Your Mind and Cancer Treatment:

Understanding and Addressing Cognitive Decline

Commonly referred to as "chemo brain" or "chemo fog," adverse effects in cognitive function are often experienced by patients going through various cancer treatments. This issue is frequently a topic in cancer support group meetings1 and has been investigated in clinical studies where it is variously referred to as "chemotherapy-related cognitive dysfunction," "cognitive deficit," or "cognitive decline."2 Changes in cognitive ability because of chemotherapy treatment may be a type of autoimmune response or the result of chemical toxicity, oxidative damage, or inflammation in neurons.3

Many different types of cancer treatments can cause cognitive damage. For example, whole-brain radiation has been reported to cause substantial cognitive dysfunction.4 Fortunately, there is some evidence that treatment with hyperbaric oxygen5 has been successful for radiation-related cognitive dysfunction; this treatment is now being investigated in a large, multi-center clinical trial network throughout Europe.6 (Information about this trial is available through www.oxynet.org.)

In contrast to radiation, cognitive dysfunction related to systemic chemotherapy is not as well understood. The purpose of this article is to specifically discuss "chemobrain" by describing the scope of the problem, outlining possible mechanisms by which chemotherapy may impair brain function, and addressing the methods used to evaluate and treat cognitive problems.

DEFINITION OF COGNITIVE FUNCTION
Cognitive function is defined as thought processes and intellectual functions such as memory, problem solving, and goal setting. Aspects of cognitive function that have been studied with respect to chemotherapy side effects include verbal ability, verbal learning and memory (speed of information processing), visual memory, spatial functioning, psychomotor functioning, attention and concentration, executive (frontal) functioning, motor functioning and coordination, and quality-of-life measures including depression and anxiety.7

WHAT IS THE EVIDENCE SEEN IN PATIENTS?
Numerous studies have been published in which the cognitive side effects of chemotherapy were investigated. In one study, for example, women with breast cancer receiving chemotherapy were found to be more likely to experience cognitive dysfunction than breast cancer patients who did not receive chemotherapy.8 In another study, women receiving chemotherapy experienced significant differences in memory and language functioning as compared to women one year post-chemotherapy and also compared to healthy controls.9

These two studies were analyzed along with others in a soon-to-be published meta-analysis conducted in Australia.10 The investigators in this study assessed the severity and nature of cognitive impairment and then identified several important patterns helpful in understanding this problem. Encouragingly, they found that cognitive impairment does diminish over time; most severe cognitive side effects of chemotherapy diminish within two years. Additionally, the Australian researchers found that the use of tamoxifen along with chemotherapy sharply exacerbates its cognitive side effects. It is not yet known whether the newer aromatase inhibitor drug anastrazole (Arimidex) has the same detrimental cognitive effects. Finally, the authors of this meta-analysis found that the cognitive side effects of chemotherapy are more severe in younger women.

WHAT IS HAPPENING IN THE BRAIN?
Measurable Physical Changes
Evidence for physical damage to the brain has been seen in studies of chemotherapy-treated cancer survivors that were compared to healthy controls.11, 12 Using magnetic resonance imaging (MRI), investigators discovered reductions in grey and white matter that were widely distributed throughout the brain.

Evidence for changes in cerebral blood flow has been provid- ed in a study of twelve breast cancer survivors, five to seven years after diagnosis, compared to a group of healthy controls.13 Using positron emission tomography (PET) scanning, investigators discovered decreased metabolic activity in the prefrontal gyrus (a part of the brain that is involved in “executive functions,” such as decision-making, planning and judgment, and arithmetic) and in Broca’s area (a part of the brain that is important for speech and language). These metabolic changes were associated with reduced short-term memory in these patients. (See "Neurotoxicity for Common Chemotherapeutic Agents" below.)

Evidence for neurophysiologic damage has been similarly provided in a study of breast cancer patients treated with chemotherapy.14 Patients were monitored with standard electroencephalogram (EEG) and tested with visual skills tasks. Compared to controls, patients who had received chemotherapy performed slower on visual tasks and had demonstrable EEG differences.

Cytokines
There may be a biochemical element to the detrimental cognitive effects of chemotherapy, specifically the possible increase in the production of cytokines in the brain. Cytokines are soluble proteins and peptides which regulate the intensity and duration of the immune response; they are produced in response to injury, infection, or toxins, and are part of the inflammatory process. For example, brain cytokine levels increase following stress exposure and decrease after stress-relieving treatments. These cytokines may be associated with cognitive dysfunction, although it is not yet known whether chemotherapy increases production of cytokines or if a measurement of cytokines in the circulating blood provides a reliable measure of their activity in the brain.1

Hormones
Various studies have suggested that hormonal involvement may also play a role in chemotherapy-related cognitive dysfunction.9, 15 Chemotherapy-induced menopause may contribute to this mechanism.16

Depression, Fatigue, and Anxiety
Psychological factors may exacerbate the cognitive side effects of chemotherapy. Potentially relevant are depression, fatigue, the stress of diagnosis,17, 18 anxiety about the possibility of disease recurrence,19, 20 and hormonal treatment.16 In the Winter 2004 issue of Avenues, we reported on the relationship between stress, serum cortisol, social support, and quality of life. These factors may play a role in the cognitive side effects of chemotherapy; stress is likely to increase these side effects and having good social support is likely to decrease them.

Genetic Predisposition
Genetic factors may play a role; the e4 allele of apolipoprotein is a genetic variation associated with an increased probability of Alzheimer’s disease.21 People who carry this gene product and who are treated with chemotherapy will be more likely to score lower on visual memory, spatial ability, and psychomotor functioning tests.22

Clotting in Small Blood Vessels
Chemotherapy is known to damage the inner lining of blood vessels, which can lead to increased clotting of blood and possible micro-strokes in the central nervous system.23 Furthermore, this damage to the vessels could lead to increased production of interleukins (compounds produced by cells of the immune system that function in the regulation of the immune system), further accentuating the changes in cognitive function.

HOW CAN CHEMOBRAIN BE TREATED?
Exercise
Exercise appears to be essential to minimize the effects of chemobrain. In the Winter 2004 issue of Avenues, we summarized the results of several studies on exercise and quality of life for people with cancer. Many studies now demonstrate the positive effects of exercise in both preventing and treating chemotherapy-related cognitive dysfunction.3, 24-29

Medications
The use of aspirin in preventing or treating chemobrain was discussed at a 2003 researchers' workshop in Banff, Canada, on chemotherapy-related cognitive dysfunction. This approach might work through preventing micro-coagulation of the blood caused by chemotherapy. Aspirin additionally suppresses production by the body of prostaglandin E2 (PGE2), a compound which suppresses immune function and enhances tumor cell growth.30

Donepezil (Aricept) has been shown to improve cognitive function in people who have mild to moderate Alzheimer's disease and may be beneficial in the treatment of chemobrain.31 Also promising, the medication naltrexone has shown some evidence in animal studies for treating cognitive side effects of interferon treatment,32 but has not yet been tested with chemotherapy drugs for its potential to reduce adverse cognitive effects.

Erythropoietin (EPO)7 is a neuroprotective compound that is produced by the brain in response to stroke.33 When given as a treatment, the compound EPO can improve the outcome of stroke recovery.34 In a recent study in which 94 patients receiving chemotherapy for breast cancer were randomized to either EPO or placebo, the treatment group had improved cognitive performance after the fourth cycle of chemotherapy as compared to controls who had slight deterioration.35 Additionally, some researchers speculate that EPO would have a preventive effect if given before chemotherapy.7 However, two recent trials suggest EPO may adversely affect survival in breast cancer patients.36, 37 This may be due, in part, to the presence of erythropoietin receptors on breast cancer cells.38, 39

Methylphenidate (Ritalin) can improve behavioral function in patients with malignant glioma brain tumors40 and cognitive function in survivors of childhood cancers.41 A trial of Ritalin in 170 women receiving chemotherapy for breast cancer is currently underway at the University of Toronto.

Antioxidants have a potential role in preventing oxidative damage to the brain and neurons. A substantial body of literature has been generated, specifically investigating the ability of antioxidants to enhance chemotherapy effectiveness and reduce its toxicity. These are efficiently reviewed in a series of review articles published in 1999 and 2000;42, 43 some of the studies reviewed in these two articles had already been conducted over 25 years ago. (See "Antioxidants & Chemotherapy" below.)

Reduced toxicity of chemotherapy to healthy tissues has been demonstrated by antioxidants and other compounds: For alkylating types of chemotherapy (cyclophosphamide, ifosfamide, busulfan, and melphalan), selenium,44 coenzyme Q-10,45 melatonin,46 N-acetylcysteine, and glutathione49, 50 have been shown to reduce toxicity to healthy tissues. For antibiotic types of chemotherapy (Adriamycin, bleomycin, epirubicin, and daunorubicin), vitamin A,51 vitamin E,52 selenium,53, 54 coenzyme Q-10,55-58 melatonin,59 and N-acetylcysteine have been effective.60 For anti-metabolite types of chemotherapy (5-FU and methotrexate), vitamin A,51, 61 coenzyme Q-10,45 and glutathione have shown benefit in reduced toxicity.62, 63 Lastly, for platinum chemotherapy (cisplatin and carboplatin), selenium,64-67 melatonin,68, 69 N-acetylcysteine,70, 71 and glutathione have been shown to reduce toxicity to healthy tissues.49, 50

Compensatory Strategies
Cognitive rehabilitation to help compensate for impaired brain function has been shown to be helpful. Such rehabilitation can include behavioral training, learning techniques to organize information, and training in memory enhancement techniques.1, 2, 72-74 Some of these approaches are the focus of a new journal, Rehabilitation Oncology (www.oncologypt.org/pubs), which deals specifically with approaches to recovery from cancer treatment-related complications.75

A poignant moment occurred at the 2003 Banff chemobrain workshop when one of the presenters, herself both a physician and a breast cancer survivor, reported on her own cognitive problems resulting from high-dose chemotherapy. She described several strategies she used to cope with her difficulties, such as avoiding attempting multiple tasks simultaneously, planning ahead to avoid emergency situations, reducing her workload, making lists to organize her daily tasks, and getting more sleep.2

WHAT NEEDS TO BE DONE NEXT?
It is clear that a substantial amount of work needs to be done to develop better ways to prevent and treat chemotherapy-related cognitive dysfunction. Participants at the 2003 Banff chemobrain workshop itemized the challenges faced by researchers studying this important problem:76
» A well-designed study should quantify the amount of cognitive decline with measurements made before and after chemotherapy. However, problems occur in measuring baseline brain function; for most people, a cancer diagnosis is a time of significant stress, which can itself impair concentration and memory.
» A change may be statistically significant, but not clinically meaningful. What is clinically meaningful in measuring cognitive decline, however, has not yet been defined. Furthermore, questionnaires and tests used to measure cognitive function have not yet been designed that would be valid in different cultural settings.
» While a patient may measure within normal limits on a test of cognitive function, it may still be below what is their own acceptable norm.
» Previous studies have identified discrepancies between subjective (by questionnaire) and objective (by neurological testing) measurements of cognitive function. This may be due to limitations of test methods. However, it may also be due to the cognitive damage of chemotherapy having also diminished the person’s ability to accurately gauge their own condition; this is referred to as a "disorder of insight."
» Problems with memory and concentration are often most obvious when people return to daily life at work and home. Most neurological tests currently in use are conducted in the medical office or research setting, away from "real life" context and demands. One good example is the Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog), a simple self-reported questionnaire developed in consultation with cancer patients and medical practitioners.

CONCLUSIONS
It is encouraging that researchers have focused on this important problem. Although only limited evidence is available, there are several promising approaches that may satisfy the conservative principle of “it could help, probably won’t hurt”: (1) if anticipating chemotherapy treatment, do what you can prior to beginning treatment to improve your physical stamina through exercise, (2) do your best to maintain physical exercise during chemotherapy treatment, (3) ask your doctor about the advisability and safety of combining Ritalin and/or aspirin with your chemotherapy treatment, (4) minimize your stress levels and practice techniques that cultivate relaxation, and (5) ask your doctor what vitamins and antioxidants can be safely used between cycles of chemotherapy.

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ANTIOXIDANTS & CHEMOTHERAPY
The following two articles can provide an intelligent forum for initiating discussion with your oncologist about the use of antioxidants along with chemotherapy.

Antioxidants in Cancer Therapy: Their Actions and Interactions with Oncologic Therapies
There is a concern that antioxidants might reduce oxidizing free radicals created by radiotherapy and some forms of chemotherapy, thereby decreasing the effectiveness of the therapy. The question has arisen whether concurrent administration of oral antioxidants is contraindicated during cancer therapeutics. Evidence reviewed here demonstrates exogenous antioxidants alone produce beneficial effects in various cancers and, except for a few specific cases, animal and human studies demonstrate no reduction of efficacy of chemotherapy or radiation when given with antioxidants. In fact, considerable data exists showing increased effectiveness of many cancer therapeutic agents, as well as a decrease in adverse effects, when given concurrently with antioxidants. [References: 180]

Lamson, D W and M S Brignall (1999). "Antioxidants in cancer therapy: their actions and interactions with oncologic therapies." Alternative Medicine Review 4(5): 304-329.

Antioxidants and Cancer Therapy II: Quick Reference Guide
The previous lengthy review concerning the effects of antioxidant compounds used concurrently with radiotherapy and chemotherapy has been reduced to a reference guide. There are only three presently known examples in which any agent classifiable as an antioxidant has been shown to decrease effectiveness of radiation or chemotherapy in vivo. The vast majority of both in vivo and in vitro studies have shown enhanced effectiveness of standard cancer therapies or a neutral effect on drug action.

Lamson, D W and M S Brignall (2000). "Antioxidants and cancer therapy II: quick reference guide."Alternative Medicine Review 5(2): 152-63.

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NEUROTOXICITY FOR COMMON CHEMOTHERAPEUTIC AGENTS6
Drug - Relative Degree of Neurotoxicity
Fluorouracil - High
Methotrexate - High
Tamoxifen - Moderate
Vincristine - Moderate
Cyclophosphamide - Possibly Increased
Paclitaxel - Possibly Increased
Doxorubicin - Possibly Increased
Dexamethasone, methylprednisolone - Uncertain

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