The novelty of our approach is that we are going to be using multiple modalities” to study the effects of chemotherapy and hormonal therapy on the brain, looking for structural changes within the brain and how these changes might affect psychomotor function, particularly upper-extremity movements that require fast responses and two-limb coordination,” explained Didier Allexandre, PhD, a research scientist at the Kessler Foundation, based in West Orange, New Jersey, and a co-investigator of the study.

“The uniqueness of this research is that we are doing a longitudinal study, assessing changes in the quality of neural fibers in the brain—these fibers connect and conduct signals between neurons located in different regions and between brain and muscle, and are collectively referred to as white matter—following the therapies,” Guang Yue, PhD, noted. Dr. Yue is Director of Human Performance and Engineering Research at the Kessler Foundation, Professor at Rutgers New Jersey Medical School, and the study’s principal investigator.

“If chemotherapy drugs damage the white matter, signal conduction will be slowed and communication between brain regions (eg, left vs right sides) will be compromised. Consequently, the movement response will be slowed due to prolonged traveling time of the motor command from the brain to move the hand, and ability to coordinate movements of the two arms will be impaired because of deterioration in communication between two sides of the brain,” Dr. Yue continued.

“We will be looking for objective changes in brain white matter on neuroimaging, electroencephalographic (EEG) parameters, and transcranial magnetic stimulation–evoked muscle responses, and we’ll be correlating those alterations with psychomotor performance using the arms in women being treated for breast cancer, summed up study co-investigator ­Serena Wong, MD. Dr. Wong is a medical oncologist at Rutgers Cancer Institute of New Jersey and Assistant Professor of Medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick.

The study is funded by the National Institutes of Health, with support from the Kessler Foundation, a nonprofit organization involved in research to improve cognition, mobility, and outcomes for people with neurologic disabilities. The three investigators described their “chemobrain” translational study in a conference call with The ASCO Post.

Concentrating on Hand Movements

The condition commonly known as chemobrain is usually associated with problems in concentrating, remembering, and multitasking, but it also can make it more difficult to do tasks requiring rapid, precise, and coordinated hand movements.

“Earlier studies have varied widely in their conclusions of how common chemobrain is, from as little as 5% of patients up to as many as 60%,” according to an article about the current study in the Newark Star-Ledger.¹ Dr. Wong estimated that from her own experience, cognitive changes seem to affect about one-third of breast cancer patients during and immediately after treatment.

Because of the capability to obtain precise performance measures and explain changes in performance by the white matter structural and neurophysiologic adaptations, “we decided to concentrate more on the psychomotor and less on the classic chemobrain effects such as impaired memory, cognition, and problem-solving,” Dr. Allexandre said. Some tests being used in the study “are more heavily related to cognition, and some are more heavily related to motor,” Dr. Allexandre noted, but all tests “have a motor component.” They would include timed tests during assigned tasks, such as moving pegs on a board.

“We are looking at brain structure. We are looking at the health of the connection within the brain,” by using structural magnetic resonance imaging, Dr. Allexandre said. “We are going to look as well at the actual motor, or psychomotor function, using performance tests, for example, how fast patients react to stimuli by pressing a button.” Transcranial magnetic stimulation will “assess the health of the nervous system from the brain to the hand,” Dr. Allexandre explained, and EEGs will “measure brain function while performing motor tasks.”

Tests Designed for Specific Purposes

“The designs of the tests all have very specific purposes,” Dr. Yue elaborated. “For example, we are going to measure brain white matter structure, the fibers connecting neurons from one to another or from one region to another region. Previous studies have shown that cancer survivors treated by chemotherapy have damage in the brain white matter. But these studies all compare cancer patients with healthy controls.”

The current study, however, will follow patients after they finish chemotherapy and compare quality of the brain fibers then to the baseline measurements. “If the fibers are damaged, we would assume the conduction velocity or the quality of the conduction would be affected,” Dr. Yue said. “Then what we will do is stimulate a motor area of the brain and measure how fast the muscles will respond. If the fiber quality is affected, the signal will travel more slowly from the brain to the muscle,” he said, and the patient will not be able to react as quickly on motor tasks.”

The ability of patients to coordinate movements between their two arms will also be measured. “The hypothesis is that if fibers connecting the two sides of the brain are damaged, then the patient’s ability to cooridinate movements of the two arms will be impaired.”

Teasing Apart the Role of Hormonal Therapies

“The phenomenon of cognitive dysfunction in breast cancer can be somewhat confusing because it is multifactorial. There are many potential factors that can contribute to a patient’s cognitive dysfunction, such as anxiety or depression, which are, of course, common in cancer patients, as well as sleep disturbances, fatigue, or medication side effects,” Dr. Wong explained.

“But a lot of women being treated for breast cancer are given hormonal therapy. We know that when women go through menopause, and the estrogen levels drop, regardless of whether or not they have a cancer diagnosis, we often hear complaints about cognitive changes. We don’t know to what extent hormone therapy contributes to cognitive decline in those who report this ‘chemobrain,’ and so we want to really tease that apart,” Dr. Wong continued. “We want to know how much of it is due to chemotherapy and how much of it is due to hormones, and that is why we have the three arms of the study: (1) chemotherapy plus or minus hormonal therapy; (2) hormonal therapy alone; and (3) the healthy control arm.”

“We are looking mainly at chemotherapy and comparing it with the other two groups,” Dr. Allexandre elaborated. “We want to perform baseline tests before chemotherapy and then 1 month and again 6 months after treatment so that we can observe the short-term and permanent to mid-term effects of the therapy. It is well known that some of the symptoms recede relatively quickly after treatment.”

“Most people generally recover within a year, although some patients even a few years out report they are never quite back to baseline functioning,” Dr. Wong noted. “There have been a few studies looking at women who had been treated several years prior for breast cancer. They were imaging studies, and they showed that there were still some structural changes that could be seen on imaging. Whether or not those translated into real-life cognitive deficits that the patients complained about was not always clear, but at least some of the studies seemed to suggest that this was in fact the case,” she added.

Actively Recruiting

“This study will enable investigators to better understand the relationship between cancer treatments and brain function. Our goal is to find ways to minimize or even prevent the effects of ‘chemobrain,’ thus helping to improve the patient’s quality of life,” Dr. Wong added in a statement announcing the study.²

“We are actively recruiting,” Dr. Wong said. “We would like to get 20 patients in each arm of the study.” Postmenopausal women between the ages of 50 and 70 years old who have had or are scheduled to have breast cancer surgery are eligible for the study if they are receiving or scheduled to receive chemotherapy and/or hormonal therapy. For the chemotherapy arm, “we are only including women who have received an anthracycline or a taxane—two of the most common chemotherapeutic agents given in early-stage breast cancer,” Dr. Wong noted.

“It was our goal to be able to recruit patients just before they start their treatment,” Dr. Allexandre said. “But it has been extremely difficult to approach these patients at a time when it is extremely stressful” and ask them to consider yet another issue—chemobrain—that they may not even foresee. “So now we are trying to find a compromise. We are still looking for people before they start treatment—that would be the ideal—but we will also enroll patients who have already started chemotherapy,” Dr. ­Allexandre said.

“If they’ve had one or two cycles of chemotherapy, we could potentially enroll them,” Dr. Wong said. That would still allow the investigators to observe the immediate effects of therapy and then the longitudinal effects 4 to 6 months after the end of chemotherapy.

Eligible patients must also be right-handed. This criterion was included to eliminate handedness as a confounding factor if a certain area of the brain is highlighted more during specific tests.

For the control group, investigators are seeking healthy postmenopausal women who have no evidence of breast cancer and who meet the other criteria.

Physicians interested in finding out more about the study or referring patients should contact Dr. Allexandre at 973-324-3525. ■

Disclosure: Drs. Allexandre, Yue, and Wong reported no potential conflicts of interest.

References

1. O’Brien K: How you can help Rutgers unlock the mysteries of ‘chemo brain.’ Newark Star-Ledger, January 3, 2015.

2. Rutgers Cancer Institute of New Jersey aids in clinical trial examining effects of ‘chemo brain’ in breast cancer patients. Rutgers Cancer Institute press release, January 5, 2015.