Impairment of cognitive function can have a profound effect on the quality of life of cancer survivors. Cognitive function is a multidimensional concept that describes the brain’s transcription of information necessary to direct behavior and decision making (Muscari, 2006a; Jansen et al., 2005b). Cognitive disorders can occur as a result of dysfunctions in brain anatomy or physiology caused by injury, degenerative disease, neoplasms, arterial or infectious processes, metabolic or nutritional conditions, and medications or substance abuse (Barry, 2002).

Normal, healthy brain function involves the domains of attention and concentration, learning and memory, psychomotor and visuospatial skills, manual dexterity, language, and intelligence (Table 7-1) (Muscari, 2006a; Jansen et al., 2005a). The processes of brain functioning are so interrelated that impairment in one domain unavoidably affects another (Jansen et al., 2005b). Symptoms of cognitive dysfunction can range on a continuum from decreased concentration and short-term memory loss to confusion and delirium. Mild cognitive dysfunction can be misdiagnosed as a psychological problem, such as anxiety or depression. Cognitive dysfunction is associated with a poorer prognosis and difficult patient management issues (Walch et al., 1998). Impairments in learning, memory, focus, and concentration have negative effects on the patient’s quality of life, relationships, and safety. Negative effects may include poor job performance, academic difficulties, poor self-esteem, and altered social relationships. Most important are the risk to the patient’s safety (e.g., unable to remember medication schedules) and problems with taking care of children (e.g., inability to multitask) (Staat & Segartore, 2005).

Multiple factors contribute to cognitive dysfunction in cancer patients. These can be classified as direct/disease-related factors and indirect/treatment-related factors (Muscari, 2006a; O’Shaughnessy, 2003). Disease-related factors include primary tumors of the central nervous system and brain metastases. Primary brain tumors often cause diffuse cognitive dysfunction or focal deficits related to the site of the tumor (Walch et al., 1998). Frontal lobe tumors have been associated with behavioral symptoms such as emotional lability, apathy, poor judgment, and socially inappropriate behaviors. Temporal lobe tumors have been associated with mania or depressed mood, irritability or anxiety, and seizures. Tumors in the parietal lobe have been associated with sensory abnormalities (e.g., agraphesthesia [loss of tactile recognition]) and motor problems (e.g., apraxias [motor abnormalities]). Occipital tumors have been associated with visual problems such as hemianopsia (loss of half of the visual field in both eyes) (Walch et al., 1998). Even though few research studies have focused on cognitive dysfunction related to primary brain tumors, the findings of these studies can help health care providers use the site of the tumor or metastasis in the brain as a guide for assessment of possible cognitive deficits.

Other direct/disease-related factors that contribute to cognitive dysfunction are age, intelligence, and educational level (Muscari, 2006a). Cognitive decline is expected as adults age and may be exacerbated by the decline in hearing and sight. Normal, expected cognitive changes among the elderly must be differentiated from disease- or treatment-related cognitive impairment, psychiatric diagnoses (e.g., depression and anxiety), dementia (Muscari, 2006a; Smith & Buckwalter, 2006), and delirium (Bond et al., 2006; Boyle, 2006). Although not yet investigated in the oncology population, cognitive reserve, or the baseline intelligence quotient (IQ), may be a protective mechanism against brain trauma (Muscari, 2006a).

Indirect/treatment-related factors that contribute to cognitive dysfunction can be classified according to (1) the adverse effects of treatment modalities (e.g., radiation, chemotherapy, biologic response modifiers) and (2) indirect factors, including the metabolic, endocrinologic, and nutritional abnormalities that commonly occur with malignancies or as side effects of treatment and primary psychiatric co-morbidities. Radiation therapy to treat metastatic disease or used prophylactically puts patients at risk for cognitive impairment. Variables that contribute to neurotoxicity include the dose of radiation, the volume of tissue irradiated, and the number of treatments (Walch et al., 1998). Adverse effects of radiation therapy include cerebral edema, demyelination, leukoencephalopathy, and radiation necrosis (Walch et al., 1998). Assessing the true impact of radiotherapy on cognitive function is difficult, because problems arise with following patients long term and differentiating between progression of CNS disease and the negative effects of radiotherapy (Muscari, 2006a). Patients who receive high doses of cranial radiation while undergoing high-dose chemotherapy may be at greatest risk (Walch et al., 1998).

Cognitive impairment caused by chemotherapeutic agents often is referred to as chemo brain or chemo clutter (Muscari, 2006a; Jansen et al., 2005b; Staat & Segatore, 2005; Walch et al., 1998). Most research on chemotherapy-related cognitive dysfunction has involved patients treated for breast cancer. As many as 50% of these patients reported mental changes, such as difficulties with memory, thinking, and concentration (Muscari, 2006a; Jansen et al., 2005a; Staat & Segatore, 2005). The impairment has been described as subtle, mild to moderate changes that can last as long as 10 years after treatment (Staat & Segatore, 2005).

A review of the literature investigating chemotherapy-induced cognitive impairment in women treated for breast cancer (Jansen et al., 2005a) provided a comprehensive analysis of the cognitive domains that may be impaired by the neurotoxicity of chemotherapy. Three hypothetical mechanisms for neurotoxicity have been postulated: direct neurotoxicity, inflammatory or immunologic responses, and microvascular invasion (Staat & Segatore, 2005; Saykin et al., 2003). Neurotoxicity has been described as including encephalopathy, leukoencephalopathy, cytokine-induced inflammatory response, cerebellar symptoms and, most often, chemotherapy-induced anemia and chemotherapy-induced menopause (Jansen et al., 2005b; Walch et al., 1998).

The direct impact of certain chemotherapeutic agents has been described (Table 7-2), but drawing definitive conclusions is difficult because of the numerous drug combinations and schedules (Walch et al., 1998) and the need for valid, reliable, and sensitive neuropsychological tests (Jansen et al., 2005a). Agents such as cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil have been reported to correlate with dysfunction, especially in doses that enable the drug to cross the blood-brain barrier (Jansen et al., 2005b; Staat & Segatore, 2005). High-dose, intensive chemotherapy regimens, combination chemotherapy and radiation protocols, and bone marrow transplantation may also exacerbate short- and long-term cognitive dysfunction. Pre-existing neurologic abnormalities (e.g., cerebral atrophy, brain metastases) and variables such as gender (e.g., hormonal differences) and age (e.g., normal cognitive decline in the elderly) compound the difficulty of drawing definitive conclusions about treatment-related neuropsychological effects (Muscari, 2006a; Walch et al. 1998). Interestingly, subjective complaints do not always seem to correlate with objective tests of cognitive function (Statt & Segatore, 2005).

Additional indirect effects that exacerbate cognitive impairment in patients with cancer are listed in Box 7-1. Common adverse effects of the disease and its treatment, such as infection, fever, and vitamin and nutritional deficiencies, may also contribute to cognitive loss. Deficiencies in estrogen and progesterone (e.g., chemotherapy-induced menopause and estrogen-blocking medications) have been shown to have deleterious effects on attention, learning, and memory (Muscari, 2006a; Staat & Segatore, 2005). Research has shown that anemia (e.g., a hemoglobin level less than 12 g/dL in women and less than 13 g/dL in men) has a deleterious effect on cognitive function (Muscari, 2006a; Cunningham, 2003); administration of epoetin alfa or darbepoetin to patients with a hemoglobin level less than 10 g/dL may have a neuroprotective effect (Cunningham, 2003). In addition, concurrent use of medications such as antiemetics and antidepressants may adversely affect cognitive ability, and the negative effect of substance abuse must not be overlooked.

The associated risks and the incidence of cognitive dysfunction for patients undergoing cancer treatment require further investigation. However, emerging research has confirmed the existence of treatment-induced impairments and the negative impact on the patient’s quality of life (Jansen et al., 2005a; Staat & Segatore, 2005). The symptoms of cognitive dysfunction are extremely distressing to both the patient and the family, and the devastating and demoralizing impact of these dysfunctions must not go unrecognized (Staat & Segatore, 2005). Neuropsychological changes can persist only during treatment, for a short time after treatment stops, or for many years after treatment, as is the case with patients who undergo bone marrow transplantation (Walch et al., 1998).

The prognosis is influenced by the patient’s intelligence and educational level before diagnosis; by the patient’s age and gender; and by treatment variables, such as the chemotherapeutic drug used and the dosage, the radiation dose and fractionation schedule, and the intensity, duration, and combination of treatment protocols. The prognosis also is influenced by any concurrent neuropsychiatric illnesses, such as depression and anxiety.