CHEMOBRAIN Cancer free but losing my mind

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1 REVIEW ARTICLE CHEMOBRAIN Cancer free but losing my mind Edel D.M. Masembe (B.Pharm) 1 1 Department of Pharmacy, Makerere University College of Health Sciences ABSTRACT Background: Chemotherapy, the mainstay of cancer treatment alongside surgery has numerous toxic effects one of which is called chemobrain Aim: To provide an overview of chemobrain by reviewing its literature Objectives: To describe the meaning, etiology, pathophysiology, diagnosis and treatment of chemobrain Methods: A search was conducted using the following databases: PubMed, Google scholar, HINARI, Africa portal library and Africa Journal online. Articles that described the etiology, pathophysiology, diagnosis and treatment of chemobrain were reviewed. The references at the end of each article were used to find other articles on the subject. Results: Two databases: PubMed and Google Scholar yielded articles that were included in the review because they described the etiology, pathophysiology, diagnosis and treatment of chemobrain. Conclusion: While studies are underway in the west, one needs to be carried out in Uganda to determine if cancer survivors are suffering from chemobrain. This will facilitate the design of suitable interventions that restore their quality of life as fully as possible, especially as as regards returning to work to earn a living. Abbreviations: BC-Breast cancer; CBT-Cognitive Behavioral Therapy; CRCI-chemotherapy related cognitive impairment; CT computer tomography; EEG-electroencephalogram; fmri functional magnetic resonance imaging; IL-Interleukin; MRI-magnetic resonance imaging; NO- Nitrous Oxide ;NSCLC-Non-small cell lung cancer; PET-Positron emission tomography; SERMS-selective estrogen receptor modulator; SNPs- Single Nucleotide Polymorphisms; TNF-Tumor Necrosis Factor Keywords: Chemobrain, Chemo brain, Cancer, Chemotherapy, Uganda, Chemotherapy Induced Cognitive Impairment. MPJ 2014: 12(1): e6-12 Corresponding Author: Edel D.M. Masembe- Department of Pharmacy, Makerere University College of Health Sciences (MakCHS). edelmoraa@gmail.com Tel +256(0) Article Details: Received February 18, 2014 Reviewed March 16, 2014 Accepted April 10,2014 Conflicting Interests: None declared Citation: Edel D.M. Masembe. Chemo brain cancer free but losing my brain (Review Article).MPJ (1). e6-12 Copyright 2014 by Makerere University Pharmacy Students Association. Unauthorized use, distribution and reproduction in any medium is prohibited unless the author and source is credited. INTRODUCTION Cancer remains one of the leading causes of death globally with 8.2 million lives lost in 2012 alone. (WHO 2014) This high global burden is increasing despite the advancement of treatment modalities especially in the developed world. In parts of Africa

2 with high HIV/AIDS mortality rates, the most common cancer is Kaposi Sarcoma (KS). In Uganda, cancer is underreported with the latest prevalence statistics being from stating 1968 male cases and 2248 female cases in Kampala alone. These cases were representative of all cancers with KS being the most prevalent for both males (31%) and females (22%). The cancer with the highest burden in males was prostate cancer at 12% and in females was cervical cancer at 22% and breast cancer at 19%. (Wabinga, Max and Nambooze 2012) Annually and nationally, the incidence rates for prostate cancer and breast cancer are growing at a rate of 3.7% and 5.25% respectively. (H. R. Wabinga 2014) Chemotherapy is the mainstay of cancer treatment in Uganda for both HIV-associated and non-hiv associated cancers. However, in the backdrop of Uganda s poverty, it is a long and very expensive process in terms of cost of the drug and accessibility with patients travelling far and wide to receive it. Uganda Cancer Institute (UCI) is the only national referral clinic for cancer patients in Uganda and serving as far as Western Kenya and Sudan and providing some of the anticancer drugs free of charge. Despite these challenges, cancer patients, especially breadwinners, are willing to try chemotherapy with the hope of restoring the quality of life they had prior to falling sick. A major challenge to recovery after chemotherapy is chemobrain, a term that describes the loss of cognitive function at the end of chemotherapy. To highlight the attention that this toxic side effect has received, the term, chemobrain is now part of the Merriam- Webster dictionary where it has been defined as, Impaired cognition (as memory loss or lack of concentration) that has been observed in patients who have received chemotherapy (Merriam Webster Dictionary n.d.) Chemobrain was first recognized after numerous patients had reported that several months postchemotherapy, they found themselves experienced mental difficulties such as forgetting where their car was parked or trying to remember details that they could easily recall prior to treatment. (Holmes 2013) In the past physicians dismissed chemobrain as either a mood disorder or stress in cancer patients. However with advancement in research especially in the area of cognitive dementia, chemobrain has been studied and knowledge about this side effect has increased exponentially with the employment of neuroimaging technologies such as MRI and CT scans. Neuropsychological tests have made the symptoms of chemobrain more objective rather than subjective as they had been in the past. Most patients that complain about this phenomenon are breast cancer survivors. Chemotherapy-related Cognitive impairment (CRCI), a medical term used to describe chemo brain further emphasizes the acknowledgment of the condition as a legitimate disease that warrants treatment. (Ganz 2012) Primary Objective: To give a general overview of the phenomenon of chemobrain Secondary objectives: 1. To define chemobrain 2. To describe the pathophysiology of the disease 3. To describe the symptoms and diagnoses of chemobrain 4. To outline possible therapies of chemobrain METHODS 1. Databases that were searched are: PubMed, Google scholar, HINARI, Africa portal library and Africa Journal online. 2. The following search words were used: chemo brain, chemo fog, cognitive dysfunction + chemotherapy, diagnosis, pathophysiology, treatment, radiotherapy, CRCI, breast cancer in Uganda. The words were either used in various combinations or together. 3. The articles were sorted according to the objectives. Only those that yielded information directly related with the definition, pathophysiology, diagnosis, treatment and future research were studied. RESULTS Of the databases searched, PubMed and Google Scholar had articles on chemobrain or links to those articles on other databases. Findings were discussed under the following sub-topics: etiology, pathophysiology, symptoms, diagnosis, and treatment. Etiology Several possible causes and pathways for chemobrain have been suggested. These include systemic inflammation and hereditary genes. However the specific drugs or regimens that cause cognitive dysfunction haven t been conclusively identified. Other causes of the phenomenon that have been considered that affect cognitive function in a similar way include: stress, chemotherapy-induced anemia, estrogen and cytokines. Stress induces release of glucocorticoids that damage the hippocampus as evidenced by the smaller hippocampi seen in stressed individuals and cancer patients through MRI imaging. Fatigue resulting from chemotherapy induced anemia can also lead to chemobrain as demonstrated by fmri. Therefore

3 multiple factors that contribute to stress such as implications of diagnosis, treatment and fatigue may exacerbate the effects of chemotherapy on the brain. (Scherling and Andra 2013) Estrogen has been demonstrated to have a neuroprotective function on the hippocampus. Therefore drugs that lowered the levels of the hormone for example SERMS such as tamoxifen may lead to chemobrain. Aromatase inhibitors such as arimidex were also suggested to cause chemobrain by inhibiting estrogen synthesis. Freeser et al studied the hippocampus in breast cancer (BC) survivors and the levels of cytokines particularly IL-1 and TNFα in which a relationship was found between the two. Increased levels of IL-1 and TNFα resulted in smaller hippocampi that were decreased in function. Cancer itself may also be viewed as a cause of chemobrain as well as a differential to it. fmris of BC patients taken postsurgery but before chemotherapy and then after chemotherapy revealed structural white matter changes that served as evidence of chemobrain. (Scherling and Andra 2013) Pathophysiology: The mechanism by which chemobrain is established remains unclear but numerous studies are underway to elucidate it. Physicians were skeptical of the condition because most anti-cancers did not cross the blood brain barrier. However, accumulating evidence suggests cytokines and genetic factors may be involved. Antitumor drugs have been shown to cause release of cytokines that can cross the blood brain barrier and in turn cause inflammation that manifests as structural damage to the white matter. Such changes are shown on neuro-images and cognitive dysfunction tests as regards attention, memory and processing speed. Genetically, individuals with single nucleotide polymorphisms (SNPs) in genes that code for IL-1, IL- 6 and TNFα are more susceptible to chemobrain. The study, which involved 93 BC survivors, showed that increasing the circulating levels of these cytokines is directly correlated to the incidence of chemobrain. SNPs of genes that code for TNFα negatively correlated with frontal gyrus metabolism resulting in more cognitive complaints. (Hyer 2011) A study done by Tangpong et al in which Adriamycin was administered to mice, demonstrated that the drug causes TNFα mediated CNS damage through the generation of reactive oxygen species (ROS) in the brain. TNFα stimulated generation of a variant of nitrous oxide (NO) synthase called cytokine-induced NO synthase which resulted in generation of reactive nitrogen species (RNS) and reactive oxygen species (ROS) that resulted in damage to neural tissue. (Tangpong 2007) However other researchers have hypothesized that cytokines play a more intermediary role with controversy about their exact level of involvement in chemobrain. Cheung suggests that investigators should study other inflammatory mediators such as Vascular Endothelial derived Growth Factor (VEGF) which has a neuro-protective function. He also recommended that anticancer regimens should be studied and if possible matched to the type of cognitive dysfunction that they cause. This would be a better approach because neurotoxicity has been associated with singular administration of multiple drugs rather than one drug. Future research into the exact mechanisms by which chemobrain is caused should be geared towards elucidating the type of cancer, drug regimen and level of cytokines in post-chemotherapy patients for treatment to be established. (Ting 2013) Symptoms: Chemobrain patients complain of symptoms of cognitive dysfunction such as loss of short term memory, trying to get the right word or phrase, difficulty thinking, and difficulty concentrating on a single task. (Michael 2014) Diagnosis: Chemobrain has largely been self-reported and there is yet to be an agreed upon criteria for diagnosis. Typically, combinations of self-reporting questionnaires, cognitive function tests and neuroimaging studies have been used to diagnose the disease. One such example is a prospective study by Whitney et al which evaluated cognitive function in patients with Non-small cell lung cancer (NSCLC) before and at the end of chemotherapy (n=14). The study employed the use of neuropsychological functional tests coupled with computer tomography (CT) scans taken prior to administration of the chemotherapy regimen, during therapy and at the end. Neuropsychological tests such as the list learning test were administered as well as tests for conceptual flexibility such as the Wisconsin Card Sorting Test which revealed the most cognitive impairment at baseline. A month after chemotherapy, 62% of the patients (one died during chemotherapy) showed cognitive decline. 7 months post chemotherapy, only one patient showed further significant cognitive decline when test results were compared with his baseline results and this deduction was made from only one test. (Kriscinda and Lysaker 2008)

4 In the above study CT scans were done in order to rule out brain metastases rather than to study structural white matter changes possibly related to chemotherapy. However, in research about chemobrain, the use of imaging has increased widely and has provided further evidence on the structural changes in the white matter, size of hippocampi and functional changes. Most of the technologies now used include MRI, f MRI, CT scan, EEG, and fluorodeoxyglucose PET. MRI is a very precise method as it gives excellent slices that display even the slightest changes in structural anatomy. It s also non-invasive and doesn t employ the use of radioactive tracers. It detects changes in both the white matter which are induced by drugs for example, leukoencephalopathy in leukemia patients after taking immunosuppressive drugs. It is used in assessing both structural and functional changes in the brain. Ferguson et al studied anatomical and functional changes in the brain using MRI and fmri respectively in a pair of monozygotic twins one of whom suffered from cancer and was treated with chemotherapy. The brain scan of the chemotherapy treated twin revealed more lesions in white matter. This twin had also previously complained of subjective cognitive changes. fmri carried out during the working of an active task revealed changes in the chemotherapy treated twin such as diffuse activation of bilateral frontal and parietal regions. (Scherling and Andra 2013) EEG is used to measure the time taken during neuronal firing. Hall-Moore is the title of the first prospective study to use this tool together with cognitive tests to assess chemobrain in BC patients before, during and after chemotherapy with healthy non-cancer patients as controls. (Scherling and Andra 2013) Fluorodeoxyglucose PET was also used to study chemobrain in 16 BC survivors of 5 years post long term chemotherapy (including 11 who had been treated with tamoxifen) with memory problems, 8 nonchemotherapy treated cancer survivors and a previously acquired standard reference group of 10 healthy individuals. This test demonstrated that chemotherapytreated patients had lower resting metabolism in the brain than other non-chemotherapy treated patients. Basal ganglia metabolism was also lower in patients treated with chemotherapy and tamoxifen. (Scherling and Andra 2013) A study by Sabrina Deprez et al followed postmenopausal women with breast cancer who underwent chemotherapy and a control group comprising healthy postmenopausal women and postmenopausal cancer patients that didn t undergo chemotherapy. Images obtained using MRI together with cognitive function tests such as memory tests, attention tests and psychomotor speed demonstrated that the two control groups performed significantly better than the test group that underwent chemotherapy. This showed a direct relationship between structural white matter changes and cognitive performance. (Holmes 2013) Abraham et al studied the brain, using PET, of 128 women with breast cancer after finishing chemotherapy treatment 6 months prior. The images revealed changes in metabolic brain activity in the same areas as those by Deprez and colleagues. (Holmes 2013) Various anticancer drugs have also been tested in animal models. For example, Tracy Shors et al studied cognitive dysfunction associated with the administration of temozolomide in rats. The rats were taught new behavior prior to administration and then after. Behavior learned before administration was not affected, however the rats failed to make new associations between stimuli post treatment and had to be retaught behavior taught during administration. Therefore old memories were not affected. This demonstrated that patients suffering from chemobrain experience loss of short term memory and not long term memory (Holmes 2013) Therefore matching neuroimaging results to cognitive function tests is playing a major role in the diagnosis of chemobrain. Diagnosis of chemobrain is made more complex in brain cancer patients in whom CNS changes are due to the tumor itself. (Scherling and Andra 2013) Treatment In March 2012, the International Cancer and Cognition Task Force held its second full-scale conference where investigators participated. The conference whose subject was chemobrain discussed the pathophysiology, etiology and two treatment studies as possible interventions both of which were based on Cognitive Behavioral Therapy (CBT). (McNeil 2012) CBT is the most widely studied therapy with several clinical trials that investigate it either underway or scheduled for completion this year. Alana Schuurs used group sessions to investigate aspects of cognitive function such as thinking and memory. The trial used patients on the waitlist as controls and found that participants had improved cognitive function as compared to those on the waitlist. Another trial carried out in 2012 at the University of Washington and led by Monique Cherrier taught assistive techniques to participants such as how to use a

5 calendar. This improved participants attention and working memory. The study also used patients on the waitlist as controls. However Cherrier says that questions such as how long the intervention should be carried out, the frequency, should it be through individual or group sessions, computerized or in person, which cancer patient should receive which treatment, must be answered in order to design CBTs that are effective. More studies need to be carried out in order to answer this question as well as define risk factors to identify cancer patients most in need. (McNeil 2012) Pharmacologic therapy for chemobrain has also been examined. Of the drugs so far studied (modafinil, methylphenidate, donazepil), modafinil has shown the most positive results. Kohli et al carried out a randomized clinical trial in which 68 BC patients were randomized to receive modafinil 200mg or a placebo. It should be noted that these patients were previously part of a clinical trial titled Modafinil to Treat persistent Fatigue in Patients following Treatment for Cancer. A battery of standardized tests that assessed all aspects of cognitive function was used. All patients received 200mg modafinil at week 1. At week 4, they were split into 2 groups with one continuing therapy on modafinil while the other received the placebo. This was done in order to assess the effects of modafinil at week 4 and at week 8. Those patients who did not show improvement at week 4 did not proceed to week 8. They were assessed using various standardized cognitive tests at baseline (before receiving modafinil) at week 4 and at week 8 after chemotherapy. It was found that at week 8, patients showed improved memory speeds and attention. (Sadhna 2009) Modafinil is a eugeroic that enhances wakefulness and is currently approved for the treatment of narcolepsy. Its exact mechanism of action is being studied but it is hypothesized that it inhibits the dopamine transporter (DAT), norepinephrine transporters (NET) or it increases dopamine, serotonin, glutamate and histamine. (Young and A. 2010) CONCLUSION Studies continue to be carried out in the western countries. However a study to determine if Ugandan cancer survivors are suffering from this side effect of chemobrain needs to be carried out. Patients at the end of chemotherapy hope to resume normal life as quickly as possible. This is especially important in situations where the cancer survivor was previously the breadwinner of the family. However, cognitive dysfunction associated with chemobrain leaves the patient unable to perform daily tasks. This makes it difficult for the cancer survivor to resume work to earn a living. Therefore in order to restore the patient to full health, this side effect must be addressed. In the African setting where diseases like cancer plunge families into deeper poverty during treatment, the benefits of interventions against chemobrain are even larger. ACKNOWLEDGEMENTS The author wishes to thank Semuyaba Samuel Andrew (BPHARM III) for his guidance. REFERENCES Ganz, Patricia A. "Doctor will the treatment you are recommending cause Chemo brain"?" Journal of Clinical Oncology vol 30, 2012: Gertrude, Linda. "war." peace, 1992: Holmes, David. "Trying to unravel the mysteries of chemobrain." THe lancet, June 2013: Hyer, R. "TNF-Alpha Activity Eyed for Role in 'Chemo Brain'." Frontline Medical News, July 8, Kriscinda, Whitney A., and Paul Lysaker. "Is Chemobrain a Transient State? A Prospective Pilot Study Among Persons with Non-Small Cell Lung Cancer." The Journal of Supportive Oncology 6, no. 7 (2008): McNeil, Caroline. "Treating Chemobrain: Rehabilitation Therapies Emerge." Journal of the National Cancer Institute Advance Access, Merriam Webster Dictionary. n.d. Michael, Herbst C. "Fact Sheet on Cancer and Mental Health." Sadhna, Kohli, et al. "The Effect of Modafinil on Cognitive Function in Breast Cancer Survivors." Cancer, 2009: Scherling, Carole S., and Smith Andra. "Opening up the Window into "Chemobrain": A Neuroimaging Review."." Sensors, 2013: Semuyaba, Sam. "Insulin storage." MPJ, 2014: Tangpong, Jitbanjong et al. "Adriamycin-mediated nitration of manganese superoxide: insight into the mechanism of chemobrain." Journal of Neurochemistry, 2007: 100, Ting, Cheung Yin. "Cytokines as Mediators of Chemotherapy-Associated Cognitive Changes: Current Evidence, Limitations and Directions for Future Research." PLoS ONE, December Wabinga, Henry R., et al. "Trends in the Incidence of Cancer in Kampala, Uganda " International Journal of Cancer, Wabinga, Henry R., Parkin Max, and Sarah Nambooze. Kampala Cancer Registry Report. Kampala Cancer Registry, WHO. "Cancer Fact Sheet." Fact Sheet 297, Young, Jared W, and Geyer Mark A. "Action of modafinil increased motivation via the dopamine transporter inhibition and D1 receptors?" Biological Psychiatry, 2010:

Who is at risk? What should we do in the clinic?

Who is at risk? What should we do in the clinic? Cognitive Changes after Cancer Treatment Patricia A. Ganz, M.D. Professor, UCLA Schools of Medicine & Public Health Director, UCLA-LIVESTRONG Survivorship Center of Excellence Jonsson Comprehensive Cancer