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ALTERED BRAIN FUNCTION AFTER CHEMOTHERAPY
Imaging studies conducted in breast cancer survivors five to 10 years after they had undergone chemotherapy showed that the "chemo brain" syndrome of forgetfulness and mental fog that many of these patients experience is rooted in significant alterations of brain function. The changes were worse for patients treated with adjuvant regimens that included tamoxifen.
"People with chemo brain often can’t focus, remember things, or multitask the way they did before chemotherapy," said lead investigator Daniel H. S. Silverman, MD, PhD. "Our study demonstrates for the first time that patients suffering from these cognitive symptoms have specific alterations in brain metabolism." Dr. Silverman is Head of Neuronuclear Imaging and Associate Professor of Molecular and Medical Pharmacology at the David Geffen School of Medicine at the University of California, Los Angeles. He and his research team published their findings in the September 29 online edition of Breast Cancer Research and Treatment.
EFFECTS OF CHEMOTHERAPY
Dr. Silverman used neuropsychologic testing and positron emission tomography (PET) to examine brain function in 16 women who had had adjuvant chemotherapy for breast cancer five to 10 years earlier and in eight age-matched control subjects who had never received chemotherapy. Eleven of the 16 chemotherapy-treated women had also taken tamoxifen.
The investigators used neurocognitive assessment with the Rey-Osterrieth Complex Figure Delayed Recall test to determine whether any differences in cerebral activity that were observed on PET correlated with neuropsychologic test performance. They used 15O water PET during control and memory-related tasks to evaluate cognition-related cerebral blood flow and 18F fluorodeoxyglucose PET to evaluate resting cerebral metabolism rates.
When participating in a short-term verbal memory task, the chemotherapy-treated patients had significantly greater activation in the inferior frontal gyrus, in the vicinity of Broca’s area in the dominant hemisphere. "Peak activation occurring in the inferior frontal gyrus corresponded to a 2.3% increase of activity during recall and was highly significant," Dr. Silverman reported. The control women had little, if any, increased activity in this area but instead had greatest cortical activation in the parietal cortex.
Dr. Silverman told Neurology Reviews that due to the decrease in resting metabolism in the inferior frontal gyrus in the chemotherapy-treated women, these patients probably had to "ramp up" activity more than the control subjects did in order to recall the same information. "We found that the lower the patient’s resting brain metabolism rate, the more difficulty she had performing the memory test," he said. The scans revealed that blood flow to the frontal cortex and cerebellum spiked as the chemotherapy patients performed the memory tests, indicating a rapid jump in these brain regions’ activity level.
The researchers also found that resting metabolism rates among patients treated with tamoxifen-containing regimens were significantly different from those in patients who were not treated with such regimens. "Metabolism in the lentiform nucleus was 7% to 8% lower in patients receiving cytotoxic therapy plus tamoxifen than in patients receiving cytotoxic chemotherapy only, while metabolic activity of the lentiform nucleus in subjects who received cytotoxic chemotherapy only did not differ from that of subjects who had received no therapy, which in turn did not significantly differ from metabolism in subjects having neither breast cancer nor therapy," they reported.
CLINICAL IMPLICATIONS
Dr. Silverman pointed out that the changes in brain metabolism following chemotherapy become apparent years before cognitive or neurologic symptoms occur, a finding with two important clinical implications. First, PET could be used to monitor the cerebral effects of chemotherapy, just as multiple gated acquisition scans are used to monitor the cardiac toxicity of doxorubicin-containing regimens. Because many breast cancer patients already have routine whole-body PET to monitor tumor response, this might be accomplished by extending the routine scan (which usually begins at the base of the skull) to include the whole head. Data correlating altered cerebral metabolism with cognitive deficits could be used to establish a benchmark for risk of cognitive impairment, which could then be used as a signal to consider modifying the anticancer regimen.
The second implication is that cognitive risk should be considered in developing individualized treatment regimens for cancer patients. Dr. Silverman noted that the additional cognitive risk associated with tamoxifen is well documented but seldom considered. "Tamoxifen is added to the regimen of almost everyone who is eligible, in an effort to prevent metastasis," he said. "That is based on data from very large studies showing a statistically significant but pretty small survival benefit. If a patient’s PET scan shows reduced cerebral metabolism, that patient might opt to forego long-term tamoxifen rather than risk lasting cognitive impairment."
Dr. Silverman also noted that chemo brain is well-known among cancer survivors but seldom discussed with oncologists in advance of treatment. "This should be mentioned as a possible side effect, along with hair loss or nausea and vomiting," he said.
Dr. Silverman urged neurologists who are treating a cancer survivor presenting with apparent chemo brain to do two things—reassure the patient that that memory or cognitive problems are a common side effect and obtain PET scans to determine whether metabolic changes have occurred. "Tell them they are not crazy. Patients find this reassuring," he said. "And use imaging to establish a secure differential diagnosis, since these patients might also have early Alzheimer’s or other problems."
The researchers are launching a five-year longitudinal study to extend this work. That trial will be supported by the National Institutes of Health and will be led by Patricia A. Ganz, MD. Dr. Silverman said that the researchers expect to begin PET in the spring of 2007 and to include 100 to 200 cancer patients in the study, with follow-up of at least two years.
NR
—Janis Kelly
Suggested Reading
Silverman DHS, Dy CJ, Castellon SA, et al. Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res Treat. 2006 Sep 29; [Epub ahead of print].
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