In this follow-up article, we discuss and summarize some of the latest research that has been published since 2005. We also identify recent research on vitamin, herbal, and dietary compounds that are known to help support brain cells, which may possibly provide protection from chemotherapy. This research on these “neuroprotective” compounds may point the way towards practical steps patients can take, in collaboration with their health-care providers, to help reduce or minimize the negative effects chemotherapy treatment can have on the mind.

EVIDENCE OF THE PROBLEM
Earlier data suggested that among breast cancer patients receiving standard-dose chemotherapy, 18% showed cognitive deficits on post-treatment evaluations two years after treatment.1 Among patients treated with high-dose chemotherapy, that proportion rose to 30%. However, these numbers may be conservative as a recent longitudinal study involving breast cancer patients showed that high-dose chemotherapy caused changes in the brain’s white matter in up to 70% of individuals, usually with a delayed onset of several months after treatment.

JOURNAL OF BIOLOGY
In the November 2006 issue of the Journal of Biology, researchers report that chemotherapy drugs – specifically carmustine, cisplatin, and cytosine arabinoside – were associated with increased cell damage and death in the brains of mice; this effect was seen for weeks after the drugs were administered.2

Researchers also found that neural progenitor cells (sometimes called “neural stem cells” since they have the ability to restore function in damaged nerve tissues) and oligodendrocytes (a type of cell found in the brain and spinal cord that helps improve the speed and reliability of impulse conductions, allowing faster information processing and better motor control) are exceptionally vulnerable to the action of chemotherapeutic drugs; this is the first study to show definitive evidence of chemotherapy’s damaging effects on the physical structure of the brain.

What is particularly interesting about this study is that this damage was found both in vitro (cells cultured or tested in the laboratory) and in vivo (in live animals). This is important because it means that researchers could potentially test the effects a drug may have on brain cells in the lab before testing it on human subjects. Similarly, researchers could also lab test the effectiveness of treatments to help minimize the cognitive side effects of chemotherapy before involving actual patients.

In the same issue of the Journal of Biology, another author notes that it had been previously believed that irradiation was the key culprit to cognitive decline but now there is growing evidence that confirms that chemotherapy itself – even when used without radiotherapy – is indeed toxic to the central nervous system.3

JOURNAL OF THE AMERICAN CANCER SOCIETY
In a study published in the November 2006 issue of Cancer, the journal of the American Cancer Society, researchers used high-resolution brain MRIs of breast cancer patients and controls and observed the differences. They found that breast cancer patients had smaller grey and white matter in the prefrontal cortex, parahippocampal gyrus, cingulate gyrus, and precuneus one year after chemotherapy treatment. These areas of the brain are responsible for attention, concentration, and visual memory. Encouragingly, no difference between breast cancer patients and controls was observed at three years after treatment, suggesting that such damage is not necessarily permanent.

BREAST CANCER RESEARCH & TREATMENT
While the study in the journal Cancer used MRI images to determine the effect of chemotherapy on the brain, a study published in the August 2006 issue of Breast Cancer Research & Treatment used PET scans to monitor blood flow in specific regions of the frontal cortex and cerebellum. They found that blood flow was significantly altered in patients who had received chemotherapy and that this was associated with patients’ ability to perform short-term memory tasks.4

Researchers also found that for patients who received tamoxifen along with their chemotherapy, the metabolism of the basal ganglia (a part of the brain responsible for motor movement) was significantly decreased when compared with patients receiving chemotherapy alone and compared to a control group.

In contrast to the findings of the other studies discussed in this article, these researchers found that changes in blood flow were found five to ten years after completion of chemotherapy, suggesting chemotherapy can have very long-term detrimental effects on brain cells and cognitive function.

PRACTICAL STEPS
While there is increasingly compelling evidence suggesting that chemotherapy does indeed have negative effects on the brain and central nervous system, there is relatively little research providing guidance for what patients can do to prevent or minimize these effects.

Neuroprotective Vitamin and Plant-derived Compounds
While generally not specific to patients undergoing chemotherapy, a considerable amount of work has been done investigating readily available, over the counter herbal medicines and dietary supplements that may have neuroprotective benefits. It is important to note that most of this work has been done using cell cultures in the laboratory or on animals; relatively few research studies have been completed that recruited human subjects.

Many of these herbal medicines and dietary supplements have long been used by practitioners of Chinese medicine or have been studied and used for health benefits unrelated to neuroprotection in humans. Additionally, for most of these compounds, safe doses have been established for human consumption.

The research that still remains to be done is on what specific herbal medicines or dietary supplements would help protect brain cells from damage due to chemotherapy, and at what specific dosage levels. Therefore, we encourage people considering using the information presented here to review this material with their healthcare providers prior to proceeding with treatment. Important information to discuss in consultation include the individual suitability of specific compounds, appropriate dosage levels, and whether they may interact with other treatments, such as chemotherapy. An excellent resource for clinicians detailing herb-drug or vitamin-drug interactions is the Natural Medicines Comprehensive Database.

Ginsenoside Rg1
Ginsenoside Rg1 is an active ingredient isolated from ginseng and is most abundant in both Chinese and Korean ginseng. Ginseng is one of the most widely known herbal medicines in the world, commonly used for its immunostimulating and anti-tumor properties.5 Specific to its potential neuroprotective effects, ginsenoside has been shown to enhance survival rate of neural stem cells in vitro in a study using rat stem cell cultures.6 Commonly used dosage levels of ginseng extract range between 200 and 1000mg.5

Ren Shen Yang Rong Tang
Ren Shen Yang Rong Tang is a Chinese herbal formula first published in a Song Dynasty Chinese medical text in 990 AD. This combination of herbs, which includes ginseng, has been shown to improve the capability of rat oligodendrocyte precursor cells to grow and differentiate four to five fold.7

Acupuncture
Acupuncture is a technique used in Chinese medicine for many different health concerns. A review paper has discussed the possibility that acupuncture can promote proliferation of neural stem cells in the hippocampus (a part of the brain used for memory and spacial navigation). Acupuncture has been used to help Alzheimer’s patients in this way.8

Antioxidants
Progenitor cells and immature oligodendrocytes are affected by oxidative stress (damage to cells by oxidation).5,6 When oxidative stress is lower, the body promotes self-renewal of progenitor cells and when oxidative stress is higher, the body promotes the growth of fully matured neural cells.7

Oxidative stress has not yet been identified as a cause of progenitor cell death due to chemotherapy. However, many chemotherapy agents cause oxidative stress throughout the body, which contributes to both the desired therapeutic effects – and the undesired side effects – of chemotherapy.12-15 As explained above, the growth and survival of neural stem cells and their precursor cells (progenitor cells and oligodendrocytes) is in part regulated by the level of oxidation, so decreasing oxidative stress may help to protect them.

Antioxidants (whether they are produced by the body, taken as a supplement, or eaten in foods) can combat oxidative stress and promote better survival and increased proliferation of neural stem cells. Below are various antioxidant compounds that have been shown in animal or laboratory studies to promote growth or survival of neural stem cells, progenitor cells, and oligodendrocytes. (Work is already underway for a future report in Avenues reviewing the evidence for how various antioxidants interact with chemotherapy – including whether they increase or decrease chemotherapy effectiveness – and their impact on chemotherapy side effects.)

Melatonin
Melatonin is a hormone released from the pineal gland in the evening, and secretion diminishes significantly with age. It is known to help maintain cell health and many people take it to improve sleep. Melatonin has also been shown to slow down neural cell death through its antioxidative effects. Melatonin receptors in neural and glial progenitor cells have been detected and play a role in neuroprotective strategies for Alzheimer’s patients.16,17 Melatonin also has neuroprotective effects on both axons and myelin sheaths of white matter after spinal cord injury, which helps improves recovery.18,19 (Melatonin’s neuroprotective benefits are akin or better to the steroid medication methylprednisolone, which is also used after spinal cord injury.)20 Melatonin has also been demonstrated to protect nerve fibers from damage due to lack of blood flow.21 Melatonin is typically used in doses ranging from 1 to 10mg per capsule. Research studies on its anti-tumor effects have reported on its use at up to 20mg per day.5

Epigallocatechin-gallate (EGCG)
EGCG is an active compound found in green tea leaves. It is an antioxidant that is 25 to 100 times more potent than vitamins C and E.22 According to an animal study, EGCG may promote neural stem cell survival or differentiation.23 This compound also inhibits the proliferation of many cancer cell lines.5 Research studies on its anti-tumor effects have employed a dosage range between 460 to 550mg per day.5

Alpha-lipoic Acid
Alpha-lipoic acid is an important antioxidant that can regenerate other essential antioxidants, such as vitamins C and E, coenzyme Q10, and glutathione. It is also a co-factor for some of the key enzymes (alpha-keto acid dehydrogenases) involved in generating energy. In animal research that investigated the aging process in rats and mice, alpha-lipoic acid has been shown to slow down the development of age-related cognitive dysfunction and brain cell deterioration.24 According to a laboratory study, alpha-lipoic acid protects oligodendrocytes against oxidative damage.25 Alpha-lipoic acid is typically used in a dosage range between 200 and 600mg per day.5

Coenzyme Q10
Coenzyme Q10 (CoQ10) is produced by the human body and is necessary for the basic functioning of cells. It is a vitamin-like substance that can also act as an antioxidant. Among other functions, it is incorporated into the mitochondria of cells throughout the body and facilitates and regulates the transformation of fats and sugars into energy. Patients with heart problems often use CoQ10. According to laboratory studies, the oxidative damage to oligodendrocytes can be prevented using coenzyme Q10.25 It may also protect oligodendrocytes during the terminal stages of maturation.26 Coenzyme Q10 is typically used in a dosage range between 30 and 200mg per day.

Quercetin
Quercetin is the most abundant of the plant-derived flavonoid molecules and is a very active antioxidant. In laboratory studies, quercetin has been demonstrated to prevent oxidative damage in oligodendrocytes.27 Quercetin is typically used in a dosage between 500 and 1500mg. Studies have been published on its use as an anti-tumor treatment at doses up to 3.8g per day.5

Glutathione
Glutathione is a molecule synthesized in the body from three amino acids: L-glutamic acid, L-cysteine, and glycine. Glutathione is one of the body’s most important and powerful antioxidants and a depletion of glutathione can be damaging to oligodendrocyte progenitor cells.28 Glutathione is typically used in a dosage range between 250 and 500mg per day.

N-acetyl Cysteine
N-acetyl cysteine is an efficiently absorbed and used form of the amino acid, L-cysteine. In laboratory studies, N-acetyl cysteine has demonstrated protective properties in the process of oligodendrocyte maturation.26 It is typically used in dosages ranging between 600 and 1800mg per day.

Folic Acid
Folic acid has been shown in laboratory studies to help stem cells proliferate.29 Folic acid is a member of the B vitamin family and is typically used in dosages ranging between 50 and 400μg.

Vitamin K1 and K2
Vitamin K has been shown in laboratory studies to help in preventing oxidative injury to developing oligodendrocytes and neurons.30

SUMMARY
Since chemotherapy is currently an important element in many treatment protocols, future research must focus on developing strategies to help shield the brain from the toxic effects of chemotherapy as well as on the development of more selective and targeted cancer drugs with a lower side-effect profile. We believe that some of the work cited above can suggest potentially non-toxic vitamin or plant-derived compounds worthy of testing for their neuroprotective potential before, during, or after chemotherapy treatment.

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FROM STEM CELLS TO NEURONS

Step One – Neural Stem Cells
Neural stem cells (NSC) are cells that can mature into any type of cell and can continually renew themselves.

Step Two – Progenitor Cells
Progenitor cells do not themselves perform active neurological functions but are “reserve” cells that become activated when mature nerve tissue is damaged. When there is injury, the progenitor cells then develop into mature active cells in order to repair or replace the damaged tissue. Progenitor cells include:

GRP: Glial-Restricted Precursors
NRP: Neuron Restricted Precursors
O-2A/OPC: Oligodendrocyte-Type-2 Astrocytes

Step Three – Mature Nerve Cells
Astrocytes are cells in the central nervous system that, while they are not themselves nerve cells, provide several functions: (1) they provide a framework of structural support in the brain for nerve cells, (2) they provide metabolic support, assisting neurons to obtain nutrients, such as glucose, and (3) they are part of the blood-brain barrier which protects the brain.

Neurons are the primary nerve cells in the nervous system that process and transmit information via electrical signals.

Oligodendrocytes are cells in the central nervous system that, while they are not nerve cells themselves, provide support and nutrition to nerve cells, help form the myelin coating of nerve cells, and participate in signal transmission in the nervous system.

Adapted from Dietrich J, Han R, Yang Y, Mayer-Proschel M, Noble M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol. Nov 30 2006;5(7):22., Page 3, Figure 1.

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REFERENCES

1. Meyers CA, Abbruzzese JL. Cognitive functioning in cancer patients: effect of previous treatment. Neurology. Feb 1992;42(2):434-436.
2. Dietrich J, Han R, Yang Y, Mayer-Proschel M, Noble M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol. Nov 30 2006;5(7):22.
3. Duffner PK. The long term effects of chemotherapy on the central nervous system. J Biol. Nov 30 2006;5(7):21.
4. Silverman DH, Dy CJ, Castellon SA, et al. Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5-10 years after chemotherapy. Breast Cancer Res Treat. Sep 29 2006.
5. Boik J. Natural Compounds in Cancer Therapy. Princeton: Oregon Medical Press; 2001.
6. Shen LH, Zhang JT. [Culture of neural stem cells from cerebral cortex of rat embryo and effects of drugs on the proliferation ability of stem cells]. Yao Xue Xue Bao. Oct 2003;38(10):735-738.
7. Kobayashi J, Seiwa C, Sakai T, et al. Effect of a traditional Chinese herbal medicine, Ren-Shen-Yang-Rong-Tang (Japanese name: Ninjin-Youei-To), on oligodendrocyte precursor cells from aged-rat brain. Int Immunopharmacol. Jul 2003;3(7):1027-1039.
8. Tang Y, Yin HY, Zeng F, Yu SG. [Pondering in-situ induction of endogenous neural stem cells in hippocampus of rats with Alzheimer disease by acupuncture]. Zhong Xi Yi Jie He Xue Bao. Sep 2005;3(5):351-354.
9. Faiz M, Acarin L, Peluffo H, Villapol S, Castellano B, Gonzalez B. Antioxidant Cu/Zn SOD: expression in postnatal brain progenitor cells. Neurosci Lett. Jun 19 2006;401(1-2):71-76.
10. Madhavan L, Ourednik V, Ourednik J. Increased “vigilance” of antioxidant mechanisms in neural stem cells potentiates their capability to resist oxidative stress. Stem Cells. Sep 2006;24(9):2110-2119.
11. Smith J, Ladi E, Mayer-Proschel M, Noble M. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci U S A. Aug 29 2000;97(18):10032-10037.
12. Abushamaa AM, Sporn TA, Folz RJ. Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen. Am J Physiol Lung Cell Mol Physiol. Aug 2002;283(2):L336-345.
13. Atessahin A, Ceribasi AO, Yuce A, Bulmus O, Cikim G. Role of Ellagic Acid against Cisplatin-Induced Nephrotoxicity and Oxidative Stress in Rats. Basic Clin Pharmacol Toxicol. Feb 2007;100(2):121-126.
14. Cortez-Pinto H, Alexandrino P, Camilo ME, et al. Lack of effect of colchicine in alcoholic cirrhosis: final results of a double blind randomized trial. Eur J Gastroenterol Hepatol. Apr 2002;14(4):377-381.
15. Woiniak A, Drewa G, Wozniak B, et al. The effect of antitumor drugs on oxidative stress in B16 and S91 melanoma cells in vitro. Med Sci Monit. Jan 2005;11(1):BR22-29.
16. Niles LP, Armstrong KJ, Rincon Castro LM, et al. Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT1 receptor with neuronal and glial markers. BMC Neurosci. Oct 28 2004;5(1):41.
17. Antolin I, Mayo JC, Sainz RM, et al. Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res. Jul 12 2002;943(2):163-173.
18. Ganguli M, Vander Bilt J, Saxton JA, Shen C, Dodge HH. Alcohol consumption and cognitive function in late life: a longitudinal community study. Neurology. Oct 25 2005;65(8):1210-1217.
19. Cayli SR, Kocak A, Yilmaz U, et al. Effect of combined treatment with melatonin and methylprednisolone on neurological recovery after experimental spinal cord injury. Eur Spine J. Dec 2004;13(8):724-732.
20. Kaptanoglu E, Tuncel M, Palaoglu S, Konan A, Demirpence E, Kilinc K. Comparison of the effects of melatonin and methylprednisolone in experimental spinal cord injury. J Neurosurg. Jul 2000;93(1 Suppl):77-84.
21. Sayan H, Ozacmak VH, Ozen OA, et al. Beneficial effects of melatonin on reperfusion injury in rat sciatic nerve. J Pineal Res. Oct 2004;37(3):143-148.
22. Pillai SP, Mitscher LA, Menon SR, Pillai CA, Shankel DM. Antimutagenic/antioxidant activity of green tea components and related compounds. J Environ Pathol Toxicol Oncol. 1999;18(3):147-158.
23. Chen CN, Liang CM, Lai JR, Tsai YJ, Tsay JS, Lin JK. Capillary electrophoretic determination of theanine, caffeine, and catechins in fresh tea leaves and oolong tea and their effects on rat neurosphere adhesion and migration. J Agric Food Chem. Dec 3 2003;51(25):7495-7503.
24. Cui Y, Shu XO, Gao YT, Cai H, Tao MH, Zheng W. Association of Ginseng Use with Survival and Quality of Life among Breast Cancer Patients. Am J Epidemiol. Apr 1 2006;163(7):645-653.
25. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med. Sep 30 1999;341(14):1013-1020.
26. Cammer W. Protection of cultured oligodendrocytes against tumor necrosis factor-alpha by the antioxidants coenzyme Q(10) and N-acetyl cysteine. Brain Res Bull. Sep 30 2002;58(6):587-592.
27. van Meeteren ME, Hendriks JJ, Dijkstra CD, van Tol EA. Dietary compounds prevent oxidative damage and nitric oxide production by cells involved in demyelinating disease. Biochem Pharmacol. Mar 1 2004;67(5):967-975.
28. Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ. Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci. Aug 15 1998;18(16):6241-6253.
29. Sato K, Kanno J, Tominaga T, Matsubara Y, Kure S. De novo and salvage pathways of DNA synthesis in primary cultured neurall stem cells. Brain Res. Feb 3 2006;1071(1):24-33.
30. Li J, Lin JC, Wang H, et al. Novel role of vitamin k in preventing oxidative injury to developing oligodendrocytes and neurons. J Neurosci. Jul 2 2003;23(13):5816-5826.

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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