Cognitive dysfunction due to cancer therapy. Aziz Yazar, MD Department of Medical Oncology Acıbadem University-Istanbul

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1 Cognitive dysfunction due to cancer therapy Aziz Yazar, MD Department of Medical Oncology Acıbadem University-Istanbul

2 Typical chemotherapy side effects temporary hair loss fatigue nausea pain depression increased risk of infection increased sun sensitivity numbness in the hands and feet

3 Cancer Survivorship Number of patients receiving chemotherapy for cancer has increased Number of cancer survivors has increased Number of survivors who are experiencing long term side effects has increased Cognitive dysfunction is one of these long term side effects

4 What does it all mean? While many patients with cancer experience some kind of cognitive problem, difficulties continue to be under-reported by patients and underdiagnosed by health care professionals. Cognitive impairment is often not included on the laundry list of potential side effects given to patients who are considering treatment.

5 I can t concentrate. I used to teach and lecture. Now, I have trouble putting sentences together. I ve lost my focus. I can t even keep track of the characters in a movie!

6 Afew examples of what patients experience with cognitive dysfunction: Forgetting things Difficulty concentrating, focusing attention Trouble remembering details like names, dates Trouble multi-tasking Taking longer to finish things Trouble finding the right words to say Feeling in a chemo fog

7 Terminology

8 Do physicians recognize cognitive dysfunction? Many physicians attribute patient s cognitive concerns to: Menopause Depression Anxiety

9 Cognitive Dysfunction in Cancer Survivors Studies show : 50-70% of breast cancer patients self report cognitive impairment 15-50% have impairment on neuropsychological (NP) testing ~30% cognitive impairment prior to CTh Poor association between self reported cognitive function and NP testing

002 Normal NP and self report normal cognition Impaired NP

10 Self Report and NP Results Colorectal Cancer Breast Cancer Males Females p = Normal NP and self report normal cognition Impaired NP and self report normal cognition Normal NP and self report impairment Impaired NP and self report impairment

11 Survivorship: Women with a history of breast cancer constitute the largest disease group in the cancer survivor community. The effects of chemotherapy on cognition have been most studied in patients with breast

12 Cognitive function, fatigue and menopausal symptoms in women receiving adjuvant CT for breast cancer Tests performed 2-6 weeks after chemotherapy CMF, CEF, AC+PACLITAXEL HEALTHY CONTROLS n (paired) Cognitive dysfunction ,008 (Severe+Moderate) Fatique score 83% poorer 10% <0,0001 Menopausal symptoms 61% poorer 14% <0,0001 Quality of life 65% poorer 20% <0,0001 Strong correlation between fatique, menopausal symptoms and quality of life None were significantly associated with the presence of cognitive dysfunction J Clin Oncol. 2003;21:

13 Prospective evaluation of cognitive dysfunction in breast cancer CT(n=85)* TMX/AI(n=43)** Control(n=49) Baseline 55% 62% 16% 6 months 51% 24% 18% 18 months 18% 21% 24% *: ± Endocrine therapy and/or radiotherapy **: ± radiotherapy Jerkins V, et al. British Journal of Cancer,2006.

14 Late effect of adjuvant chemotherapy on cognitive function n 2-year 4-year CTC FEC CMF Control Control group received only local therapy. Hihg dose CTC: Cyclophosphamide 6 gr/m 2, thiotepa 480 mg/m 2, carboplatin 1,6 gr/m 2 m No difference between TMX users, completed use of TMX or never used TMX Ann Oncol 13: , 2002

15 High dose chemotherapy and cognitive impairment in breast cancer n 5-year assessment 4xEC + 3xCMF 23 13% 4xEC + CTM + SCS 24 8% Control breast cancer 29 3% P 0,43 CTM days 1-4: CTX:1500 mg/m 2, Thio:150 mg/m 2, Mitoxantron 10 mg/m 2 SCS: stem cell support Annals of Oncology 2006;17:

16 Endocrine therapy In the ATAC trial (n=94) verbal memory and processing speed were impaired compared to healthy women (n=34). Tamoxifen users consulted for memory problems more than nonusers. Jenkins etal, 2004 Paganini-Hill and Clark, 2000

17 The MA.17 Trial Postmenopausal breast cancer (n=5187) 5 years TMX ± chemotherapy Randomization Letrozole Placebo Mental health measurements did reveal small to moderate differences of questinable clinical significance that favored placebo over letrozole in some domains.

18 Premenopausal breast cancer pt 1cm,N0 pn+(1-3 nodes) pn+( 4nodes) 6xCMF 6xCMF+RT RANDOMIZATION (n=293) Control Goserelin Goserelin+TMX TMX No difference in memory or concenration. Nystedt M, et al. JCO, 2003.

19 Does endocrine therapy increase cognitive dysfunction?

20 Cognitive dysfunction within domains of Information processing speed Attention Memory retrieval Executive function

21 How long does cognitive dysfunction last? Varies from person to person Once chemo treatment ends most gain back cognitive function within a year Approximately 20% of people affected by chemo brain say that they regain function to a certain extent and then plateau without full cognitive recovery

22 Longitudinal study in breast cancer patients Breast cancer 5-FU, doxorubicin, cyclophosphamide x 6 cycles 3-wk after completion of CT %33 cognitive dysfunction %61 cognitive dysfuntion n=18 1 year after CT %34 cognitive dysfunction Cancer. 2004;100: Cancer 2004;100:

23 Cognitive function in women after adjuvant chemotherapy for breast cancer: 1- and 2- year follow-up Healthy n Patients (%) n Controls (%) p Mild/Mod-Sev Mild/Mod-Sev Initial ,6 / ,3 / yıl 91 30,8 / ,3 / Yıl 81 21,3 / ,1 / No significant difference between patients ER-positive and ER-negative Strong association between fatique, menopausal symptoms and QoL No association between these factors and cognitive dysfunction J Clin Oncol 2005;23:

24 Postulated mechanisms of chemotherapy-associated cognitive changes Vardy, J. et al. Ann Oncol 2007

25 Animal models Brain of animals that received chemotherapy have demonstrated cell death and slowing of cell division in structures critical for memory and learning. Rzeski W, et al. Ann Neurol 2004.

26 Electrophysiology Electrophysiologic studies examining the P- 300 event-related brain potential reported decreases in amplitude (intensity and neural activation) and latency (timing and duration of activation) of P-300 associated with chemotherapy. Kreukels BP, et al. Breast Cancer Res Kreukels BP, et al. Clin Breast Cancer 2006.

27 Fluid attenuated inversion recovery magnetic resonance images of white matter hyperintensities Hyperintensites were more prominent throughout white matter in A. A: Chemotherapy + B: Chemotherapy - Ferguson, R. J. et al. J Clin Oncol; 25:

28 Functional magnetic resonance images of 60-year-old identical twins during a working memory task with incrementally increasing levels of difficulty (left to right) Ferguson, R. J. et al. J Clin Oncol; 25:

29 Neuopsychological tests are expected to be; Valid, reliable Have good sensitivity and specificity To be sensitive to detect subtle cognitive impairment To incorporate enough tests in the battery To be administered in short time

30 Neuropsychological assessment: Areas of examination Visual, auditory & tactile sensation and perception Attention and concentration Orientation, learning and memory Language Intelligence Speed of information processing Executive functions: problem solving, planning, organization, judgment & abstract reasoning Personality and emotion

31 Tests used for evaluation of cognitive dysfunction 1. High Sensitivity Cognitive Screen (HSCS) 2. Mini-Mental Status Exam (MMSE) 3. The Corner s Continuous Performance Test (CPT) 4. The Trail Making Test 5. Test Battery For Attentional Performance (TAP) 6. Hamburg-Wechsler-Intelligenztest für Erwachsene

32 Criticisms to the trials Small sample size Lack of optimal controls (with similar type of cancer who received only local treatment) Lack of baseline assessment Lack of longitudinal design Failure to control for confounding variables (such as hormonal factors) Selection of different cognitive domains and neuropsychological tests

33 What if I never return to my pre-cancer cognitive function?

34 94 breast cancer patients receiving chemotherapy randomized to erythropoietin alfa vs. placebo Result: Improved cognitive performance O Shaughnessy Clin Breast Cancer, (2002)

35 Myers et al Treatment with methylphenidate (psychostimulant) was associated with dramatic subjective and objective improvements in cognition and daily functioning in 30 pts with brain tumor.

36 Other pharmacotherapies Donepezil (acetylcholinesterase inhibitor) After radiation therapy in brain tumors Paroxetine (selective serotonin reuptake inhibitor) Alleviate cognitive dysfunction in cancer patients Naltrexone (opioid resceptor antagonist) In interferon treatment for hematological malignancies.

37 In severe cases, neuropsychologists are recommended to assess to treat symptoms Neuropsychologists may recommend cognitive rehabilitation

38 Treatment: The role of neurorehabilitation Neuropsychology can assess the specific dysfunctions underlying a patient s cognitive impairments as well as help ferret out the role of emotional factors.

39 Treatment: The role of neurorehabilitation (continued) Cognitive rehabilitation implemented by a variety of professionals is imperative for the design and implementation of compensatory mechanisms to improve efficiency and help minimize functional limitations.

40 Use a detailed daily planner Exercise the brain: do word puzzles, or learn a new language Track and document difficulties

41 Set up and follow routines Write reminder notes Get enough rest and sleep Get physical activity and eat a healthy diet Don t try to multi-task. Focus on one thing at a time Share this problem with your family

42 Nearly two-thirds of people treated with chemotherapy develop some level of cognitive problems Most recover on their own in the weeks or months after treatment stops As many as 20% to 25% of patients may develop lasting problems Cognitive neurorehabilitation techniques may help

43 Conclusion Cognitive dysfunction is real Its cause is unknown How offen it happens, What may trigger it, What can be done to prevent it, is also unknown.

Chemo Brain : What We Know and What We Need to Learn

Chemo Brain : What We Know and What We Need to Learn Rachel Isaksson Vogel, Ph.D. Assistant Professor Department of Obstetrics, Gynecology and Women s Health Masonic Cancer Center s Women s Health Scholar