Management of Chemotherapy Induced Cognitive Impairment

Aleah J. McHenry, MSN, RN
University of Pennsylvania School of Nursing
Last Modified: October 16, 2012

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Clinical Significance

One in every three people in the United States are expected to be diagnosed with cancer in their lifetime, and more than half of those diagnosed will require chemotherapy as part of their treatment regimen (National Cancer Institute, 2009). Chemotherapy is the mainstay of treatment for various cancer types, and although survival is greatly increased with its use, it can also cause many adverse effects during and following treatment. Cognitive impairment, commonly referred to as ‘chemo brain', is one of the most frequently reported post-chemotherapy symptoms among breast cancer survivors, which is also the most studied group in regard to this symptom (Boykoff, Moieni, & Subramanian, 2009).

Inconsistencies exist concerning the impact of cognitive impairment and comparative relationships between self-reporting and cognitive testing. Numerous older studies include cross-sectional designs that failed to utilize a control group within their studies or failed to perform baseline assessments of cognitive functioning. Because of this, there is a wide variation in the incidence of chemo brain in the literature, with occurrence rates ranging from as little as 16% to as many as 75% of all patients (Bender et al., 2006; Hurria et al., 2006; Schagen et al., 1999; Van Dam et al., 1998; Wieneke & Dienst, 1995).

Common changes in cognitive functioning associated with chemotherapy include executive functioning (including judgment, hindsight and foresight), processing speed or reaction time, working memory, and organizational skills. Chemotherapy-induced impairment of language ability, concentration, memory, and/or attention can cause increased levels of stress and decreased work performance when higher cognitive functioning is required (Ahles et al., 2002; Coyne & Leslie, 2004; O'Shaughnessy, 2003; Saykin, Ahles, & McDonald, 2003).

Numerous studies have evaluated cognitive impairment following chemotherapy and are consistent with a meta-analysis of earlier findings (Jansen, Miaskowski, Dodd, Dowling, & Kramer, 2005). Recent literature suggests that chemotherapy has a negative impact on cognitive functioning (Bender et al., 2006; Hurria et al., 2006; Quesnel, Savard, & Ivers, 2009; Scherwath et al., 2006). In a controlled longitudinal and cross-sectional study of breast cancer patients receiving chemotherapy, Quesnel et al. (2009) reported cognitive decline in the domains of verbal fluency for patients who received chemotherapy compared to healthy matched controls at three-month follow-up assessments. In a prospective and longitudinal study conducted by Bender et al. (2006), three groups were described, including one who received chemotherapy alone, one who received chemotherapy with tamoxifen, and another group who did not receive either. Data were collected at three points in time. Cognitive decline in verbal working was found in both treatment groups one year following chemotherapy, and the group who received both chemotherapy and tamoxifen also had cognitive decline in visual memory; interestingly, women who received neither treatment had an improvement in cognitive functioning (Bender et al.).

Hurria et al. (2006) found that 25% of women older than sixty-five years old had difficulty in visual memory, psychomotor function, attention and spatial function following chemotherapy for breast cancer, compared to pre-treatment assessments. Additionally, Scherwath et al. (2006) compared patients who received either high dose or standard dose chemotherapy five years after therapy to healthy controls. They found impairments in verbal memory and attention in 13% of the standard dose patients and 8% of the high dose patients, compared to only 3% in the matched controls (Scherwath et al.). In some patients, cognitive impairment is present up to ten years following chemotherapy (Ahles et al., 2002; Saykin et al., 2003; Schagen et al., 2002; Silverman et al., 2007).

Oncology nurses are in a position to not only assess for signs of cognitive decline, but to also educate patients about its presence and available management strategies (Myers, 2009). Many patients are not aware that this impairment they are coping with could be related to their treatment. Patients tend to confide their symptoms to nursing staff, and when a nurse understands the status of the literature on chemotherapy induced cognitive impairment (CICI), he or she can listen intelligently, with empathy and provide tips to managing their lives with CICI (Staat & Segatore, 2005). It is important for oncology nurses to understand not only the detrimental effects of cognitive deficits on patients' quality of life, but also the impact these deficits have on one's ability to use complex thinking in making treatment decisions and providing informed consent (Ahles et al., 2002; Nelson, Nandy & Roth, 2007). Although research to date has yet to determine the exact mechanism and cause for CICI, patients may feel better to know that other patients also experience this phenomenon (Evens & Eschiti, 2009).

Pathophysiology

The cause of CICI is unknown, however many theories exist for its presence during and following cancer treatment. The establishment of chemotherapy-induced cognitive decline is not well established; however, an association of CICI is evident in much of the literature. Although there is little research that shows the exact mechanism of cognitive impairment following chemotherapy, associated causes are well documented and discussed below.

There are numerous theories that propose the etiology of CICI, although it is unlikely that one alone can explain its complex nature. It is further proposed that cognitive impairment related to cancer and its treatment is multi-factorial and encompasses a cluster of symptoms (Miaskowski et al., 2006); however, only CICI will be discussed in this paper. Some potential mechanisms of CICI include: chemotherapy induced neurotoxic injury as a result of direct injury to neurons, cerebral white or gray matter microvasculature obstruction via vascular mechanisms that cause direct ischemia, altered levels of neurotransmitters (Saykin, Ahles, & McDonald, 2003; Wefel et al., 2004; Ahles & Saykin, 2007), or DNA damage and subsequent oxidative stress (Ahles & Saykin; Chen, Jungsuwadee, Vore, Butterfield, & St. Clair, 2007).

Imaging studies have shown changes in white and gray matter with the use of magnetic resonance imaging (MRI) and positron emission tomography (PET) in cancer survivors that received chemotherapy compared to patients who never received chemotherapy (Saykin, Ahles, & McDonald, 2003; Inagaki et al., 2007). Additionally, two studies showed increased activation while performing memory tasks on functional MRI for patients who had received chemotherapy compared to those who did not (Ahles & McDonald; Saykin et al., 2003).

In addition to imaging changes that have supported cognitive impairment after chemotherapy, theories propose that cellular impairment also occurs following chemotherapy. The blood-brain barrier (BBB) is comprised of tight junctions of endothelial cells that prevent large molecules and toxic substances from entering the central nervous system (CNS) and the brain (Ahles & Saykin, 2001). In standard doses, carmustine, cisplatin, cytarabine, ifosfamide, lomustine, methotrexate, procarbazine, & temozolomide are the only known agents that can cross the BBB, which may help to explain why these agents cause neurotoxicity and potentially greater cognitive dysfunction than other chemotherapeutic agents (Wilkes & Barton-Burke, 2007). It is further theorized that chemotherapy or the immunologic responses toward the cancer itself may disrupt the BBB and/or the cellular and chemical processes in the brain and cause cognitive impairment (Nelson et al., 2007).

Cytokine levels are increased in patients with cancer and during chemotherapy treatment (Maier & Watkins, 2003; Pusztai, et al., 2004). Pro-inflammatory cytokines (including interleukins 1, 6 and tumor necrosis factor-alpha) are thought to penetrate the BBB via peripheral blood and cause the same pro-inflammatory cytokines to be present in the CNS, thus causing cognitive impairment (Maier & Watkins, 1998; Myers, Pierce & Pazdernik, 2008; Saykin et al., 2003; Wilson, Finch & Cohen, 2002).

Anemia is known to commonly occur following chemotherapy when other blood counts fall. The resultant anemia causes fatigue and reduced cerebral oxygenation (Ahles & Saykin, 2007; Chen, Jungsuwadee, Vore, Butterfield, & St. Clair, 2007). Moderate or severe anemia has been shown to cause executive functioning and visual memory deficits (Jacobsen et al., 2004), yet this cognitive impairment is limited to the anemia itself and would not explain long term cognitive dysfunction after the anemia is corrected.

Clinical Presentation/Risk Factors

The intensity or number of chemotherapy doses has been shown to have an impact on the degree of cognitive impairment in a few studies. Ahles et al. (2002) found an association between the number of cycles of chemotherapy and cognitive impairment. Additionally, high dose chemotherapy has been shown to have a greater effect on cognitive dysfunction compared to standard dose chemotherapy in two studies (Mehnert et al., 2007; Schagen, Muller, Boogerd, Mellenbergh, & van Dam, 2006). Many chemotherapeutic agents are known to cause direct neurotoxicity. Cyclophosphamide, 5-fluorouracil, and methotrexate have been studied and shown to have more impairment than regimens containing anthracyclines (Tannock, Ahles, Ganz, & van Dam, 2004; Wefel, Kayl, & Meyers, 2004; Vezmar, Becker, Bode, & Jaehde, 2003).

There are psychosocial risk factors associated with CICI. A strong correlation has been found between fatigue and reported cognitive impairment, although objective testing has failed to show the same association (Ahles, et al., 2002; Bender, et al., 2005; Servaes, Verhagen, Bleijenberg, 2002). Similar to studies assessing fatigue as a cause of cognitive impairment, research has shown that anxiety and/or depression and perceived cognitive dysfunction are strongly correlated, whereas objective tests fail to determine this correlation (Castellon, Ganz, Bower, Petersen, Abraham, & Greendale, 2004; Cimprich, So, Ronis & Trask, 2005; Cull, Hay, Love, Mackie, Smets, & Stewart, 1996)

Advancing age is also a known risk factor for cognitive impairment. Additionally, the presence of the apolipoprotein (APOE) allele may increase a patients risk for cognitive impairment following chemotherapy. Ahles et al. (2003) states that this gene has been associated with an increased risk for Alzheimer's disease development and increases the cognitive decline found in the geriatric population, although it is unknown why this occurs. A study was performed that found significantly decreased cognitive functioning in patients who carried the 4th allele of the APOE gene compared to patients who did not carry this allele (Ahles et al.).

The assessment of CICI can only be done by interviewing the patient and obtaining a health history concerning his or her perceived cognitive dysfunction (Bender et al., 2005; Booth-Jones, Jacobsen, Ransom, & Soety, 2005). Additionally, cognitive impairment that is self-reported by the patient may or may not show significance on standardized neurophysiologic tests (Vardy & Tannock, 2007). Cognitive dysfunction can also be screened through observational assessment, yet subtle changes will not be detected in this manner (O'Shaughnessy, 2003).

To date, the Functional Assessment of Cancer Treatment – Cognitive (FACT-Cog) is the only screening tool specifically created to assess cognitive impairment during and following cancer treatment. The FACT-Cog includes a scale of measures that a patient can self-report. This tool evaluates memory, mental acuity, attention, concentration, functional interference, deficits that others observe, functioning changes, quality of life impact, and verbal fluency, although it has yet to be validated for clinical nursing use (Evens & Eschiti, 2009).

Asking patients specific questions concerning chemotherapy-related symptoms of cognitive impairment will assist the nurse in providing a comprehensive patient assessment (Evens & Eschiti, 2009). Patients should be asked about difficulties with concentration, memory and daily functional capacity. Specifically, symptoms of CICI include: a decreased ability to follow directions, attention deficits, comprehension or understanding difficulty, an inability to multitask, difficulty with remembering details (such as names or dates), short and long term memory deficits, difficulty performing math calculations or balancing a checkbook and even behavioral changes (Evens & Eschiti).

The clinical presentation of patients suffering from cognitive decline may also include a cluster of symptoms related to cytokine release known as “sickness behavior”, which may include fever, lethargy, fatigue, decreased appetite, muscle aches, decreased social interactions and a decreased ability to concentrate (Barsevick, 2007; Parnet, Kelley, Bluthe, & Dantzer, 2002; Wilson, Finch, & Cohen, 2002). A thorough assessment and health history allows the nurse to devise an education plan for the patient and perform any nursing intervention that may help the patient cope with and potentially correct his or her deficit.

Differential Diagnosis

Cognitive dysfunction can be associated with numerous aspects of cancer and its treatment, and needs to be evaluated thoroughly prior to its diagnosis. Although patients are receiving chemotherapy, it does not preclude them from acquiring another medical condition or emergent condition. Severe fatigue with or without anemia, depression, anxiety, or pain can cause cognitive impairment (Staat & Segatore, 2005). Additionally, brain lesions (primary or secondary), stroke, acute brain injury, dehydration, infection, sepsis, sodium abnormalities, hypercalcemia, steroids, opiates, sedatives, tamoxifen therapy, thyroid dysfunction, diabetes, and menopause can all cause cognitive impairment in the presence or absence of chemotherapy and should be evaluated thoroughly and treated if possible (O'Shaughnessy, 2003; Staat & Segatore, 2005).

Management Strategies

Because the cause of CICI is unknown, treatment regimens are largely anecdotal based on theorized causes. Pharmacologic management has been studied, yet no known agent has been approved to combat this symptom. It is proposed that aspirin can decrease the microcoagulation that causes enhanced tumor growth and can decrease clot formation that may obstruct cerebral blood flow (Nelson et al., 2007). Antioxidants are believed to decrease the formation of free radicals, thus decreasing vascular injury that may lead to cognitive decline (Nelson et al., 2007); however, there is some evidence that antioxidants can interfere with chemotherapy and radiation by “protecting” cancer cells.

Pharmacologic

Erythropoietin (EPO) receptors surround the BBB and may increase therapeutic levels to the brain during hypoxia, which is thought to have a neuroprotective effect. Additionally, EPO treats anemia that is chemotherapy induced, thus increasing oxygen to the brain (Chang, Couture, Young, Lua & Lee, 2004). One study showed that the once weekly administration of EPO during chemotherapy significantly improved cognitive functioning in breast cancer patients (Chang et al.). However, a longitudinal study of breast cancer patients failed to show a significant impact after the use of EPO 12-30 months following chemotherapy treatment (Fan et al., 2009).

Methylphenidate is a CNS stimulant that is thought to increase dopamine levels extracellularly and increase attention. Although it is only approved for attention deficit hyperactivity use in the United States, it has been studied in the treatment of CICI. One randomized, double-blind, placebo-controlled trial failed to show that methylphenidate was effective against cognitive dysfunction in breast cancer patients during adjuvant therapy (Mar Fan et al., 2008). Despite this, researchers continue to examine the role of stimulants (methylphendiate, modafanil, dexmethylphendiate and even caffeine) in treating CICI. Additional studies are ongoing with medications and herbal therapies, such as donepezil, ginkgo biloba and monoamine oxidase inhibitors, although none of these agents are currently approved to treat chemotherapy-induced cognitive impairment (Evens & Eschiti, 2009; Nelson et al., 2007; Staat & Segatore, 2005).

Non-Pharmacologic

Cognitive rehabilitation programs are structured programs utilizing exercise, puzzles, and tasks that use memory to "rehabilitate" one's mind. These programs are typically used for people with brain injuries, but therapists have tailored programs for cancer survivors. A number of companies offer computer programs that aim to improve brain function. There are currently studies ongoing looking at the effectiveness of these programs in cancer survivors.

Puzzles using numbers, like Sodoku, may help "exercise" the brain. Though it is not known how well completing a crossword puzzle translates to an effect on verbal memory, it would be helpful if future research looked at these "brain games". However, it is likely that any brain stimulation may be helpful and certainly cannot hurt, whether through a game, taking a course at a local school or joining a book discussion club.

Other interventions that are proposed to decrease cognitive impairment following chemotherapy, yet have not been studied specifically, include: exercise, stress management, good nutrition and acupuncture. Exercise may be helpful because it increases blood flow and oxygenation to the brain, but studies have not looked at this specifically (Nelson et al., 2007). Additionally, high stress levels are prevalent in patients during cancer treatment, and may reduce one's ability to concentrate (Evens & Eschiti, 2009). Stress management strategies can include relaxation techniques, exercise, spiritual advising, increased hobby participation, counseling or even anxiolytics to decrease stress or anxiety that is caused by stress (Evens & Eschiti).

Poor nutrition can lead to anemia, so patients should be encouraged to consume B vitamins, folic acid and iron to decrease this problem (Evens & Eschiti, 2009). Additionally, because oxidative stress is theorized to cause cognitive impairment, antioxidant-containing foods such as fruits and vegetables should be suggested to patients with this symptom (Evens & Eschiti). Acupuncture has been shown to improve cerebral oxygenation and circulation, yet research has not been done on this specifically (Johnston et al., 2007). Each of these areas requires controlled studies to determine whether they can actually decrease the degree of CICI that patient's experience.

Patient education is a key intervention for CICI. Helping patients realize the benefit of incorporating creative ways to combat symptoms. This may include keeping a detailed calendar or planner, keep lists (to-do, shopping, etc), getting a navigation system and the importance of knowing your limitations so as to not take on too much.

Conclusion

Oncology nurses can play an integral role for patients who experience CICI. Nurses are key participants in screening and assessment, discussing proposed treatment options and current knowledge, as well as validating patients' symptoms and concerns and helping them find ways to cope with CICI (Evens & Eschiti, 2009). Although CICI is a common side effect in patients receiving chemotherapy, its exact cause is unknown. Because of this, it is difficult to determine management strategies for patients experiencing this symptom. However, understanding how CICI can affect a patient's ability to make complex decisions and carry out his/her daily responsibilities (career, family life, etc) allows the oncology nurse to become a patient advocate. Finally, research needs to be directed toward understanding the etiology of chemotherapy-induced cognitive impairment. Quality research will help to develop treatment options or preventative strategies to alleviate the disability that chemotherapy-induced cognitive impairment can cause.

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