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
Objectives Review cognitive dysfunction in patients with brain mets Highlight approaches to the clinical management of cognitive dysfunction Introduce emerging preclinical-translational cognitive science
Brain Metastasis Overall incidence >10-16% (lung, breast, melanoma) >170,000/year in USA Challenges related to maintaining cognitive function Disease and treatment = cognitive dysfunction Efficacy / Toxicity balance ( Therapeutic window ) Limited treatments to protect or restore cognitive function Improved OS NSCLC Breast Melanoma Sperduto, JCO, 2012; Nayak et al, Curr Neurol Rep, 2012
Brain Mets Cognitive Dysfunction 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 NCF Test Multiple % Impaired (N=401) Single % Impaired (N=80) 0 Impaired 9 36 >1 Impaired 91 64 >4 Impaired 42 10 MEMORY HVLT-R TR 60 41 PROCESSING SPEED TMT A 33 18 EXECUTIVE FUNCTION TMT B COWA FINE MOTOR CONTROL Dominant Hand Nondominant Hand 44 32 65 63 16 17 22 23 Meyers et al., JCO, 2004; Wefel, unpublished
Multimodality Treatment management Strategies Goal: Control brain disease without toxicity, and extend life while preserving function/qol Treatment Approach Surgery Radiation Chemotherapy Immunotherapy Optune (TTF) Combinations of the above Challenges Residual disease Inaccessible tumor Dose constraints location Off target tox (cognitive decline) BBB, branched evolution, chemobrain Neurotoxicity -seizure -inflammation -CRS, AMS Potential Solutions -Fluorescence -LITT -Brachytherapy, improved targeting -SRS, WBRT sparing techniques -Sensitizers? -Targeted therapy -? symptom management? -METIS trial (SRS+/-TTF in NSCLC) -Patient tolerance -Risk adapted therapy Adapted from Hardesty & Nakaji, Front Surg, 2016
Maximizing Cognitive Function 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
Preventing Cognitive Decline Technological SRS +/- WBRT for 1-3 mets (MDACC ID00-377, NCCTG N0574) Chang et al., Lancet Oncol, 2009
Preventing Cognitive Decline Technological SRS +/- WBRT for 1-3 mets (MDACC ID00-377, NCCTG N0574) Chang et al., Lancet Oncol, 2009; Brown et al., JAMA 2017
Preventing Cognitive Decline Technological SRS +/- WBRT for 1-3 mets (MDACC ID00-377, NCCTG N0574) HA-WBRT (RTOG 0933) HA-WBRT decline at 4 months = 7% vs 30% (hxl cntl) Chang et al., Lancet Oncol, 2009; Brown et al., JAMA 2017; Gondi et al., JCO, 2014
Preventing Cognitive Decline Pharmacological Neuroprotection (RTOG 0614) N=508 eligible Stratify: -RPA Class* -Prior Surgery** 20mg Memantine Daily x 24 weeks WBRT: 37.5 Gy (15 Fx of 2.5 Gy) Placebo Daily x 24 weeks Cognitive Function Failure (%) 100 75 50 25 Failures Total 219 256 p (one-sided) = 0.01 219 252 HR= 0.784 (0.621, 0.988) 0 0 3 6 9 12 15 Patients at Risk Memantine Placebo 75 66 Months from Randomization 33 25 27 19 15 12 Memantine Placebo Memantine increased time to cognitive decline, HR=0.78, p=0.001 9 9 Brown et al., Neuro-Onc, 2013
Preventing Cognitive Decline Pharmacological Neuroprotection (RTOG 0614) N=508 eligible Stratify: -RPA Class* -Prior Surgery** WBRT: 37.5 Gy (15 Fx of 2.5 Gy) Placebo Daily x 24 weeks Technological +/- Pharmacological NRG CC001: A Randomized Phase III Trial of Memantine +/- Hippocampal Avoidance in Patients with Brain Metastases Brain mets Stratify: -RPA Class -Prior Therapy WBRT + Memantine HA-WBRT + Memantine Primary: Time to cognitive failure 20mg Memantine Daily x 24 weeks NRG CC003: Phase IIR/III Trial of Prophylactic Cranial Irradiation with or without Hippocampal Avoidance for Small Cell Lung Cancer SCLC Cognitive Function Failure (%) 100 75 50 25 Patients at Risk Memantine Placebo Stratify: -Stage -Age -Planned Memantine Failures Total 219 256 p (one-sided) = 0.01 219 252 HR= 0.784 (0.621, 0.988) 0 0 3 6 9 12 15 75 66 Months from Randomization PCI (25Gy x 10) HA-PCI (25Gy x 10) Primary Ph II intracranial relapse rate, non-inferiority Primary Ph III HVLT-R DR decline at 6 months, efficacy 33 25 27 19 15 12 Memantine Placebo Memantine increased time to cognitive decline, HR=0.78, p=0.001 9 9
Maximizing Cognitive Function 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
Address Reversible Contributors 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
Maintaining Brain Health Stay Connected Get Moving -Aerobic: 150 minutes moderate / 75 minutes vigorous -Strength: 2x/week Eat Smart Keep Sharp Control Risks Rest Well Cleveland Clinic, Healthy Brains
Physical Activity Physical Activity -more new neurons -proper orientation
Maintaining Brain Health Stay Connected Get Moving -Aerobic: 150 minutes moderate / 75 minutes vigorous -Strength: 2x/week Eat Smart Keep Sharp -Stay mentally active -Remain curious -Learn new hobby, skill -Play: engage your brain Rest Well Control Risks Cleveland Clinic, Healthy Brains
Cognitive Stimulation Environmental Enrichment -more hippocampal neurons -improved memory
Maintaining Brain Health Stay Connected -Social support -Insulates against stress -Stimulating conversation Get Moving -Aerobic: 150 minutes moderate / 75 minutes vigorous -Strength: 2x/week Eat Smart **Dietician -Low-carb diet -Mediterranean diet -Avoid: saturated fat, trans fat, added sugars Keep Sharp -Stay mentally active -Remain curious -Learn new hobby, skill -Play: engage your brain Rest Well -7-9 hours sleep -Manage stress Control Risks -Blood pressure -Cholesterol -Avoid smoking -Moderate alcohol intake Cleveland Clinic, Healthy Brains
Pharmacological: Stimulants Fatigue and Cognition -no beneficial effect on fatigue (nor depression, HRQOL, cognitive function) -modest beneficial effect on fatigue -beneficial effects on hypoactive delirium in advanced cancer patients (Gagnon, 2005) Gagnon et al., J Psychiatry Neurosci, 2005
Pharmacological: CBT vs Armodafinil Fatigue and Sleep Disturbance Path diagram for a Structural Equation Model (red lines are statistically significant). CBT impacts fatigue through reduction in insomnia severity. Heckler et al., Support Care Cancer, 2016
Pharmacological: Donepezil after Radiation (> 6 mos) 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
Behavioral: Cognitive Rehabilitation 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: Computerized Training evidence that brain-training interventions improve performance on the trained tasks, less evidence that such interventions improve performance on closely related tasks, and little evidence that training enhances performance on distantly related tasks or that training improves everyday cognitive performance.
Pathogenesis of Radiation Damage Neurodegenerative processes initiated very early Vascular endothelial damage Inflammation and microglial dysregulation Oligodendrocyte injury Neuronal damage and altered neurogenesis Epigenetic aberrations
Preclinical Translational Opportunities Mesenchymal stem cells Cisplatin 2.3 mg/kg 5 daily injections Cisplatin 2.3 mg/kg 5 daily injections Intranasal MSC 1x10 66 Cognition Brain damage 0 5 10 15 Days Intranasal MSC for cisplatin cognitive impairment D is c rim in a tio n in d e x 0.4 0.3 0.2 0.1 0.0 * * - 0.1 S a lin e M S C C is p la tin C is p la tin + M S C Courtesy of Cobi Heijnen, PhD
Preclinical Translational Cognitive Lab
Merci!