Imaging study shows brain abnormalities in chemotherapy patients

- By Michelle Brandt

David Spiegel, MD, Stanford School of Medicine

David Spiegel

Researchers at Stanford University School of Medicine have used neuroimaging to gain insight into a phenomenon known as “chemo brain,” a condition in which cancer patients have difficulty thinking, focusing and remembering. The team studied a small group of women with metastatic breast cancer and found deficiencies in the part of the brain involved in storing information.

“These results suggest that women with metastatic breast cancer may be at risk for verbal memory impairments as a result of altered functional brain activation profiles,” the researchers wrote in a paper that appeared in the Nov. 1 issue of Clinical Cancer Research. They added that the cognitive deficits were “potentially specific to those treated” with a certain type of combination chemotherapy.

The study was led by Shelli Kesler, PhD, assistant professor of psychiatry and behavioral sciences, and David Spiegel, MD, the Jack, Lulu and Sam Willson Professor in the School of Medicine. Both are members of Stanford’s Cancer Center.

Previous studies have shown long-term memory problems and other cognitive deficits among cancer patients who have undergone chemotherapy. A 2006 UCLA study reported that between one-fourth and three-fourths of breast cancer patients have cognitive impairment — and researchers have pointed to the neurotoxic side effects of chemotherapy as the possible culprit. Some research has suggested that the impairment may be associated with illness-related stress.

According to Kesler, the impairments can present a real quality-of-life issue for women. She said that some of her patients have been unable to return to work because of their difficulty concentrating. There are not, however, specific treatments or preventive interventions for the cognitive impairments, she said.

“For a long time people didn’t believe it was real,” Spiegel explained. “And psychological symptoms always take a backseat to physical problems associated with treatment, such as nausea, pain and muscle wasting.”

Still, some researchers have turned their attention to the issue, and previous neuroimaging studies have shown abnormalities of the prefrontal cortex — the part of the brain known to play a critical role in planning, attention and memory — in cancer patients who have undergone chemotherapy. The Stanford team aimed to investigate further, to determine if verbal memory impairments were related to chemotherapy or chronic stress.

The research, which was the first cohort study of functional brain activation in this population, involved 14 women with metastatic or locally advanced breast cancer and a history of chemotherapy treatment, and 14 healthy women who served as controls. The researchers used functional magnetic resonance imaging to determine which parts of the women’s brain “lit up” when the participants performed two aspects of a memory task. They also examined participants’ levels of cortisol, a hormone released at high levels during chronic stress, and they administered a questionnaire designed to assess factors affecting stress.

Shelli Kesler, MD, Stanford School of Medicine

Shelli Kesler

During the first, so-called “memory encoding” part of the task, women viewed words of objects, such as “tree,” and pressed a button to indicate whether that word represented something manmade or not manmade. During the “memory recall” part, women were again presented with words of objects and asked to press a button to indicate whether they recognized the noun from the previous task. Some of the words were repeated from the earlier task; others were new but similar — for example “plant” instead of “tree.”

Although the cancer patients performed as accurately on the tests as the healthy women, they had significantly lower activation of the prefrontal cortex than healthy women during the first part of the memory task: encoding or storing the new memory. During the recall task, the women with cancer showed activation of numerous parts of the brain that should have been resting. As the researchers noted in the paper, because of the deficits related to memory encoding, the women had to exert more brainpower when recalling information.

“When storing information, the part of the brain that should help them didn’t work as well,” summarized Spiegel. “And when retrieving information, the parts of the brain that should be resting were in overdrive. It is analogous to carelessly forgetting where you put your car keys. You expend a lot of extra mental energy finding them.”

Shelli Kesler Shelli Kesler, MD

The composite image (left) shows how healthy women, with no history of cancer, have more activity in their brains’ prefrontal cortex when given tasks that involve storing memories than women who had received chemotherapy. This difference in memory encoding helps to explain the image (right), showing how breast cancer survivors, who had chemotherapy, activate more diffuse regions in their brains when asked to recall memories than healthy women do.

The researchers found no association between cognitive deficits and stress — the cancer patients were not more distressed than women in the control group during the task. They did, however, link memory impairments with a specific type of chemotherapy. Patients who had undergone a combination type of chemotherapy, called CMF, showed even lower prefrontal cortex activation during the first task than women who had been treated with other kinds of chemotherapy.

“The findings were clearer than we thought they would be,” said Spiegel, when asked about his reaction to what he and his colleagues found. “And we were surprised by the specificity of the type of chemotherapy associated with cognitive problems.”

Clinicians might want to consider the findings when deciding on the type of treatment for their patients, Spiegel said. “Our contribution here is to add another variable in the risk/benefit calculation,” he said, adding that the findings should be applicable to patients with other types of cancer who have undergone chemotherapy.

The researchers noted in the paper that the results also have important implications for potential interventions for patients experiencing “chemo brain.” Kesler, in fact, is now conducting a clinical trial of a rehabilitation program to improve cognitive functioning in breast cancer patients. She recently received a National Institutes of Health New Innovator Award and is using her award money for this research.

Co-authors on the paper are Stanford medical student F. Chris Bennett and oncology nurse Misty Mahaffey, RN. Funding for the study came from the National Institute of Aging; the Randolph H. Chase, MD, Fund II; the Jay and Rose Phillips Family Foundation; and from Kesler’s New Innovator Award.

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