Fatigue and "Chemo Brain" after Cancer Treatments
John Glaspy, MD, UCLA Professor, Medical Oncologist and Researcher; Director, UCLA Oncology Center; Associate Chief, Division of Hematology-Oncology; Associate Director, Medical Oncology Program Area
This is a summary of a lecture that was presented on January 13, 2004.
While fatigue is a problem for many patients during and after chemotherapy, it still has a limited understanding. In a survey of patients, approximately 12% indicated their fatigue was so significant they would rather be dead than be fatigued. Fortunately this is not the majority of patients; however, it underscores the importance of energy and fatigue in the day-to-day quality of life for cancer patients.
Approximately 15-20% of fatigue is associated with anemia. Scientists have learned that some patients have low levels of a hormone that stimulates red blood cell production in the bone marrow. A synthetic version of this hormone, called erythropoietin (EPO), corrects this problem. Patients who receive injections of EPO increase their red blood cell production and, in turn, have higher hemoglobin levels. When their hemoglobin improves they often feel considerably better. Several recent studies determined that there were significant improvements in energy level, activity and quality of life in cancer patients with anemia who were treated with EPO. This improvement was found even in patients who had progression of their tumor. Patients who have low hemoglobin and are experiencing fatigue should talk with their physicians about this intervention. However, patients who have fatigue and normal hemoglobin do not benefit from EPO injections.
Since fatigue is not completely understood, it is not surprising there are few interventions. Individual physicians are making efforts to try other clinical interventions. For example, some activating drugs such as Ritalin (methylphenidate) and Provigil (modafinil) are being given to patients to increase energy. These drugs are used most often with severely fatigued patients with metastatic disease. No research studies have studied these interventions in a systematic way. In a May, 2002 lecture fatigue was summarized in more detail and can be found on the Center's website, www.CancerResources.mednet.ucla.edu.
Chemo Brain
Patients have been telling their physicians for a long time that one side effect during and after chemotherapy is a "fogging" of their cognitive functions, referred to as "chemo brain." Patients report feeling cognitively impaired and cite examples of poor memory, forgetfulness, and difficulty concentrating. Usually when patients report a symptom and clinicians hear the concerns repeatedly, there is reason to believe that these symptoms are real and need attention. However, the research in this area is limited. The technical term used for "chemo brain" is chemotherapy-induced cognitive impairment (CTICI).
From a scientific perspective, it is important to document exactly what CTICI is and identify appropriate ways to measure it as well as its potential causes. There are some hypotheses that CTICI may have a relationship to fatigue. There are three conceptual models about fatigue and CTICI that are currently being considered. The first model suggests that fatigue and CTICI are two completely separate and distinct problems. The second model suggests that these two entities overlap. The third model hypothesizes that fatigue and CTICI are the same phenomenon. We know from military research that cognitive impairment is a by-product of fatigue; it does not take much sleep deprivation to impair functioning.
We know that children treated for leukemia who have had both chemotherapy and cranial radiotherapy are impacted on measures of intellectual and cognitive performances. Adults treated with high dose interferon have also been shown to have long term cognitive effects. Adult survivors of cancer have frequently noted that they experience diminished memory and poorer organizational ability during and after chemotherapy. However, CTICI is difficult to study. Its prevalence, time course and severity are not known.
There are many factors that complicate our ability to study CTICI. First, it is difficult to formulate a cause and effect relationship between chemotherapy and cognitive impairment. There have been very few studies and those that have been done have used a select population of breast cancer survivors chosen because of the high likelihood of survival. However, many of these women are peri-menopausal at the time that they receive the chemotherapy. Chemotherapy may push them into menopause. There is considerable debate about the impact of estrogen on cognitive function and thus some of the cognitive symptoms that are reported by women may be a function of their hormonal status rather than the chemotherapy. Further, these women are also placed on tamoxifen after chemotherapy, which functions as an anti-estrogen. The impact of this is not clear. Finally, the time that these events are occurring is also perfectly timed with the time in one's life when normal age-related changes often begin to appear. Memory and concentration begin to show some subtle changes with aging.
CTICI is also difficult to study because of the assessment factors. Having people report cognitive impairment is not enough. Psychometric testing of neurocognitive functions is time consuming and requires special skills. The testing also involves multiple measures that assess different kinds of cognitive functioning. Scientists struggle with how to make sense of multiple measures when some show differences and others do not.
Finally, the sample of patients is often limited to those groups of patients who are likely to survive for long periods of time disease free, and thus, the emphasis has been on the "relatively well" group of patients. However, this research is narrow and leaves out many patients who are forced to be on chemotherapy on an ongoing basis.
Consequently, it is imperative that controlled studies be done. Without them, we will never know whether CTICI is really caused by chemotherapy or whether there may be some other factors that intercede.
There are currently five published studies on this topic. There is a consistent finding that cognitive impairment does exist. There are some very important constraints to note about these studies. First, all of the studies are done on breast cancer patients who received adjuvant chemotherapy, with only one study including lymphoma patients. As a result, all of the studies were done on women except that approximately half of the lymphoma patients were men. The sample sizes ranged from 28-40 patients in the different groups for each of these studies. These are small sample sizes, making it difficult to detect differences. A good proportion of these studies included women who were on tamoxifen, which confounds the findings. There is no consistency with regard to when the assessments were made and none of the assessments were done longitudinally (more than one assessment over time on the same participants). One of the studies followed patients nine years after chemotherapy, whereas three studies followed patients two years past their last chemotherapy treatment. There are also difficulties with the control subjects. In some studies the control patients were women with breast cancer who did not get chemotherapy. In some studies healthy controls were used but the selection process was biased. It makes it very difficult to draw conclusions. In sum, the studies suggest that there are cognitive impairments in concentration, memory, and thinking, with the greatest difficulties being in concentration and memory.
It should also be noted that in one of the studies other symptoms were also assessed. The one symptom that showed a significant difference between the patients treated with high dose chemotherapy compared to those treated with standard dose chemotherapy was fatigue. It is unclear whether the cognitive impairment may be a function of the fatigue. However, in a second study this effect was not found. One study looked at whether IQ was a predictor of cognitive impairment. It was not; however, receiving treatment suggested that there was a six-fold increased risk for cognitive impairment with chemotherapy treatment. When reviewing the data, the studies suggest that there is an effect, but a simplified graph of the effects looks similar to the impact of menopause on cognitive function. In the study in which men and women who had lymphoma were included, there were some differences found in a few of the cognitive tests, but there were more tests that showed no differences. The one positive aspect of this study is that it controlled for psychological distress and fatigue.
As CTICI has been accepted as a problem, researchers have wondered how to prevent it. Hypotheses have been generated from research done in mice in which EPO was shown to have a protective effect against brain injury when given before or immediately following an event such as a stroke or head trauma. In addition, research has identified EPO receptors in the brain that has further strengthened the hypothesis that EPO might have neuro-protectant effects. Studies to evaluate EPO as a protectant against cognitive impairment were stopped by the FDA due to concerns about the safety of giving EPO to patients who are not anemic. These studies would be helpful in answering some of these questions. Hopefully, new studies will be conducted after the concerns are reviewed.
The data to date suggest more about what needs to be done than what we know. The recommendations for future work are: Conduct more trials with larger samples of patients and more diversity in age and gender, including assessments at different points in time. Carefully control for menopause, and standardize the chemotherapy regimens that are being studied. If CTICI is a real entity, then we need to look at ways to minimize the impact through dose, drug and schedule manipulation. Further work needs to be done on neuroprotectants including EPO, Ritalin and others with that potential.
For reprint authorization, contact SimmsMannCenter@mednet.ucla.edu.