randomization0 3 6 9 12 15

Patients at RiskMemantinePlacebo

Patients at Risk7566

Patients at Risk3325

Patients at Risk2719

Patients at Risk1512

Patients at Risk99

Failures219219

Total256252

p (one-sided) = 0.01HR= 0.784 (0.621, 0.988)

MemantinePlacebo

Memantine increased time to cognitive decline, HR=0.78, p=0.001

N=508eligible

WBRT: 37.5 Gy(15 Fx of 2.5 Gy)

Stratify:-RPA Class*-Prior Surgery**

20mg Memantine Daily x 24 weeks

Placebo Daily x 24 weeks

Brownetal.,Neuro-Onc,2013

PreventingCognitiveDecline

• Pharmacological– Neuroprotection (RTOG 0614)

N=508eligible

WBRT: 37.5 Gy(15 Fx of 2.5 Gy)

Stratify:-RPA Class*-Prior Surgery**

Placebo Daily x 24 weeks

PreventingCognitiveDecline

• Technological +/- Pharmacological

Stratify:-RPA Class-Prior Therapy

WBRT + Memantine

HA-WBRT + Memantine

Stratify:-Stage-Age-Planned Memantine

PCI (25Gy x 10)

HA-PCI (25Gy x 10)

Brainmets

NRG CC001: A Randomized Phase III Trial of Memantine +/- Hippocampal Avoidance in Patients with Brain Metastases

NRG CC003: Phase IIR/III Trial of Prophylactic Cranial Irradiation with or without Hippocampal Avoidance for Small Cell Lung Cancer

Primary: Time to cognitive failure Primary Ph II – intracranial relapse rate, non-inferiorityPrimary Ph III – HVLT-R DR decline at 6 months, efficacy

SCLC

20mg Memantine Daily x 24 weeks

Cog

nitiv

e F

unct

ion

Fai

lure

(%

)

0

25

50

75

100

Months from Randomization0 3 6 9 12 15

Patients at RiskMemantinePlacebo

Patients at Risk7566

Patients at Risk3325

Patients at Risk2719

Patients at Risk1512

Patients at Risk99

Failures219219

Total256252

p (one-sided) = 0.01HR= 0.784 (0.621, 0.988)

MemantinePlacebo

Memantine increased time to cognitive decline, HR=0.78, p=0.001

• Prevent cognitive decline– Technological

• SRS +/- WBRT (MDACC ID00-377, NCCTG N0574)• HA-WBRT (RTOG 0933)

– Pharmacological• Neuroprotection (RTOG 0614)• Targeted approaches, immunotherapies

• Manage cognitive deficits– Comorbidities

• Reversible contributors– Maintain Brain Health– Pharmacological

• Stimulants (fatigue, attention, processing speed)• Donepezil

– Behavioral• Neuroplasticity-based training?• Compensatory strategies

• Preclinical-Translational ‘Next Gen’ Frontier

MaximizingCognitiveFunction

• Metabolic abnormalities– Thyroid abnormality– Electrolyte abnormality– Glucose abnormality– Vitamin deficiencies – Cushing’s disease– Addison’s disease– Organ failure (liver, renal, respiratory)

• Medication side effects – Anti-cholinergics, pain meds

• Mood disturbance• Seizures• Edema• Substance use/abuse

– Poor adherence to medication schedule due to cognitive dysfunction• Pill box, alarms, caregiver support

Address“Reversible”Contributors

GetMoving

EatSmart

ControlRisks

RestWell

KeepSharp

StayConnected

Cleveland Clinic, Healthy Brains

-Aerobic: 150minutesmoderate/75minutesvigorous

-Strength: 2x/week

MaintainingBrainHealth

PhysicalActivity-morenewneurons-properorientation

PhysicalActivity

GetMoving

EatSmart

ControlRisks

RestWell

KeepSharp

StayConnected

Cleveland Clinic, Healthy Brains

-Aerobic: 150minutesmoderate/75minutesvigorous

-Strength: 2x/week

-Staymentallyactive-Remaincurious-Learnnewhobby,skill…-Play:engageyourbrain

MaintainingBrainHealth

EnvironmentalEnrichment-morehippocampalneurons-improvedmemory

CognitiveStimulation

GetMoving

EatSmart

ControlRisks

RestWell

KeepSharp

StayConnected

Cleveland Clinic, Healthy Brains

-Aerobic: 150minutesmoderate/75minutesvigorous

-Strength: 2x/week

**Dietician-Low-carbdiet-Mediterraneandiet-Avoid:saturatedfat,transfat,addedsugars

-Bloodpressure-Cholesterol-Avoidsmoking-Moderatealcoholintake

-Staymentallyactive-Remaincurious-Learnnewhobby,skill…-Play:engageyourbrain

-7-9hourssleep-Managestress

-Socialsupport-Insulatesagainststress-Stimulatingconversation

MaintainingBrainHealth

-nobeneficialeffectonfatigue(nordepression,HRQOL,cognitivefunction)

Gagnon et al., J Psychiatry Neurosci, 2005

Pharmacological:StimulantsFatigueandCognition

-modestbeneficialeffectonfatigue-beneficialeffectsonhypoactivedeliriuminadvancedcancerpatients (Gagnon,2005)

PathdiagramforaStructuralEquationModel(redlinesarestatisticallysignificant).CBTimpactsfatiguethroughreductionininsomniaseverity.

Pharmacological:CBTvs ArmodafinilFatigueandSleepDisturbance

Heckler et al., Support Care Cancer, 2016

• N= 198 (26% attrition at 24 weeks), 25% brain mets

• 24 weeks of donepezil (5mg for 6 weeks, 10mg for 18 weeks) or placebo

• After 24 weeks there was no difference between placebo and donepezil in the amount of change on the composite cognitive function variable or 13/16 other cognitive test scores

• Exploratory subgroup analysis suggested better effects in individuals with greater cognitive dysfunction prior to treatment

Pharmacological:DonepezilafterRadiation(> 6mos)

• Goal: reduce the interference of cognitive inefficiencies on everyday life• Compensatory Strategy Training

• Utilize preserved skills to support areas of cognitive weakness• Use visual memory capacity to support verbal memory disorder

• Mnemonics, chunking, elaborative rehearsal, spaced retrieval• Minimize distractions

• Cognitive prostheses• Memory prosthesis - Smart phone (calendar, alarms, etc)

• Environmental modifications• Psychotherapy and psychoeducation

• Improve coping, stress management• Brain injury and functional impact• Identify high risk situations, anticipate and plan

• Reviews: Cicerone et al, APMR, 2005; Gehring et al., Expert Rev, 2010

Behavioral:CognitiveRehabilitation

Behavioral:ComputerizedTraining

“…evidencethatbrain-traininginterventionsimproveperformanceonthetrainedtasks,lessevidencethatsuchinterventionsimproveperformanceoncloselyrelatedtasks,andlittleevidencethattrainingenhancesperformanceondistantlyrelatedtasksorthattrainingimproveseverydaycognitiveperformance.”

• Neurodegenerative processes initiated very early– Vascular endothelial damage– Inflammation and microglial dysregulation– Oligodendrocyte injury– Neuronal damage and altered neurogenesis– Epigenetic aberrations

PathogenesisofRadiationDamage

• Mesenchymal stem cells

0 5 10 15 Days

Cisplatin2.3mg/kg5dailyinjections

Cisplatin2.3mg/kg5dailyinjections

IntranasalMSC1x106

S a line

MS C

C isp la

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C isp la

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+ MS C

-0 .1

0 .0

0 .1

0 .2

0 .3

0 .4

Dis

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IntranasalMSCforcisplatincognitiveimpairment

IntranasalMSC1x106

CognitionBraindamage

CourtesyofCobiHeijnen,PhD

PreclinicalTranslationalOpportunities

PreclinicalTranslationalCognitiveLab

Merci!