Can “Chemobrain” Be Mitigated?

Kristen Garner, Dartmouth Medicine

Summer 2005

Have you ever locked your keys in the car? Forgotten an appointment? Sure, everyone has memory lapses from time to time. But for some cancer patients who undergo chemotherapy, such slips happen all too often. “Chemobrain,” as patients call the condition, is characterized by memory problems, trouble concentrating or multitasking, and difficulty summoning the right word in conversation.

Persist: “For some people these are acute side effects of the treatment, and for some people these side effects actually persist long after the treatment,” says Tim Ahles, Ph.D. The director of DMS’s Center for Psycho-Oncology Research, Ahles studies the effects of chemotherapy on long-term cognitive function. “We are very interested in why some people have these long-term cognitive defects,” he says. He and his collaborators want to know what factors make some patients more vulnerable to these effects than others.

Currently, the researchers are assessing the cognitive function of patients with lymphoma and breast cancer, both pretreatment and post-treatment. They are then evaluating associations between the development of long-term cognitive defects and several other variables. The variables they are looking at include the types and doses of chemotherapy the patients have received and the genetic differences among the individuals. For example, are patients who receive a particular regimen of chemotherapy more likely to develop long-term cognitive defects? Or is there a particular gene that triggers vulnerability to these side effects?

One particular gene the group is examining is called APOE. One version, or allele, of this gene, E4, has been associated with Alzheimer’s disease and traumatic brain injury. Recent research by Ahles’s team suggests that the carriers of APOE’s E4 allele may have a higher risk of developing long-term cognitive defects after receiving chemotherapy.

Side effects: Most patients who experience chemo-related cognitive defects find that they return to normal shortly after they finish their regimen, but “for some people these side effects actually persist long after the treatment,” explains Ahles. His group has published data showing that lymphoma and breast cancer survivors who received chemotherapy experience more cognitive defects five years after the conclusion of their treatment than do similar patients who received only nonsystemic treatment, such as surgery or local radiation.

Chemotherapy confers an increased chance of survival, of course, as well as an increased risk of cognitive defects. But these problems do affect long-term quality of life for some patients. Could it one day be possible to get the benefit without the risk? Ahles and his colleagues hope so. Their ultimate goal is not just measuring the problem but mitigating it. “If we really understood the mechanism,” he says, “there will hopefully be drug interventions that may either prevent or reduce the negative cognitive impact of chemotherapy.”

Treatment May Trigger Cognitive Problems

Carl Marziali

University of Southern California

May 27, 2005


Long-term cancer survivors may be at risk for impairment, say USC psychologists who caution that more research is needed to clarify the extent and cause of the dysfunction.
Cancer survivors are twice as likely to develop cognitive problems as individuals who have never been treated for cancer, according to an article in the June 1 Journal of the National Cancer Institute.

Previous research has raised concerns about a possible link among cancer, cancer therapies and cognitive dysfunction. This USC study found that long-term cancer survivors were at increased risk of cognitive impairment.

An accompanying editorial urged a cautious interpretation of the results pending further research on the subject.

In the study, USC psychologists studied 702 cancer survivors and their cancer-free twins in the Swedish Twin Registry.

Studying twins statistically removes genetic or early childhood causes of both cancer and cognitive deficits.

Working with colleagues at the Karolinska Institute and Gothenberg University in Sweden, the researchers evaluated the survivors through a standardized mental status interview.

Participants were scored on a scale from zero to three. Anyone who scored a three, defined as having verbal, orientation or recall problems that interfere with daily life, was considered to have cognitive dysfunction.

“The twin who had cancer was more likely to have some sort of cognitive dysfunction,” said Beth Meyerowitz, professor of psychology in the USC College of Letters, Arts and Sciences. About 15 percent of the cancer survivors in the study showed cognitive dysfunction.

Previous studies have found cognitive problems in short-term cancer survivors, said coauthor Lara Heflin, a doctoral student in psychology at USC. This study is the first to find significant cognitive differences between long-term survivors and cancer-free individuals, she said, and to focus on older adult survivors.

“This suggests that possibly the cognitive dysfunction gets worse over time with increased survival duration,” Heflin said.

The comparison with cancer-free twins means that the increased dysfunction cannot be attributed to the normal aging process.

The researchers also found a doubled risk of dementia in the survivor group. However, the result was not statistically significant.

Heflin plans to study patient data from Los Angeles County’s Cancer Surveillance Project and USC’s Alzheimer Disease Research Center to investigate the possible link between dementia and cancer.

The study does not suggest a cause for the cognitive problems in cancer survivors. The JNCI study excluded survivors of tumors that directly affect the central nervous system.

One possibility is that chemotherapy or other cancer treatments may cause long-term damage. The researchers plan a follow-up study comparing survivors who received different treatments.

“If, five, eight, 10 years down the line, having had that treatment is going to increase a person’s risk of dementia, that’s something that should be considered by the physician and the patient,” Meyerowitz said. “Maybe a lower dose might be useful for the cancer but would reduce risk of cognitive dysfunction.”

“Those with cancer might also be advised to have their cognition monitored as part of long-term follow-up,” added Margaret Gatz, professor of psychology at USC and foreign adjunct professor of medical epidemiology and biostatistics at the Karolinska Institute.

Funding for this research came from the National Institute on Aging and the national Alzheimer’s Association.


ADD Drug Shows Effectiveness Against “Chemobrain”

National Cancer Institute 

May 24, 2005 • Volume 2 / Number 21

Editor’s Note:  Consult with your doctor about this and all other articles.  This was a fatigue study not a chemobrain study.  See physician responses at ASCO.

Researchers at the ASCO annual meeting last week reported that the use of a central nervous system stimulant significantly moderated cognitive dysfunction in patients previously treated with adjuvant chemotherapy. The data come from a phase III clinical trial testing the drug dexmethylphenidate, or d-MPH (Focalin) – a drug approved by the FDA for the treatment of attention deficit disorders – in patients with cognitive dysfunction following chemotherapy, a condition sometimes referred to as “chemobrain.”

The study randomized 152 adult patients to treatment with d-MPH or to a control group. All patients had completed at least four cycles of chemotherapy for a variety of cancers. The vast majority of patients, 94 percent, were women with either breast or ovarian cancer. Only 132 patients completed the 8-week study, with the majority of dropouts related to adverse events, such as headache and nausea.

The treatment group showed weekly improvements in alertness and general cognitive function as measured by standardized assessment tools used in clinical trials, reported the study’s lead author, Dr. Elyse Lower of the University of Cincinnati. Although the study was not designed to assess memory dysfunction, the treatment group showed significant improvement. But some of the overall assessment tools, she cautioned, did not show a statistically significant difference between test groups.


Chemobrain: The Hunt for Answers

Charlotte Huff

American Psychological Association

Volume 36, No. 4 April 2005

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.”