9/29/2017. Disclosures. Objectives. Cancer-Related Cognitive Dysfunction (CRCD)

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1 Cancer Related Cognitive Dysfunction (CRCD): Diagnosis, Pathophysiology and Management Disclosures No conflict of interest disclosures M. Beatriz Currier, MD John M Cassel Memorial Breast Cancer Symposium Sept 23, 2017 Objectives Discuss the prevalence, phenomenology and course of cancer related cognitive dysfunction (CRCD) in patients with breast cancer Identify risk factors associated with CRCD Review the neuroanatomical correlates and biological mechanisms of CRCD Review CRCD treatment strategies Cancer-Related Cognitive Dysfunction (CRCD) Pattern of deficits reflecting the CNS toxic effects of cancer and its treatment: verbal memory sustained attention executive function processing speed Highly prevalent 25 % pre-treatment 75% during treatment 35% post-treatment May be subtle or dramatic Variable course temporary or permanent; stable or progressive CRCD research in infancy longitudinal, controlled studies, modest sample size Jenelsins M 2014 Intl Rev Psychiatr; Ahles T 2008 Br Cancer Res and Treat; Jansen 2011 Supportive Care in Cancer; WienekeMH 1995 Psycho Oncology 1

2 The International Cognition and Cancer Task Force (ICCTF) CRCD Longitudinal Prospective Studies Assessment of CRCD Objective test > subjective test Bedside clinical exam MMSE inadequate Neuropsychological testing focus on learning and memory, processing speed, and executive function Recommended test: Hopkins Verbal Learning Test-Revised (HVLT-R) Trails A and B Making Test Controlled Oral Word Association (COWA) of the Multilingual Aphasia Examination 20 longitudinal prospective studies predominantly breast cancer patients 581 breast cancer patients more likely to self-reportsignificant cognitive decline (FACT-Cog) when compared to 364 age-matched controls assessed at 2 time points: assessment 581 breast cancer 364 age-matched controls pre-ctx to post-ctx= 45% 10% p<.001 at 6 month follow up= 37% 14% p<.001 Controls matched for age (mean = 53 yrs), education, cognitive reserve (baseline reading ability), menopausal status Treatment regimen, hormone, radiation therapy were not significantly associated with cognitive decline scores (Wefel, 2011, Lancet Oncology; Hutchinson 2012; Janelsins M 2014 Int Rev Psychiatr Janelsins 2017 JCO; Ahles et al., 2010; Benderetal., 2006; Bigliaet al., 2012; Collins et al., 2009;Debess et al., 2010; Fan et al., 2005; Hedayatiet al.,2012; Hermelink et al., 2007, 2008; Hurria et al.,2006; Jansen et al., 2011; Jenkins et al., 2006;Mehlsen et al., 2009; Quesnel et al., 2009; Schagenetal., 2006; Shilling et al., 2005; Stewart et al.,2008; Tageret al., 2011; Vearncombeet al., 2009;Wefel et al., 2004, 2010 Cognitive Function PRIOR to adjuvant therapy Hormone therapy impacts cognitive performance 132 invasive/non-invasive breast cancer patients scored significantly lower than expected cognitive performance on neuropsychological testing prior to adjuvant treatment as compared to 45 age-matched controls. 110 BC (stage I-III) +22 BC (stage 0) 45 healthy- controls CRCD pre-ctx: 22% 0% 4% p<.002 Adjusted for psychological factors, fatigue, menopausal status, surgery duration/anesthesia, metabolic parameters (Hgb, B12, folate, WBC, TSH) Suggests that biology of cancer may contribute to cognitive decline Inflammatory response triggers neurotoxic cytokines Poor DNA repair mechanisms linked to cancer and neurodegenerative diseases Prospective controlled study, neuropsychological testing, 300 participants Post-menopausal (mean = 68 years) breast cancer patients (N=179) on adjuvant hormonal therapy compared to healthy controls (N=120) 2 assessment points : before hormone txand after 1 year on adjuvant hormonal therapy Tamoxifen users (N=80) had significant deterioration in verbal memory and executive function at one year compared to healthy controls; Exemestaneusers (N=99) did not have significant deficits compared to controls Ahles T et al 2011 Breast Cancer Res Treat, Schilder CM 2010 JCO 2

3 Risk Factors associated with CRCD Neuroanatomical Correlates of Cognition Attention /concentration: Frontal/Parietal lobes Working memory: ventrolateral and dorsolateral areas of the Pre frontal cortex (PFC) Executive functioning: dorsolateral prefrontal, anterior cingulate and orbitofrontal cortex Processing speed: Pre frontal cortex (PFC) and subcortical white matter networks Janelsins M 2014, Int Rev Psychiatr Impact of cancer and chemotherapy on brain structure and function in breast cancer patients Summary of structural and functional MRI studies in breast cancer patients Prior to CTX Widespread decrease in white matter volume and hyper-activation of fronto-parietal attention networks in breast cancer patients compared to controls Post-CTX Early diffuse decrease in gray matter and white matter volume and hypo-activation of frontal regions in breast cancer patients compared to controls Long term post-ctx Subgroup of patients with persistent decrease in gray and white matter volume coupled with hypo-activation frontal neocortex Findings suggest that early brain activation (hyperactivation) reflects neural compensation and long term hypoactivation may correspond to established deficits. Pathophysiologic mechanisms of CRCD Inflammatory cytokines impact in brain Genetic predisposition Failure of BBB integrity Direct/indirect chemotherapy induced brain toxicities DNA damage impacts neurogenesis and brain remodeling Reduction of estrogen and testosterone levels 3

4 CRCD: Role of Inflammation/Cytokines CRDC: Role of Cytokines Cancer patients have increased circulating levels of pro-inflammatory cytokines associated with Tumor microenvironment Cell death and tissue injury due to surgery, chemotherapy and XRT Physical and psychological stress Linear correlation between increase in peripheral cytokine levels (IL-1,IL-6, TNFalpha, MCP-1, IL-8) and cognitive dysfunction in breast cancer patients (Janelsins 2012; Wang, 2016) Increased levels of circulating stnfrecpetor 2 associated with CRCD, and decreased levels at 1 year after chemo assoc with improved cognitive performance (Ganz 2013) Lower hippocampal volume associated with higher levels of TNF-alpha, IL-6 among breast cancer survivors with CTX compared to controls.(kesler 2013) Currier MB,2014 Annual Rev Medicine ; Ganz PA, 2013, Brain, Behavior Immunity; Ahles TA, 2007 Nature Reviews Cancer; Janelsins MC, 2012 Supportive Care in Cancer; KeslerS, 2013 Brain, Behavior, Imunity) From: WangXM, et al. Cytokine Mar;72(1):86-96 CRCD: Neurotoxicity of Chemotherapy CRCD: Genetic Vulnerability or Protection Animal studies show very small doses of drugs can cause cell death and reduce cell division in the dentate gyrus of hippocampus (Dietrich, 2006 J Biol) Genetic variability of drug transporter at the blood brain barrier (Zhang, 2011) MTX: Coagulative necrosis of the white matter, axonal swelling, demyelination (Vezmar, 2003) 5-FU: Acute and delayed myelin damage (Han 2008) CTX-induced oxidative DNA damage associated with neurodegenerative diseases (Mariani, 2005) Chemotherapy shortens telomeres in glial cells (Schroder, 2001; Lahav 2005) Polymorphism of specific genes that regulate neural repair/plasticity and neurotransmission may predispose to CRCD Cancer survivors with APOE4scored lower on visual memory (AlhesTA, 2003 Psycho Oncology) BDNF Met/Met genotype protective against CTX induced cognitive changes including verbal memory and multitasking ability (Ng T, 2016, Neuro Oncology) Breast cancer survivors treated with chemotherapy and carriers of COMTval+ scored lower in verbal memory, attention, and motor speed as compared to COMT met homozygotes (Small BJ, 2011 Cancer) Neuronal plasticity genes, DNA damage and repair genes, inflammation genes? 4

5 Miami Cancer Institute Brain Fitness Lab Assessment of CRCD in adults/children Neuropsychiatric consultation, diagnostic work up 30 min computerized neurocognitive assessment of cognitive domains affected 90 min extended battery of neuropsychological tests ( Cognitive Remediation Treatment 65 patients have been assessed (48 adults + 17 children) 32 % adults diagnosed with CRCD 27% children diagnosed with CRCD CRCD Treatment Strategies Behavioral Therapies: (schedules, memory aids, routines, brain plasticity remediation training) 1. Therapist derived cognitive remediation Speech therapist/occupational therapist (12 week) Cognitive behavioral therapy for CRCD (6 week) 2. Web-based computerized cognitive remediation training Brain HQ by Posit Science (12 week) 30 minutes x4 days/week, monitored by neuropsychology technician Cog Med (12 week) 30 minutesx4 days/week, monitored by np tech Pharmacological Therapies: Methylphenidate; Modafinil Cox LE, 2015 Neuro Oncology Practice; Bray V, 2016 JCO; CorklinHM, 2010 JCO; Ferguson RJ,2012 Psycho Oncology; KeslerS2013 Clin Breast Cancer. CRCD Summary Highly prevalent in breast cancer patients Variable severity and course Assessment requires psychometric testing of verbal memory, sustained attention, executive function, processing speed Neuroimaging can be helpful but is not conclusive Consider pre-existent risk factors to mitigate CRCD (baseline cognitive reserve, menopausal status, genetic risk for cognitive impairment) Multiple pathophysiological etiologies (inflammation, neurotoxicity) Further research needed to develop effective cognitive remediation interventions and prevention models 5