Nail, Lillian M. PhD, RN, FAAN
Cognitive changes in people with cancer can stem from the disease, the treatment, complications of treatment, comorbid conditions, adverse effects of drugs, other symptoms, aging, and psychological responses to the diagnosis of cancer. 1–9 Impaired cognition is seen during all phases of the cancer experience: diagnosis, treatment, the period immediately following treatment, long-term survivorship, and the end of life. Cognitive changes range from small decrements in information processing speed to severe acute delirium. The range of the potential causes of cognitive changes, along with the wide variation in their nature, present challenges to nurses who wish to organize the existing knowledge and address implications for future research and practice.
The surge of interest in this issue was prompted by research with children treated for acute lymphoblastic leukemia (ALL), 10–12 which suggested that brain irradiation and intrathecal chemotherapy (drugs administered into cerebrospinal fluid via lumbar puncture) contributed to cognitive changes after treatment. These treatments were subsequently modified to decrease neurotoxicity. 13 Researchers then began investigating concerns about cognitive changes exhibited by adults treated with surgery, hormone manipulation, chemotherapy, radiation, and biologic response modifiers. 9, 14, 15
There are now hundreds of papers addressing the cognitive effects of cancer and cancer treatment, most studying the effects of specific types of treatment, and others exploring the effects of treatment complications or supportive care interventions. This article reviews the literature but excludes studies of people with central nervous system (CNS) tumors and CNS lymphomas as well as studies of CNS-directed therapies such as whole brain irradiation. Because of the importance of cancer treatment modality in interpreting the results of research on cognitive function in adults treated for cancer, studies that lacked treatment information were also excluded, as were studies that mentioned cognitive effects but did not assess cognitive function.
COGNITIVE DOMAINS AND COGNITIVE TESTING
Cognition consists of several different domains, including attention and concentration, information processing speed, verbal memory, visuospatial memory, visuospatial skill, executive function (planning, problem solving), and psychomotor skill. Cognitive tests are designed to detect impairment in one or more cognitive domains. Scores can be evaluated in relation to established norms, in relation to a control or comparison group, or in an individual over time. 16 Although test results characterize the impairment, it is important to remember that different types of impairments may affect the same function. 17 For example, attention problems will impair functions like driving, reading, and giving a presentation. Problems with visuospatial memory and information processing speed will also make driving more difficult. The functional impact of a specific impairment depends upon the individual’s ability to compensate for it—a process that generally requires the ability to recognize the problem, marshal resources, anticipate when the problem will occur, and monitor the success of the compensatory strategy.
There are at least four major challenges in using cognitive tests in clinical cancer research. First, many of the tests may be subject to practice and learning effects, such that a person’s score will improve over time when there is really no change or even a worsening in the function being tested. 16 Second, cognitive testing is time intensive for both the subject and the examiner. There are several tests for each domain, designed to capture unique elements of it, but the tests may partially overlap. Many cognitive tests require special training to standardize administration and interpretation of results, and testing sessions may take several hours. Third, variables such as education, race, age, and sex may affect test results, when comparing results either between groups or to established norms. 18 Fourth, the research design is challenging. Almost anyone who enters the cancer care system has had experiences that can influence cognition, such as surgery, anxiety from the cancer diagnosis, and sleep disruption. Because baseline data do not reflect cognitive function before the cancer diagnosis, most longitudinal studies do not contain a true baseline. Furthermore, it is difficult to identify a valid comparison group because cancer treatment is specific to cancer diagnosis, stage of disease, and biologic factors characteristic of the cancer. This means that treatment is nearly always confounded with other variables that could account for differences seen between types of treatment. As a result, very few studies of cognitive effects of cancer treatment use randomized clinical trial designs, and most longitudinal studies contain baseline data points that do not reflect cognitive function prior to the cancer diagnosis.
COGNITIVE CHANGES BY CANCER TREATMENT MODALITY
Chemotherapy and biologic response modifiers.
Cognitive changes associated with systemic cancer treatment, defined as chemotherapy or biologic response modifiers (used to enhance the body’s immune response to the cancer) used alone or in combination with radiation therapy or surgery, were examined in a rigorous metaanalysis of 29 studies. 19 Compared with controls and with normative data, people who received systemic cancer treatment were somewhat impaired in executive functioning, verbal memory, and motor functioning. Information processing was slowed in people with cancer compared with controls but not in studies where the comparison was with normative values. The metaanalysis included studies of samples with a variety of cancer diagnoses, sample sizes (seven to 70, with only four samples larger than 50 subjects), age (26 to 65 years), and time since diagnosis or treatment (end of treatment to an average of 10 years later). The researchers emphasized that the cognitive impairments identified in the studies may not be evident to someone else but are probably apparent to the person experiencing them, especially in relation to work performance in a position with high cognitive demands. 19
People who received systemic cancer treatment were somewhat impaired in executive functioning, verbal memory, and motor functioning.
A more recent report summarizing a workshop on cognitive impairment and cancer found that at least 50% of published and unpublished studies reviewed reported problems in attention, verbal memory, visual memory, and information processing speed, despite differences in the measures, samples, and treatment status of the people studied. 8 This conclusion is consistent with the results of the earlier metaanalysis: that there is a generalized, subtle effect of systemic cancer treatment on cognitive function in adults.
Two additional studies assessed cognitive function but were not part of the metaanalysis or the subsequent systematic review. A case–control study of 100 women within two to six weeks of administration of adjuvant chemotherapy for breast cancer demonstrated that patients tested significantly worse in language ability than control subjects, with a nonsignificant trend toward deficits in attention, spatial skill, and executive function. 20 In another study, women with breast cancer demonstrated statistically significant declines in attention, learning, and speed of information processing from before treatment to three weeks postchemotherapy; half of the women who experienced cognitive impairment improved over the next year. 21
These recent studies, along with the metaanalysis and several review papers, 14, 19, 22 support the conclusion that systemic cancer treatment causes both short-term and persistent subtle cognitive impairment in a variety of cognitive domains. Few studies have examined the pattern of change over time, so the extent to which people recover function that declines during treatment is not known. The specific mechanisms responsible for cognitive changes associated with systemic cancer treatment are not known, nor is the impact of the specific changes on daily life understood.
The extent to which people recover function that declines during treatment is not known.
Use of antiestrogen agents such as tamoxifen (Nolvadex), raloxifene (Evista), letrozole (Femara), and anastrozole (Arimidex) in treating estrogen receptor–positive breast cancer, and surgery or drugs to achieve complete or intermittent androgen blockade in men with androgen-dependent prostate cancer, have resulted in large numbers of women and men who undergo relatively long-term—lasting several months to more than five years—manipulation of sex hormones. Although hormone manipulation is thought to cause cognitive changes, 1, 23 only a few studies have examined cognition in people undergoing such treatments.
In a four-group randomized trial of men with prostate cancer, 24 out of 50 men who received one of three androgen-suppressing drugs showed declines in cognitive function compared to their baseline scores when tested six months after treatment. However, no men in the control group (clinical monitoring only) experienced deficits. 23 Another study examined changes in cognitive function at three time points in men with prostate cancer: at baseline, at the end of a nine-month androgen suppression regimen, and at three months after treatment ended. Most of the cognitive tests showed no change over time, but visuospatial skill declined and verbal memory improved. 24 These two published studies show inconsistent results.
In a study known as the ATAC trial, 94 women with breast cancer treated with anastrozole, tamoxifen, or a combination of both drugs were compared to 35 control subjects without cancer. 25 Patients did not differ from controls on measures of working memory, visual memory, or attention and concentration, but were comparatively impaired in verbal memory and information-processing speed.
The body of research examining the cognitive effects of hormone manipulation is relatively small but expanding. More research is needed to evaluate both the short- and long-term effects of various hormone manipulation strategies on cognitive function in both men and women and to determine if various agents and approaches to hormone manipulation produce different patterns and types of cognitive effects. 1, 23, 24, 26–28
Radiation is a local treatment and the only major systemic adverse effect is fatigue. Therefore, there are no relevant studies of the cognitive effects of radiation treatment other than in patients receiving CNS-localized treatment. Studies of cognitive function that include people receiving non–CNS-localized radiation treatment are confounded with chemotherapy or hormone manipulation and are included in those sections of this review.
Most studies of people undergoing cancer treatment either do not address the influence of surgery on cognition or mention surgery as part of a treatment regimen that includes chemotherapy, radiation therapy, or biologic response modifiers. The few published studies on the cognitive effects in patients with cancer undergoing surgery use samples of women with breast cancer. Scott found that women undergoing breast biopsy experienced impaired reasoning related to anxiety about the results of the biopsy. 29 In another study, women diagnosed with breast cancer had lower levels of attention or concentration than did a control group just before surgery. 30 Even though the sample with breast cancer improved over the three months following surgery, they continued to perform worse than controls at the three-month data collection point.
Adults with cancer can experience any of the physical and psychological problems that produce cognitive impairment in adults without cancer, such as renal failure, liver failure, sedation from analgesics, drug interactions, sepsis, hypoxia, and cerebrovascular problems. 2, 31–33 Managing these problems depends upon recognizing relatively sudden cognitive decrements and differentiating them from the subtle effects attributed to systemic treatment for non-CNS cancers. These problems should be evaluated and managed in a manner consistent with the patient’s stated preferences for the goal of care.
Attempts to prevent or minimize treatment-induced cognitive effects by changing the treatment have been tested only for childhood ALL. When possible, treatments for CNS tumors aim to minimize cognitive effects by using minimally invasive surgical techniques or more precise radiation treatment designed to spare normal tissue. In contrast, new supportive care drugs that overcome myelosuppression and the possibility of rescuing people from myeloablative high-dose chemotherapy with bone marrow or peripheral blood stem cell transplantation are allowing treatments with increased doses of chemotherapy for some non-CNS cancers in adults. Whether increased dosing will in turn increase the magnitude of cognitive problems experienced with chemotherapy will have to be determined. New treatments, such as targeted molecular therapy, may eventually replace some treatments believed to contribute to cognitive problems, but their cognitive effects will need to be evaluated as well.
Researchers are beginning to investigate the use of neuroprotective agents, such as erythropoietin (Eprex), that can prevent adverse effects when used in conjunction with cancer treatment. 34 Although various agents have been developed and several are being tested, none of them are approved for CNS protection.
Genetic factors may make some people susceptible to cognitive problems after systemic treatment. Identifying the genetics of treatment response may eventually provide guidance for who should and should not receive specific types of treatment or suggest novel approaches to neuroprotection. 8, 35
Remediation strategies focus on relearning or strengthening the skill or behavior that is affected. Rehabilitation after traumatic brain injury, such as intensive skills training in learning strategies or other compensatory strategies, can serve as a model for approaches to improve cognition after cancer treatment. To date, only three published examples of behavioral remediation strategies in people with cancers other than brain tumors exist. These are an attention-restoring behavioral intervention in women undergoing surgery for breast cancer, exercises designed to develop specific attention skills in children following cancer treatment, and intensive arithmetic instruction for childhood cancer survivors. 36–38 In the only published randomized trial of an intervention to improve cognitive function in adults with cancer, a simple concentration exercise conducted with women with breast cancer undergoing surgery demonstrated improved attention in the intervention group 19 days after surgery. 36
Psychostimulants have shown some positive effects in both children and adults. Methylphenidate (Ritalin) consistently has shown benefits to attention 39 and, in some studies, to reaction time and learning. 40–42 In people with cancer, methylphenidate has also been used to treat fatigue and to offset the sedative effects of opioid analgesics. 43–45
Teaching compensatory strategies designed to “make up for” or “work around” cognitive deficits is a major component of both rehabilitative psychology and occupational therapy, but this approach has not been tested in adults with cancer. People can learn to compensate for deficits in a specific skill or function, such as by maintaining their visuospatial orientation when driving in heavy traffic. 46 Anecdotal evidence from adult cancer survivors suggests that they may generate their own compensatory strategies and share them with others who have the same problem. Strategies used may include structuring the work environment to limit distractions, if attention is impaired; using an electronic calendar with alarms to remind the user of an appointment, if short-term memory is diminished; and using a word-based direction finder or a global positioning system device with voice prompts to keep from getting lost when driving, if visuospatial memory has declined.
Well-designed prospective longitudinal studies using normative or comparison conditions are needed to establish the incidence, prevalence, nature, magnitude, and pattern of cognitive changes associated with specific cancer treatments. In order to address the problem of confounding results because of variations in the type of treatment and whether or not subjects are currently receiving treatments, it is critical to define current and prior treatments, and address both these variables in the analysis. Identifying risk factors, characterizing the functional impact of specific cognitive deficits, and describing specific strategies used by cancer survivors to deal with cognitive changes will contribute to our understanding of the scope of the problem. Developing and testing interventions to prevent, remediate, and compensate for subtle cognitive changes from cancer and cancer treatment are essential to improving the care of cancer survivors.
The decrements in cognitive function associated with systemic cancer treatments may be too subtle to be detected through standard clinical screening tools such as the Mini-Mental State Examination. 47 Validated tests are needed that are relatively fast and easy to administer but sufficiently sensitive. Current practice standards should include routine neuropsychologic testing, and clear guidelines are necessary for identifying high-risk patients other than those with brain tumors and patients receiving radiation therapy to the brain.
People receiving cancer treatments that may cause cognitive changes should be forewarned that such changes may occur and provided with any information that is available about the nature and pattern of the changes. For example, the nurse might say, “You may find that you have a little more trouble remembering or concentrating. This is something that other people receiving this treatment have noticed. It improves for most people within a few months after treatment ends.” General awareness of the problem and planning care to accommodate cognitive changes are essential. For example, clinicians should support verbal information about critical elements of their patients’ care with written reference materials. Regular verbal and written reminders should be provided about appointments and self-care requirements, and discussions about major decisions or changes in care should be held in situations that are protected from auditory and visual distractions, and that include another family member whenever possible. Health care providers should give patients permission to talk about cognitive change, by saying, for example, “Sometimes people have concerns about their ability to concentrate. Is this a concern for you?” They should also refer patients who have concerns about cognitive changes for neuropsychological testing. Obvious deterioration in cognitive function should be carefully evaluated to identify problems such as organ failure, CNS metastasis, or drug toxicity.
Future research on cognitive effects of specific cancers or cancer treatments may have implications for choosing one form of therapy rather than another. For example, therapy may be selected based on the individual’s genetic profile, and relevant information about cognitive effects will need to be incorporated into the consent process for specific treatments. 9, 35 Obtaining this information about all new systemic cancer treatment will require the addition of sensitive measures of cognitive function in cancer treatment trials.
Further research on pharmacologic and behavioral strategies is needed to provide a set of research-based interventions for clinical practice. At this point, most survivors use self-generated compensatory strategies and, occasionally, psychostimulants are prescribed. Referral resources for neuropsychologic testing, careful examination of the content of patient and family educational materials to assess the adequacy of information on cognitive changes, and ensuring that any information that is given verbally is supported with written reference materials to compensate for memory and processing problems are important in all cancer care settings. Incorporating a general assessment of self-perceived cognitive changes by asking people if they have noticed or have any concerns about changes in memory, concentration, or other relevant cognitive domains will also be appropriate, based upon the risk associated with specific types of cancer treatment.
What to Ask Cancer Survivors
* Sometimes people feel as if they are starting to have problems with ordinary functions like paying attention, remembering things, finding words, or solving problems. Have you noticed any changes like these that are a concern for you?
* (If the response is affirmative) So, tell me how often you notice this; whether it is getting better, not changing, or getting worse; and how big a problem it is for you.
* (If the problem is significant or is worsening) Have you had any detailed testing done? If not, is this something you might be interested in order to learn more about what’s going on?
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