Cognitive Function After Systemic Therapy for Breast Cancer
Cognitive Function After Systemic Therapy for Breast Cancer
Anecdotal reports of cognitive compromise among patients treated with chemotherapy are relatively common among breast cancer survivors and may play an important role in adversely affecting functioning in multiple domains. As noted by Dr. Olin, the empiric exploration of the neurocognitive effects of chemohormonal treatment among breast cancer survivors has been initiated only in the past few years. In her article, she cogently reviews the relevant literature with a focus on the relationship between neurocognitive status and quality of life, and concludes by offering several suggestions for directing future research endeavors in this field. We agree that this topic is a timely one, especially with the increasing indications for adjuvant therapy in patients with earlier-stage disease, who, with therapy, can anticipate nearly normal life expectancies. If neurocognitive changes are prevalent and/or disabling, then this late effect must be considered in the process of informed decision-making.
Dr. Olin’s review of the literature suggests that a significant minority of studied breast cancer survivors demonstrated some degree of cognitive deficit. Exact rates of impairment are bound to vary, depending in part upon how neurocognitive compromise is operationalized. Some studies have failed to use adequate control groups and have relied instead on comparison with extant normative data. As Dr. Olin points out, this approach has serious limitations, particularly if premorbid differences exist between the individuals comprising normative samples and patients with breast cancer; also, the quality of the normative data for women in this age group varies tremendously from task to task.
Comparison to normative data often leads to an inflated estimation of neurocognitive compromise when the comparison group represents a clinical population that may suffer from some combination of medical, psychiatric, and/or neurologic condition(s). Unfortunately, the two reviewed Dutch studies used the same control group and, therefore, their results should be interpreted with caution. However, their findings strongly suggest a dose-response relationship between chemotherapy and cognitive function, with more intensive systemic treatment leading to higher rates of impairment and lower group mean scores on various neuropsychological instruments. The implications of such findings are particularly important in light of recent findings that fail to suggest that high-dose chemotherapy is superior to conventional-dose chemotherapy for adjuvant treatment.
Another noteworthy finding that Dr. Olin briefly discusses is the fact that some change in cognitive function is present during, shortly after, and up to (on average) 2 years posttreatment. In fact, a recent study by Ahles and Saykin, along with pilot data from our own lab, suggest that some cognitive compromise was noted in a subset of breast cancer survivors more than 5 years posttreatment and was more likely to be present in patients receiving more intense therapy. Data from both our own lab and Ahles and Saykin suggest that tasks that place demands on working memory (eg, simultaneously storing and manipulating information), verbal memory, and accelerated information processing are particularly affected.
Correlates of Neurocognitive Compromise
Dr. Olin notes that there are undoubtedly multiple pathways to cognitive compromise in survivors of breast cancer. Systemic treatment effects are clearly one but certainly not the only etiologic agent responsible for decreased cognitive efficiency. Research to date has suggested that constructs, such as depression, fatigue, and pain, which are often associated with each other among breast cancer survivors, are unlikely to explain the cognitive deficits that were observed in the reviewed studies. This finding is not surprising given the presence of psychiatric exclusionary criteria and/or the generally low levels of depression reported in the studies published to date.
While depression, fatigue, and pain are all known to adversely affect cognitive function, it is typically when these symptoms or syndromes are present to a pronounced and persistent degree that a consistent relationship to cognition is noted. Also, in some patients, depression and fatigue may be consequences of central nervous system involvement, in which case their presence may have more prognostic significance (ie, be more likely to be related to cognitive compromise) than when these constructs are instead a response or reaction to loss or increased stress.
Individual differences in age and premorbid intellectual level are likely to be associated with neurocognitive performance following chemotherapy as each of these constructs has shown a clear and consistent relationship with various cognitive domains (including verbal learning and memory, information-processing speed, and complex attentional function). Finally, there does seem to be a relationship between menopausal status and neurocognitive function, meaning that this important potential confound (or moderator variable) should be carefully accounted for in future studies.
Consequences of Cognitive Compromise
The impact of cognitive compromise can vary tremendously, from subtle changes in information-processing speed and efficiency to frank dementia syndromes. There is currently insufficient evidence to conclude with any surety the clinical significance of lower performance on neuropsychological tasks among a subgroup of breast cancer survivors. Characteristics of the injury or insult (eg, structural vs neurochemical, location, severity), characteristics of the individual (eg, premorbid cognitive functioning, age, presence of comorbid conditions), and characteristics of the environment (eg, demands of job, degree of social support, presence of rehabilitation opportunities) each influence how disruptive the cognitive dysfunction will be.
Dr. Olin notes that quality of life may be dependent upon many of these factors and does not always share a linear relationship with the degree of cognitive deficit. An important "next step" in this research will be the elucidation of mediators of cognitive dysfunction within this population of breast cancer survivors. Assessment tools borrowed not only from psychology and neuropsychology, but also from psychiatry and neuroradiology, will be important in determining which individual and/or environmental differences are most relevant in predicting cognitive function.
Cautions and Future Directions
Neuropsychological findings drawn from research in other populations suggest that we should avoid overinterpreting poor performance on any one task until more data accumulate. Many neurocognitive tasks are multifactorial in nature, meaning that they measure cognitive processes in addition to that process or domain that is the main target of assessment. For example, a task purporting to index "verbal memory" is also likely to make demands on other cognitive domains such as language comprehension, sustained attention, information-processing speed, and/or auditory perception. The tendency to interpret low scores on such a task as evidence of verbal memory deficits runs the risk of mislabeling the deficit if, for example, it is indeed a problem with sustaining attention that is driving poor performance on this task. It is not uncommon to find that one or two more basic cognitive processes (eg, processing speed) mediate performance on higher-order tasks such as memory or executive functioning (ie, planning, organization, initiation).
The role of neuroimaging techniques in helping to better elucidate the neuroanatomic and neurophysiologic substrates associated with neurocognitive compromise among affected breast cancer survivors may be particularly informative. More specifically, using positron-emission tomography and magnetic resonance imaging, the brain function of breast cancer survivors can be examined using activation paradigms in which brain glucose metabolism is measured and compared to controls. Finally, the role of cognitive rehabilitation in increasing quality of life among affected survivors has received little empiric attention, but is clearly a topic with important real-world ramifications.
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