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."

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."