Maintaining Cognitive Function in Patients ... - Brain...
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Maintaining Cognitive Function in Patients with CNS Metastases Receiving Multimodality Treatment Jeffrey S. Wefel, PhD, ABPP Section Chief and Associate Professor Section of Neuropsychology Department of Neuro-Oncology and Department of Radiation Oncology
Transcript of Maintaining Cognitive Function in Patients ... - Brain...
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Meyersetal.,JCO,2004;Wefel,unpublished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
t in
C isp la
t in
+ MS C
-0 .1
0 .0
0 .1
0 .2
0 .3
0 .4
Dis
cri
min
ati
on
in
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* *
IntranasalMSCforcisplatincognitiveimpairment
IntranasalMSC1x106
CognitionBraindamage
CourtesyofCobiHeijnen,PhD
PreclinicalTranslationalOpportunities
PreclinicalTranslationalCognitiveLab
Merci!
