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Cognitive changes and fatigue in lung cancer

Cognitive changes and fatigue in lung cancer. Fremonta Meyer, MD Department of Psychosocial Oncology and Palliative Care Dana-Farber Cancer Institute, Brigham and Women’s Hospital Assistant Professor of Psychiatry, Harvard Medical School. Acknowledgments. Dana-Farber and the NCCN

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Cognitive changes and fatigue in lung cancer

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  1. Cognitive changes and fatigue in lung cancer Fremonta Meyer, MD Department of Psychosocial Oncology and Palliative Care Dana-Farber Cancer Institute, Brigham and Women’s Hospital Assistant Professor of Psychiatry, Harvard Medical School

  2. Acknowledgments Dana-Farber and the NCCN Ilana Braun, MD David Silbersweig, MD Hadine Joffe, MD Jean Alvarez, EdD Sue Harden

  3. Outline • Impact • ‘Chemobrain’ and other causes • Research findings • Interventions

  4. Patient experiences • “I have been so lost [while driving], I just pull over, and break down and start crying. Because it’s places I’ve been before and I know where I am going…” • “I couldn’t remember if I looked at a stoplight. I felt like it was putting myself at risk.” • “What I have to do sometimes is have my son come over and pay my bills.”* * Boykoff et al, J Cancer Surviv, 2009

  5. Impact • Invisible –> not always acknowledged by medical community, family, friends • Difficulty with job performance, driving, other important activities • Avoidance of social occasions • Depression and anxiety * Boykoff et al, J Cancer Surviv, 2009

  6. Chemobrain affects many areas of cognitive function. • Memory • Attention and concentration • Information processing speed • Executive function • Initiation • Planning • Organization • Multi-tasking • Response inhibition

  7. The majority of people on chemotherapy experience cognitive side effects. • 67% of patients described memory and concentration problems during chemotherapy • These problems do not necessarily resolve immediately after a break in treatment Memory Concentration *Kohli et al, J Oncol Practice, 2007

  8. Chemobrain leads to dysfunction of frontal-subcortical brain networks.

  9. Chemobrain ≠ dementia • Chemobrain is not a progressive condition • Chemobrain does not increase risk for Alzheimer’s disease • Cancer patients who received chemotherapy may actually have a LOWER risk of developing dementia (Du XL et al, Am J Clin Onc, 2010) • There are different cognitive findings in Alzheimer’s disease • In Alzheimer’s, memory cues don’t help • In chemobrain, memory cues help

  10. *Ferguson et al, JCO, 2007

  11. New studies confirm: something is going on. 18 people with breast cancer performed a multitasking exercise in the fMRI scanner -- before chemo and 4-6 months after chemo They were compared to 16 people who did not get chemo, and 17 healthy people No differences at baseline People who got chemo had decreased activation in the brain’s “multitasking network” and this was associated with cognitive complaints No changes in activation for the other two groups *Deprez S et al, JCO, 2014

  12. The dentate gyrus of the hippocampus is involved in the formation of new memories.

  13. A close-up of the dentate gyrus

  14. What is the blood-brain barrier (BBB)? • Microscopic objects (e.g. bacteria) can’t get in. Neither can hydrophilic molecules. But it doesn’t keep everything out…

  15. Cyclophosphamide (cytoxan) and 5-fluorouracil can cross the BBB. • Doxorubicin and paclitaxel (sometimes used in lung cancer) do not directly cross the BBB.

  16. In mice, chemotherapy agents may slow cell growth in the dentate gyrus of the hippocampus. *Janelsins et al, Cancer Investigation, 2010

  17. Take-home point Even chemotherapies that do not cross the blood-brain barrier (BBB) might cause decreased growth (but not death) of neurons!

  18. “Seed” “Soil” “Pesticide”

  19. Cancer and chemotherapy… • Leads to increased production of inflammatory chemicals called cytokines • e.g. TNF (tumor necrosis factor) • Higher levels may predict worse cognitive function after chemotherapy for breast cancer* • Some women had genetic differences in the TNF gene that made them less likely to develop problems • What are these differences? *Ganz P, Bower JE, et al, Brain Behav Immun 2013

  20. Variations in sequences of DNA A single allele is different Make us differentially susceptible to (or protected from!) all kinds of diseases Examples: TNF BDNF (brain-derived neurotropic factor) Apolipoprotein (ApoE4=more prone to Alzheimer’s disease) These SNPs may make some people unable to repair the DNA damage that causes cognitive problems Single nucleotide polymorphisms (SNPs)

  21. Hormonal fluctuations can also affect cognition • High levels of estrogen increase verbal memory, verbal fluency and fine motor skills • Abrupt menopause (e.g., due to chemotherapy) • Acute decline in verbal memory • It’s unclear that hormone replacement therapy truly protects against dementia

  22. Other causes of cognitive problems Previous brain radiation (preventive in small cell lung cancer) Brain metastases Leptomeningeal disease (spread of cancer cells into the fluid surrounding brain and spinal cord) It’s uncommon that cognitive problems are the only symptom Talk to your oncologist if you have cognitive problems + new or worsening headaches, unsteady gait, nausea/vomiting, dizziness

  23. Chemobrain is associated with several common, treatable problems. • Sleep disturbance • Fatigue • Depression • Anxiety

  24. Fatigue • Up to 90% of patients after lung cancer surgery and/or chemotherapy • 16-40% of patients on immunotherapy • If fatigue severe, important to consider thyroid, pituitary or adrenal insufficiency as these can be side effects of immunotherapy

  25. What can be done?

  26. Medications • Stimulants • Methylphenidate (Ritalin, Concerta, Focalin), Dextroamphetamine (Adderall)* • Most effective for fatigue, attention/concentration • Especially helpful if on opioid medications for pain • Modafinil (Provigil)* • Improved attention and memory in a group of breast cancer survivors with fatigue • Armodafinil (Nuvigil) *Mar Fan et al, Support Care Cancer, 2008 *Kohli et al, Cancer, 2009

  27. Medications • Antidepressants help some people with cognitive issues. • Celexa (citalopram), Zoloft (sertraline), Lexapro (escitalopram), Prozac (fluoxetine), Paxil (paroxetine) • Effexor (venlafaxine), Cymbalta (duloxetine) • Wellbutrin (bupropion) • Remeron (mirtazapine) • It’s important to limit use of medications with cognitive side effects. • Opioid pain medications (if possible) • Benadryl (diphenhydramine) • Benzos - lorazepam (Ativan), clonazepam (Klonopin), alprazolam (Xanax), diazepam (Valium) • Sleep medications such as zolpidem (Ambien), eszopiclone (Lunesta)

  28. Certain antidepressants (the SSRIs citalopram, fluoxetine, sertraline) increase levels of BDNF, increase neurogenesis, and increase branching of dendritic connections.

  29. Treatments for brain metastases Stimulants (Ritalin) helpful for fatigue after whole brain radiation Memantine (Namenda) may help prevent additional cognitive problems from developing after whole brain radiation Donezepil (Aricept) may help memory and motor speed after radiation *Rapp et al, JCO, 2015; Brown PD et al, Neurooncology, 2013

  30. Regular aerobic exercise May improve neural proliferation in the dentate gyrus In a review of many studies, this was the only factor associated with lowering the risk of dementia Social connections Good nutrition e.g. fish w/omega 3’s, antioxidants, flavanols Other activities

  31. Weight gain from cancer treatment puts people at higher risk Masks are more comfortable than they used to be Don’t give up!! Start with a few hours a night and work up gradually Sleep apnea…

  32. Cognitive rehabilitation • It’s done by a speech-language pathologist • This is often covered by insurance – specifically, your physical/occupational therapy benefit • Exercises to retrain your brain • Tracking and understanding what causes cognitive worsening • e.g. fatigue • Coping strategies • PDAs; 1 notebook w/3 sections; Note taking • Stress relief strategies • Diaphragmatic breathing; muscle relaxation; guided imagery

  33. The idea behind cognitive rehabilitation is to compensate for the deficits by learning to work around them. “But… I want my backhand to come back!!”

  34. Newest developments are taking advantage of brain plasticity to restore function. • Brain fitness exercises improved objective (memory/processing speed) and subjective cognitive function in RCTs (total n=82; n=42)32-33(von Ah D, Carpenter JS, Saykin A, et al, Breast Cancer Res Treat, 2012; 135:799-809; Kesler S, HadiHosseini SM, Heckler C, et al, Clin Breast Cancer 2013;13(4):299-306) www.positscience.com, www.lumosity.com

  35. EEG biofeedback (neurofeedback) may also offer promise • EEG biofeedback improved subjective cognitive function, sleep, fatigue, anxiety/depression in waitlist control trial (n=23) (Alvarez et al, J Integrative Cancer Therapies, 2013) • See www.zengar.com/research

  36. In order to have chemobrain, you have to be alive.

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