Neurocognitive Dysfunction in Brain Tumor Patients

1. Neurocognitive Dysfunction in Brain Tumor Patients Renee Hinsley Raynor, Ph.D. Clinical Neuropsychologist The Preston Robert Tisch Brain Tumor Center at Duke

2. The Neurocognitive Impact of Brain Tumors: A Growing Problem • In 2012, an estimated 688,000+ people in the US were living with a primary brain or CNS tumor diagnosis (138,000 malignant and 550,000 benign) • An estimated 69,720 new cases of primary brain tumors were expected to be diagnosed in 2013 and includes both malignant (24,620) and non-malignant (45,100) brain tumors • CBTRUS Statistical Report (2012)

3. The Neurocognitive Impact of Brain Tumors: A Growing Problem • Agencies funding cancer research are calling for a increased emphasis on disease-related symptoms and/or quality of life (in addition to survival and response rates) • As cancer treatment becomes more successful, more patients will live longer and expect to return to their baseline level of functioning

4. Brain Tumors: Impact of Neurocognitive Impairment • Personal loss of independence and dignity for patients • Caregiver demand on family and friends • Financial burden on patient and family to supply adequate care • Financial burden on society due to lost productivity of patients and caregivers

5. Sound familiar?

6. Neurocognitive Impairment in Brain Tumor Patients • Memory loss • Distractibility and inattention • Difficulty with multi-tasking • Mood disturbance • Decreased executive control • Decreased initiative, increased apathy • Decreased inhibition, behavioral dysregulation

7. Etiology of these Neurocognitive Deficits • Direct effects of cancer within CNS • Indirect effects of certain cancers (paraneoplastic disorders) • Effects of cancer treatments on brain (surgical and medical) • Effects of pharmacological treatments for the cancer and related complications • Co-existing neurologic or psychiatric disorders

8. Effects of Lesion Location • Although cognitive symptoms caused by brain tumors may exhibit relatively focal effects, they tend to be less dramatic than those seen in patients with more acute onset lesions • Cognitive impairment is often associated with tumors of either hemisphere in any lobe (cortical and subcortical)

9. Effects of Lesion Location • Neurocognitive impairment tends to be less localized in brain tumor patients than in patients with more acute neurologic lesions • This may be due to destruction of collateral tissue by the tumor or may be related to diffuse effects of treatment modalities and agents

10. Effects of Lesion Location • Impairment in frontal lobe function is ubiquitous in brain tumor patients • (decreased mental flexibility, abstraction, motivation, planning, organizational skills, ability to benefit from experience; increased personality changes) • Large proportion of patients have frontal lobe tumors • Frontal lobes have rich afferent and efferent connections with all other brain regions

11. Effects of Neurosurgery • Whether patients undergo biopsy or resection, neurosurgery is an invasive procedure and neurocognitive recovery time is measured in months • While some patients eventually return to near baseline cognitive functioning post-op, many do not due to the tumor’s invasion of previously normal brain

12. Wouldn’t this be nice?

13. Effects of Histology • Level of impairment varies depending on lesion location, treatment modalities used, and host characteristics (e.g., age, concurrent medical problems) • Higher grade tumors are associated with greater cognitive impairment in most cases, but it is unclear whether this is inherently related to histology or perhaps more due to degree of progression and associated destruction of normal brain tissue

14. Effects of Histology • Patients with low grade tumors that have been present for many years may have little to no cognitive change because of cerebral plasticity and reorganization • Alternatively, patients with large low grade tumor burden or with low grade tumors in critical cognitive areas may show devastating cognitive/behavioral decline

15. Effects of Lesion Location and Histology • Patients with left hemisphere tumors and GBM demonstrated testable differences in neuropsychologic functioning and QOL* • Hahn CA, Dunn RH, Logue PE, King JH, Edwards CL, Halperin EC. A Prospective Study of Neuropsychologic Testing and Quality of Life Assessment of Adults with Primary Malignant Brain Tumors. International Journal of Radiation Oncology, Biology, Physics 55(4):992-999, 2003.

16. Effects of Lesion Location and Histology • Female gender, lower tumor grade, presence of comorbidities, and lower education level were associated with generalized anxiety and depressive mood symptoms* * Arnold, SD, Forman, LM, Brigidi, BD, Carter, KE, Schweitzer, HA, Quinn, HE, Guill, AB, Herndon II, JE, and Raynor, RH. Evaluation and Characterization of Neuropsychiatric Symptoms in Patients with Primary Brain Tumors. Neuro-oncology. 10(2):171, 2008.

17. Effects of Radiation Therapy • Cognitive areas impaired may include processing speed, executive function, memory, sustained attention, and psychomotor coordination • Some of these deficits are thought to be related to periventricular white matter damage; hyperintensities observed on neuro-imaging

18. Effects of Radiation Therapy • Pattern of cognitive deficits is not unlike that seen in other subcortical diseases of the white matter such as MS • Children are particularly vulnerable to radiation injury; even relatively low doses of cranial irradiation is associated with mild intellectual declines in older children (younger children show more severe deficits)

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21. Effects of Radiation Therapy • Literature presents conflicting evidence as to whether concomitant chemotherapy increases the neurotoxicity of radiation therapy • Fatigue from radiation therapy can be physical and mental and may cause a deleterious effect on cognition for a period of time that extends far beyond completion of treatment • With relatively recent dramatic improvements in the delivery of radiation therapy, we expect to see increased sparing of neurocognitive functioning

22. Effects of Chemotherapy • Neurocognitive effects of chemotherapy were previously thought to be reversible; growing literature suggests persistent cognitive deficits in patients who have received standard-dose chemotherapy • The risk appears greater after high-dose chemotherapy such as with bone marrow transplant (long term effects unknown)

23. Effects of Chemotherapy • Most impairment related to chemotherapy tends to be relatively diffuse, affecting sustained attention and speed of processing • Fatigue and hematologic toxicity related to chemotherapy likely negatively impact cognition, but evidence suggests persistent deficits for considerable time after treatment concludes

24. Effects of Chemotherapy • Mechanisms underlying chemotherapy-related cognitive impairment • Metabolic disturbances secondary to other organ toxicities • Differences between human subjects and animals used in pre-clinical toxicity studies • Unanticipated breach of the blood-brain-barrier • Pre-existing host characteristics

25. Effects of Other Cancer Therapies • Immunotherapy-cytokines such as Interferon-alpha appear to cause a wide range of persistent cognitive deficits; perhaps due to proinflammatory actions and/or stress hormone cascade • Hormone ablation therapies-Tamoxifen has been associated with depression, decreased concentration, and irritability; perhaps due to effects on dopamine and serotonin

26. Effects of Other Cancer Therapies-Avastin • Avastin (bevacizamab) is an anti-angiogenesis compound that received FDA accelerated approval in GBM in 2009 • Conflicting data between AVAglio and RTOG 0825 as to impact on neurocognitive functioning and QOL • PRTBTC clinical results more in line with AVAglio study showing longer PFS and improved cognition and QOL (reduced steroid reliance)

27. Effects of Adjuvant Medical Treatment • In addition to the primary cancer therapy agents, many brain tumor patients require a number of medications to manage disease and treatment-related symptoms • Many of these drugs have cognitive and mood effects which further complicate the picture of neurocognitive decline

28. Effects of Adjuvant Medical Treatment — Common Drugs • Steroids • Anti-convulsants • Pain meds/narcotics • Psychotropics • Anti-emetics • Immunosuppressive agents

29. Effects of Comorbid Conditions • Age-related neurocognitive disorders • Cerebrovascular disease/hypertension • Traumatic brain injury • Attention Deficit Hyperactivity Disorder • Developmental disorders • Learning disorders • Mood/Psychiatric disorders • Metabolic disorders, infections, etc.

30. Role of Neuropsychological Assessment • For treatment options that may offer only slightly different survival/response rates, the rationale for selecting a particular therapy may be highly related to impact on cognitive function and quality of life • “Baseline” neurocognitive evaluation can provide data useful in monitoring disease progression/response to treatment (in addition to scans, neurologic exams, etc.)

31. Role of Neuropsychological Assessment • The specific cause (or causes) underlying cognitive dysfunction is important in guiding interventions and treatment planning • The type of intervention recommended may be quite different depending on the specific pattern of the cognitive deficit and/or the etiology of the deficit

32. Role of Neuropsychological Assessment

33. Role of Neuropsychological Assessment • Repeat neuropsychological evaluations can quantify the potential efficacy of any interventions implemented • Neuropsychological assessment is often crucial in assisting patients in obtaining disability benefits, or alternatively, in helping them maintain or return to their jobs if they are cognitively intact

34. Neuropsychological Interventions — Rehabilitation • Supportive and solution-focused psychotherapy • Adjustment to disability/grief for losses • Problem solving to increase independence • Cognitive retraining • Restoring the impaired cognitive skill • Learning strategies to compensate for the impaired cognitive ability • Self cognitive rehab (e.g., Lumosity)

35. Neuropsychological Interventions — Rehabilitation • Memory strategies • Attention strategies • Problem solving strategies • Organizational strategies • Behavior management (for impulsivity, emotional dysregulation, etc.) • Social skills retraining

36. Neuropsychological Interventions — Rehabilitation • Internal aids – emphasize conscious utilization of cognitive facilitation techniques (e.g., rehearsal training) • Perceptual grouping (e.g., clustering) • Organization (e.g., categorizing) • Mediation (e.g., mnemonics) • Mental imagery/association (e.g., linking)

37. Neuropsychological Interventions — Rehabilitation • External aids – incorporating external cues/props already familiar to the patient into the overall assistive device planning (e.g., “memory notebook”) • Autobiographical data/important numbers • Daily events log/schedule • Calendar • To-do list • Transportation/medication information

38. Resources for Rehabilitation • Neuropsychologists (evaluation based cognitive retraining modules/programs) • Speech/occupational/physical therapists • Vocational rehabilitation programs • Brain injury treatment programs • Self-study and caregiver interventions with commercial workbooks, computer programs, etc.

39. Neuropsychological Interventions — Pharmacologic • Stimulants (RitalinTM, AdderallTM, etc.) – may improve fatigue, somnolence, slowed speed of processing, inattention, decreased motivation, mood, etc. • Best to titrate the dose up slowly over time; our typical dose is 10-15 mgs bid for RitalinTM but some patients can tolerate fairly high doses (30 to 40 mg bid) • Possible Complications – lowered seizure threshold, agitation, irritability, weight loss

40. Neuropsychological Interventions — Pharmacologic • Memory Agents (e.g., AriceptTM, NamendaTM, etc.) – clinical trial at PRTBTC at Duke showed subtle clinical efficacy of AriceptTM in brain tumor patients with documented memory deficits • Promising results with these agents in other neurologic populations (TBI, VAD) in addition to Alzheimer’s disease

41. Neuropsychological Interventions — Pharmacologic • Psychotropics (antidepressants, antipsychotics, anxiolytics, etc.) – may be useful in controlling mood and/or behavioral dysfunction associated with cancer and/or related treatment • Anecdotal responses in brain tumor patients for reducing depression, anxiety, perseverative thoughts, irritability, disinhibition, etc.

42. Neuropsychological Interventions — Pharmacologic • Other agents with CNS effects and potential efficacy in treating cognitive deficits in brain tumor patients: • Dopamine agonists (e.g., Amantadine) • Narcolepsy meds (e.g., ProvigilTM) • Hormone replacement (e.g., Testosterone) • Other (e.g., Vitamin E, antioxidants)

43. Patient/Family Interventions — Education and Support • Educating patients and caregivers early about possible cognitive deficits/mood and behavioral disturbances helps them cope and plan for such changes • Support groups/websites help patients with cognitive deficits related to their brain tumors (and their caregivers) feel less isolated and alone

44. Patient/Family Interventions — Education and Support • Simple strategies such as using memory lists, taking brief naps, and using written reminders instead of verbal “nagging” can improve the quality of life for patients and caregivers • Providing hope, while helping patients and caregivers adjust to their “new normal”, is crucial for improved coping

45. Embracing the “new normal” is not easy, but we can try to help

46. Sample References • Weitzner, M.A. & Meyer, C.A. (1997). Cognitive functioning and quality of life in malignant glioma patients: A review of the literature. Psycho-oncology, 6, 169-177. • Meyers, C.A., Hess, K.R., Yung, W.K., & Levin, V.A. (2000). Cognitive function as a predictor of survival in patients with recurrent malignant glioma. Journal of Clinical Oncology, 18, 646-650.

47. Sample References • Carlson, R.H. (2000). ‘Chemobrain’ Cognitive loss confirmed in adult cancer patients receiving systemic chemotherapy. OncologyTimes, 22, 35-38. • Meyers, C.A. (2000). Neurocognitive dysfunction in cancer patients. Oncology, 14, 75-79. • Meyers, C.A. (2001). Neurocognitive aspects of cancer and cancer treatment. Presentation at the International Neuropsychology Society, Chicago.

48. Sample References • Meyers, CA, Hess, KR (2003) Multifaceted end points in brain tumor clinical trials: cognitive deterioration precedes MRI progression. NeuroOncol 5(2): 89-95. • Zuccharella C, Bartolo M, Di Lorenzo C, VillaniV, Pace A (2013) Cognitive impairment in primary brain tumors outpatients: a prospective cross-sectional survey. J Neurooncol 112: 455-460.

49. Sample References • Wefel, JS, Schagen, AB (2012) Chemotherapy-Related Cognitive Dysfunction. CurrNeurolNeurosci Rep 12: 267-275. • Breindl, A (ed.) ASCO 2013: GBM Trials Bring Frustrating Answers and New Questions. Bioworld.com.

50. Activism  Awareness  Funding  Research  Cure