Study: Chemotherapy Can Alter Brain by Killing Cells

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USA Today
NOV 30, 2006

Doctors once dismissed complaints of “chemobrain,” a common side effect of cancer therapy in which patients experience memory problems or mental fuzziness.

Research now shows that chemotherapy can cause real changes in the brain, ranging from forgetfulness to seizures, vision loss and even dementia. More than 80% of cancer patients develop memory and concentration problems, according to a study in June from the University of Rochester Medical Center in New York.

In a paper in today’s Journal of Biology, scientists found that even low levels of chemotherapy can kill brain cells. The study showed that cancer drugs were even more toxic to healthy cells than to malignant ones, says Mark Noble, a professor at the University of Rochester Medical Center.

Noble tested three common chemo drugs — cisplatin, cytarabine and carmustine — on rats and in human cells in lab dishes. Chemo killed 40% to 80% of cancer cells, but 70% to 100% of healthy brain cells. Some of the normal cells continued to die for several weeks after treatment, according to the study, funded by the National Institutes of Health and the James P. Wilmot Foundation.

Significantly, chemo killed not just rapidly dividing cells — the typical target of cancer therapy — but brain cells that weren’t reproducing, including those responsible for creating the insulation around nerve cells, Noble says. This insulation is important because it helps nerve signals travel quickly.

Other recent studies also document chemo’s effects on the brain.

In a study to be published in January in Cancer, researchers studying breast cancer patients found that chemo may temporarily shrink certain brain areas. And in a small study published last month in Breast Cancer Research and Treatment, Daniel Silverman of the University of California-Los Angeles found that women with chemobrain symptoms had changes in the functioning of their brain’s frontal cortex.

Silverman, head of UCLA’s neuronuclear imaging section, says Noble’s paper doesn’t definitively prove that killing brain cells causes cognitive problems. He says something else may actually cause chemobrain. To really prove the connection between chemobrain and cell death, Silverman says, researchers should repeat the experiments, but also test the lab rats to see if those who lost brain cells have more trouble than others on intelligence tests.

But Patricia Duffner, a professor at the Hunter James Kelly Research Institute at the University of Buffalo, says Noble’s study is “likely to act as a wake-up call.” Doctors have long recognized that radiation can damage the brain, says Duffner, who wrote a review accompanying Noble’s article. She says researchers should look more closely at ways to protect the brain from chemotherapy.

“It was imperative to define the problem,” Noble says. “Now it is imperative to find ways to treat it.”

Temporary Brain Shrinkage May Explain ‘Chemobrain’

By Neil Osterweil, Senior Associate Editor, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
November 27, 2006

CHIBA, Japan, Nov. 27 — The thought-fogging phenomenon known as “chemobrain” appears to be related to a reversible shrinking of brain structures induced by chemotherapy, researchers here have found.

MRI scans of breast cancer survivors within a year of completing adjuvant chemotherapy showed significantly smaller regional volumes of gray and white matter in areas involved in cognitive function compared with other survivors or healthy controls, they reported in an online release from the Jan. 1 issue of Cancer.

By three years after treatment, however, those differences had vanished, said Masatoshi Inagaki, M.D., Ph.D., of the National Cancer Center Hospital East, and colleagues.

“Results lead to the idea that adjuvant chemotherapy could have a temporary effect on brain structure,” the authors wrote. “These findings can provide new insights for future research to improve the quality of life of cancer patients who receive adjuvant chemotherapy.”

Patients undergoing chemotherapy often complain of cognitive and memory problems, and clinical studies have confirmed cognitive declines. Evidence from animal studies has also shown that systemic chemotherapy can have neurotoxic effects.

“Chemotherapeutic agents are hypothesized to have neurotoxic potential through their ability to interfere with DNA and RNA synthesis and function, inhibition of microtubule formation, and/or immunosuppressive properties,” the investigators wrote.


They performed a retrospective study to determine whether there were significant regional brain-volume differences between breast cancer survivors exposed to adjuvant chemotherapy and those who did not undergo chemotherapy.

The authors compared gray and white matter volumes as measured on high-resolution 1.5-tesla brain MRI scans from databases of breast cancer survivors, both in breast cancer patients who were within one year of their surgery, and those who were three years out from surgery. They also compared data on cancer survivors with scans taken from healthy controls recruited from the local population for the study.

They found that in the one-year study survivors who underwent chemotherapy had smaller gray matter and white matter in areas involving cognition and memory, including the prefrontal, parahippocampal, and cingulate gyrus, and precuneus regions, compared with patients who were not exposed to chemotherapy.

When they looked at the three-year data, however, they saw no differences between the patients who had received adjuvant chemotherapy and those who had not.

The authors also performed an analysis to determine whether the volume of key brain structures correlated with scores on the Weschler Memory Scale-Revised, and found that the volumes of the prefrontal, parahippocampal gyrus, and precuneus regions were significantly correlated with indices of attention and concentration and/or visual memory.

When they compared the brain regions of all cancer survivors at the one- and three-year intervals with those of healthy controls, however, they did not see any significant differences, suggesting that there were no significant effects of the cancer itself on cognitive function.

The authors noted that the effects of chemotherapy on specific brain regions were unclear, and that the potential pathophysiologic mechanisms for the differences they saw in regional brain volumes were unknown.

They also noted that “the reason we did not explore effects of each chemotherapeutic agent in the study setting was that interactions between each chemotherapeutic agent may exist and may make our inference difficult.”

They also pointed out that the current study did not have any specific functional targets related to each of the detected regions.

Nonetheless, “these results indicate a potential effect of adjuvant chemotherapy on brain structure, and the change of the brain structure may be associated with memory function,” they wrote.

 

 
‘Chemobrain’ Effects Revealed in PET Imaging
By Crystal Phend, Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
October 05, 2006
 
LOS ANGELES, Oct. 5 — PET scans suggest that mental fog and memory problems after chemotherapy and other adjuvant therapy, the chemobrain phenomenon, may be caused by metabolic changes in the basal ganglia and frontal cortex.

The scans showed more mental exertion to recall the same information by women after breast cancer chemotherapy, compared with those who had not had such treatment, reported Daniel H.S. Silverman, of the University of California at Los Angeles, and colleagues, online in Breast Cancer Research and Treatment.

Chemotherapy-treated women also had lower resting metabolism in a key region of the frontal cortex, which was correlated with poorer performance on a memory test administered to the study participants.

Furthermore, women who underwent hormonal therapy with tamoxifen in addition to chemotherapy had an 8% drop in resting metabolism in their basal ganglia, which has previously been shown to be an area of the brain that bridges thought and action.

These changes in brain function seen five to 10 years after administration of therapy may help to explain the previously confirmed but unexplained cognitive effects of chemotherapy, said Daniel H.S. Silverman, of the University of California, Los Angeles, and colleagues.

“Understanding the basis of long-term neurocognitive effects of endocrine and chemotherapy regimens may help in seeking strategies to prevent them,” the researchers wrote.

The study included 16 women who had completed treatment with chemotherapy for breast cancer five to 10 years previously. Eleven of these women had also taken tamoxifen.

Another eight women with a previous diagnosis of breast cancer who had not received chemotherapy acted as controls. They were matched to the chemotherapy group in time elapsed since diagnosis (7.4 years for both groups) as well as age at enrollment (53.2 years and 50.4) and at diagnosis (45.8 and 43.0).

Both groups had PET scans to measure changes in cerebral blood flow as they performed specific cognitive tasks, such as recall of paired words. The positron-emitting glucose analog F-18 fluorodeoxyglucose (FDG) was also administered to observe metabolic requirements associated with different cognitive tasks and give a picture of how hard the brain worked to fulfill a task.

Previously recorded brain metabolism data from a standard reference group of 10 healthy women (average age 44) also served as a comparison.

All three groups were administered a battery of cognitive tests within 72 hours of brain PET imaging. The groups had similar years of education and estimated premorbid I.Q.

The researchers found abnormal activation in the inferior frontal cortex during a short-term verbal memory task in the chemotherapy-treated group. There was a 2.3% increase of activity in the inferior frontal gyrus during recall at peak activation in chemotherapy-treated patients (P< 0.0005 after correction for multiple comparisons).

Conversely, controls showed the greatest cortical activation in the parietal cortex during the same task but only weakly increased activity in the left inferior frontal gyrus (P=0.960 after correction for multiple comparisons).

“Thus, overall, the altered cortical activation associated with performance of a memory task in chemotherapy-treated patients could be characterized as involving greater recruitment of frontal cortical tissue,” Dr. Silverman and colleagues wrote.

In the brain metabolism portion of the study, the left inferior frontal gyrus was again most significantly correlated with short-term delayed recall memory task performance in chemotherapy-treated subjects (P<0.0005). Each standard deviation decline in performance of the task corresponded to a 3% decrement in metabolic activity in chemotherapy treated women though no such relationship was found in the untreated patients.

This finding adds further weight to the suggestion that the changes in the inferior frontal gyrus associated with chemotherapy could be responsible for chemobrain, the researchers ventured.

“It also raises the possibility that the increased frontal activation during performance of the memory task may represent a compensatory response to lower resting metabolism found in this region of the brain in treated impaired patients,” they wrote.

The most significant metabolic effect was found in the basal ganglia, which was 7% to 8% lower in patients treated with chemotherapy plus tamoxifen than in patients receiving chemotherapy only (P<0.01). Interestingly, metabolic activity in this area of the brain was no different between participants who received chemotherapy or no medical therapy or those who had never been diagnosed with breast cancer.

The authors speculated on that on the basis of the outcome of the study imaging might be used prophylactically.

“A pertinent clinical question raised by the current findings is whether it may be feasible to employ the kind of neuroimaging tools used here to diminish future cognitive impact of particular treatment regimens,” they wrote.

“For example, FDG PET studies might be used to monitor cerebral response to potentially neurotoxic therapies-analogously to our current use of MUGA studies to monitor cardiac response to chemotherapy regimens containing doxorubicin or other cardiotoxic agents — taking advantage of the typical lead time (two to 10 years) by which cerebral metabolic changes precede development of neurologic symptoms,” they wrote.

The authors noted that the study was limited by the small number of participants typical of expensive functional brain imaging studies. They also noted, “One limitation inherent in the design of this type of exploratory study is that it is quite possible for differences to exist between treatment groups in factors that could affect cognitive function, other than the treatment itself.”

The study was funded by the Breast Cancer Research Foundation and an American Cancer Society Clinical Research Professorship award to one of the authors.