Dr. Julie Olin has highlighted an important issue for patients and providers contemplating systemic therapy for breast cancer: how the brain works after such treatment. Her excellent article summarizes four important studies, identifies the research design problems and questions raised by these and other studies, and proposes a model for how chemohormonal therapy might affect cognitive functioning and quality of life (see Figure 1 of her article). Finally, she identifies how actual, as well as potential, cognitive impairment might influence patient decisions and care (the author’s Table 1).
Dr. Olin notes that cognitive dysfunction has been reported in approximately one-third of patients in these four studies. Patients have been describing this phenomenon to clinicians and calling it "chemobrain." A major challenge for researchers is how to validly and reliably define and measure cognitive functioning in this heterogeneous (in terms of type of chemotherapy, stage of disease, demographics, etc) patient population.
Ongoing Problems Wtih Measuring Cognition
Why are problems of measurement in this line of research so vexing? First, the measurement of normal neurocognitive function is nested in the larger question of whether or not one has returned to "normal" following treatment. Thinking is one aspect of overall quality of life, and for better or worse, changes in the quality of thought may be subtlea moving target that is more or less undetectable under any but the most well-controlled conditions of measurement, except of course by subjective patient reports.
Second, Dr. Olin has highlighted the fact that there were no baseline neuropsychological tests given prior to the beginning of adjuvant therapy. Thus, it is impossible to know to what degree any cognitive changes (observed at the point of measurement) were the direct result of the treatment itself. Furthermore, the question of whether a patient has regained normal cognitive functioning posttreatment is superimposed upon the process of normal growth, development, and life change. While treatments can drastically alter how patients think and feel, some changes would have occurred even in the absence of these treatments.
An example of this could be difficulties in short-term memory. (What adult has not experienced the temporary frustration of searching for the name of a colleague who is encountered unexpectedly?) These changes may simply reflect normal functional changes, especially when a considerable amount of time has passed since the initial diagnosis, treatment, and neuropsychological assessment. The studies cited by Dr. Olin have a range of 6 to 36 months from the time of treatment completion to the time that the neuropsychological assessments were administered.
Third, a comparison/control group is critical before causal relationships between cognitive dysfunction and chemohormonal treatment can be firmly established. It is difficult to design a control group for this type of study.
Fourth, measuring cognitive functioning is costly. In the study by van Dam and colleagues, the testing procedure took approximately 2 hours to complete and included at least 12 different measures. Imagine a large cooperative group clinical trial in which patients were required to take 2 hours of neuropsychological testing. Also, the tests themselves must be administered by a well-trained expert or technician.
However, assuming changes in cognitive function are subtle, it will be necessary to test large numbers of people to detect the "just noticeable" differences in patientsie, differences that are evident only to patients themselves. Perhaps the High Sensitivity Cognitive Screen utilized by Brezden et al could be used if it highly correlates with other more sensitive measures of cognitive functioning. It remains the task of researchers to establish a fairly consistent battery of tests that can be utilized in a variety of different settings. These results could then be compared across studies.
Why Is This Area of Study So Important?
Dr. Olin, a practicing clinician, describes the significance of this field of study, and illustrates this nicely in her Table 1, where she identifies five important points/questions. For example, what are the implications of how clinicians discuss informed consent? Adjuvant systemic chemotherapy may provide a slight increase in survival potential for some patients, but it may also result in cognitive problems of some sort, perhaps memory deficit. What is the tradeoff here? Would a patient be willing to accept reduced survival for the hope of better memory and concentration? Or is it preferable to remember less while accepting the promise of living longer?
Some research on patient preferences suggests that patients are willing to sustain high toxicities and even potential death for very minimal increases in survival time. Thus, it seems unlikely that subtle losses in the way one thinks would stand in the way of choosing additional adjuvant therapy if it provided increased survival. Nevertheless, patients and providers should know of this potential disruptive side effect so they can make more informed choices. Additionally, the literature on cognitive functioning in this population can validate patients’ subjective sense of what has happened to them and that they are not imagining things or losing their minds.
When Dr. Olin asks the question, "Why are patients affected differently?" she directs researchers to the mechanisms by which chemohormonal therapeutic agents affect brain functioning. Have these agents penetrated the blood-brain barrier in ways that have yet to be measured? Further research can better address the question of mechanisms and could lead to the use of imaging techniques, in addition to neurocognitive tests, to identify the measurable brain changes that are associated with treatment.
Subjectivity of Effects on Daily Life
It is clear from the studies reviewed here that cognitive dysfunction is a measurable and disturbing reality of postchemohormonal treatment for some patients. However, it is less clear how this affects daily life. What difference does cognitive impairment make in the day-to-day lives of patients? The answer is likely to be that for some people, all the difference in the world, and for others, none at all. Thus, one patient may sustain significant cognitive changes as measured by complex neuropsychological testing, yet these changes may have little impact on her quality of life due to the nature of her work, leisure life, and/or her adaptability to such situations. Another patient sustaining ever-so-subtle changes may report significant distress due to her inability to accomplish tasks such as playing chess and/or recalling the names of characters in Russian novels.
To further complicate matters, apparently some patients report memory difficulties that are not measurable on objective tests. The study by van Dam and colleagues suggests that cognitive impairment was found in 32% of patients treated with high-dose chemotherapy, 17% of patients treated with standard-dose chemotherapy, and 9% of controls. What difference does this make in the daily lives of these patients? Would it be possible to have a patient who has measured deficits, does not notice or mind them, and reports an acceptable quality of life?
The Central Question
In order for progress to be made in this area of research, a complex array of variables will need to be controlled in well-designed studies. The question that challenges researchers might be summarized as follows: What patients under what conditions experience what type of cognitive deficits (by whose definition), and what difference does it make to them? Fortunately, Dr. Olin and her colleagues at the Vermont Cancer Center have initiated a well-designed study that has the potential to address these issues and contribute to the field.