Chemobrain: the hunt for answers

Nausea, anemia, fatigue--these are all well-known side effects of chemotherapy. Along with such physical ailments, accumulating evidence suggests that chemotherapy affects cognitive functioning in some patients as well.

The cognitive frustrations, dubbed "chemobrain'' by cancer survivors, refer to a range of difficulties--from diminished executive function to reduced verbal memory--that can emerge in the weeks and months after chemotherapy's completion. The difficulties appear in a variety of cancer diagnoses, including breast cancer and other malignancies in which chemotherapy does not target the brain itself, psychologists say.

Cancer survivors may, for example, struggle to recall recently acquired information, such as the name of someone they just met, researchers explain. They may have more difficulty following overlapping conversations at a business meeting or handling the demands of multitasking.

"I've spoken to patients who were formerly lawyers and had to completely change their strategy for preparing for trial," says psychologist and chemobrain researcher Lynne Wagner, PhD, an assistant professor in the department of psychiatry and behavioral sciences at Northwestern University Medical School.

However, not everyone experiences the cognitive side effects, says psychologist Tim Ahles, PhD, who also studies the phenomenon and is program director for the Center for Psycho-Oncology Research at Dartmouth Medical School. "It is a subgroup phenomenon," Ahles says. "And there are certain people who are vulnerable."

Ahles and fellow Dartmouth researchers are investigating one such subgroup--individuals who carry the ε4 allele of the Apolipoprotein E (APOE) gene. Also implicated in Alzheimer's disease, this mutation might make some people more vulnerable to chemo-related cognitive decline, Ahles suspects.

Identifying a clear pattern, though, hasn't been easy. Researchers aren't yet sure what percentage of chemotherapy patients will develop cognitive problems, or even which of the many chemical-based cancer treatment regimens are most likely to cause cognitive problems. Wagner used to tell cancer patients that 20 to 25 percent would develop some cognitive problems. But recent research, she says, is making it more difficult to provide a solid figure.

One problem is that the patients involved in the studies to date often are already highly functioning, so they may still test in the normal range, psychologists say. And it's difficult to separate cognitive difficulties from the various confounding factors, says Cay Anderson-Hanley, PhD, a New York-based psychologist who conducted a research review published in 2003 in the Journal of the International Neuropsychological Society (Vol. 9, No. 7). Depression, fatigue and the sheer terror involved with a cancer diagnosis all may spawn cognitive problems as well, Anderson-Hanley says.

Though nearly 30 papers had explored the phenomenon of chemobrain by 2002, none took pre-chemotherapy measures of cognitive function, according to Anderson-Hanley's 2003 review article. The studies compared patients' mental acuity after chemotherapy with groups that received other treatment, such as surgery alone. What was missing was a baseline comparison, says Anderson-Hanley, a research psychologist at the Cancer Center at Glens Falls Hospital in Glens Falls, N.Y. That is, how mentally sharp were the patients prior to chemo? Some recent studies are beginning to suggest some answers.

Pretreatment decline

A study published in June 2004 in the journal Cancer (Vol. 100, No. 11) was one of the first to conduct neuropsychological evaluations in breast cancer patients after diagnosis, but before the start of chemotherapy. Researchers at the University of Texas M.D. Anderson Cancer Center showed that 11 of the 18 breast cancer patients (whose mean age was 45) in the study demonstrated cognitive difficulties shortly after chemotherapy. The shocker: six of the 11 patients showed measurable cognitive impairment even before chemotherapy began--possibly related to the cancer itself.

"It was pretty surprising," says Wagner, who is finding similar pre-chemo results in her own research and now is using brain imaging for more insights. "These were what we would expect to be relatively healthy young women. I think we've all been operating on the assumption that coming into chemotherapy, patients have been functioning at baseline."

A second study, published in August 2004 in Cancer (Vol. 101, No. 3), also examined pre-chemo cognitive data from a group of 84 breast cancer patients involved in M.D. Anderson cancer treatment trials. The study also found cognitive problems in roughly one-third of the women before chemotherapy. The researchers also observed impairments in verbal learning and memory more frequently in the study cohort than in the comparison group of normal control patients.

While both M.D. Anderson studies determined that depression and anxiety can accompany cognitive problems, they don't appear to directly cause the decline cancer patients discuss, says Jeffrey Wefel, PhD, a co-author for both articles.

"It's unclear what's going on," Wagner says. One theory is that it's the body's response to fighting the cancer, rather than the malignancy itself, that's causing the cognitive changes, she says. Another theory is that chemotherapy damages blood vessels, leading to increased blood clotting, and thus mini-strokes, according to a 2004 article in the Journal of Clinical Oncology (Vol. 22, No. 11).

While questions remain as to the causes of chemobrain, the M.D. Anderson study did provide some encouragement, says Wefel, an instructor in the Department of Neuro-Oncology at M.D. Anderson. Nearly half of the 18 patients demonstrated some cognitive improvement after one year. They also self-reported an improved ability to work. The long-term profile for these cancer survivors remains unknown, Wefel says.

Identification and treatment

A simple self-report questionnaire might make it easier for researchers to track cognitive difficulties, Wagner says.

By taking cancer patients' responses to 50 questions and comparing them to their functioning on a battery of neuropsychological tests, Wagner hopes to arrive at a short list of about 15 questions. For example, the self-report questionnaire Wagner developed asks patients if they have more trouble with word-finding or remembering new information, like simple instructions. If the tool proves effective, it could one day be used in clinical trials to assess the drugs' impact on cognition, says Wagner, also a clinical research scientist at the Center on Outcomes, Research and Education at Evanston Northwestern Healthcare.

Adults are not the only cancer survivors vulnerable to chemotherapy's effects. About 30 percent of children develop some post-chemo cognitive problems, says psychologist Robert Butler, PhD, an associate professor of pediatrics at Oregon Health & Science University. Butler believes that children experience more cognitive difficulties than adults, because they tend to suffer from malignancies, such as brain tumors, that require high doses of chemotherapy delivered directly to the central nervous system.

Butler leads a National Cancer Institute-funded trial that used a multi-pronged approach, including cognitive remediation and clinical psychology, to help children cope better in the years following chemotherapy. The research, conducted from 1999 to 2003, involved 160 children ages six through 18.

Based on preliminary results, Butler says that the intervention improved the children's scores in two areas, academic performance and parental feedback. Teacher reports and the children's neuropsychological scores also improved, though not enough to reach statistical significance. To refine and target the intervention, Butler is now working to identify why some children responded better than others.

In the meantime, pharmaceutical options for either children or adults remain limited, according to the 2004 Journal of Clinical Oncology article. For example, researchers are studying attention-deficit drugs; one ongoing trial involves methylphenidate, known as Focalin.

In the end, effective treatments won't be found until the cause of chemobrain is more clearly understood, psychologists say.

In pursuit of the latter, Ahles has enrolled about 160 breast cancer and lymphoma patients in his own pre- and post-chemo cognitive analysis. In addition to comparing the participants' pre-chemotherapy baseline to later assessments, Ahles' study also will screen participants for the ε4 allele. In a previous study, published July 2003 in the journal Psycho-Oncology (Vol. 12, No. 6), Ahles showed that 21 percent of breast cancer or lymphoma survivors carry at least one ε4 allele.

The ε4 allele intrigues Ahles because it's been associated with Alzheimer's disease, as well as increased vulnerability for cognitive problems resulting from head injuries and other types of trauma. Understanding some of the underlying genetic vulnerabilities for chemobrain, Ahles says, could provide some hypotheses regarding what's causing cognitive problems.

If all goes well, the next wave of studies will start answering these types of questions, Ahles says. "I think in the next couple of years," he says, "we are going to have a whole new level of better data than we've had."