For many years, cancer survivors have complained about a mental
fogginess after chemotherapy that interferes with multitasking, processing
speed, concentration and memory.
Health care professionals initially rejected these claims, contending
the problems — reported both during treatment and, in some cases, years
after — were psychosomatic.
Recent research, however, has shown that these cognitive issues are not
imagined. In fact, two studies have demonstrated brain changes in patients who
display symptoms of this mental fog, commonly referred to as “chemo
“Calling it chemo brain is probably a misnomer because patients may
have cognitive changes that could come on with just surgery, just radiation,
surgery with radiation or chemotherapy, or even some targeted therapies,”
Patricia Ganz, MD, director of cancer prevention and control at Jonsson
Comprehensive Cancer Care Center and a professor of medicine and health
services at UCLA, told HemOnc Today. “It’s more appropriately
termed ‘cancer brain.’”
Most of the research into cognitive impairment has focused on patients
with breast cancer because they have been the most vocal about this issue.
However, there is evidence that these cognitive challenges also plague patients
who have been treated for several other types of cancer.
Patricia Ganz, MD, director of cancer prevention and control at Jonsson Comprehensive Cancer Care Center and a professor of medicine and health services at UCLA, said researchers are trying to determine what causes cognitive impairment after cancer treatment and which patients are most at risk.
Photo courtesy of Patricia Ganz, MD, reprinted with permission.
Some of the most recent studies have shown that there are measurable
changes in the brain after cancer treatment.
Shelli R. Kesler, PhD, and colleagues at Stanford University
School of Medicine compared 25 women with breast cancer who were treated with
chemotherapy with 19 women with breast cancer who did not receive chemotherapy
and 18 healthy female controls. The researchers used functional MRI to
determine which part of the brain was activated when the women performed a
card-sorting task. In addition, they used questionnaires to evaluate the
patients’ perceptions of their cognitive abilities.
The results showed that women with breast cancer who were treated with
chemotherapy had significantly reduced function in the prefrontal cortex, the
area of the brain responsible for skills such as problem-solving, working
memory and multitasking.
Additionally, the chemotherapy group showed more perseverative errors
and reduced processing speed. There was a significant correlation between
reduced left caudal lateral prefrontal cortex activation and higher disease
severity and increased subjective executive dysfunction in the women treated
“[This study] contributes to the growing body of literature
[showing] that there are measurable changes in brain functioning following
chemotherapy for breast cancer,” said Kesler, an assistant professor of
psychiatry and neuropsychologist at Stanford University Medical Center in Palo
Alto, Calif. “This was a study focused on breast cancer, but there is some
evidence that other cancers that are treated with chemotherapy may be at risk
for similar problems. It tells us that this is a real issue in cancer
survivorship, and we need to come up with some treatments for those patients
who are reporting these problems.”
White matter changes
Sabine Deprez, MD, and colleagues at the University Hospital
Gasthuisberg of the Katholieke Universitet Leuven in Leuven, Belgium, evaluated
cerebral white matter integrity before and after chemotherapy with magnetic
resonance diffusion tensor imaging (DTI). Participants also completed a
detailed cognitive assessment.
In all, 34 premenopausal women with early stage breast cancer underwent
DTI testing and cognitive assessment before chemotherapy and 3 to 4 months
after treatment. Sixteen patients with cancer who were not exposed to
chemotherapy and 19 age-matched healthy controls underwent the same testing.
Shelli R. Kesler
After treatment, the chemotherapy group had significantly worse scores
on tests of attention, psychomotor speed and memory. In addition, they had
significant decreases of white matter fractional anisotropy — a DTI
measure that indicates white matter tissue organization — in frontal,
parietal and occipital white matter tracts after treatment. The researchers saw
no changes in the other groups.
The results also showed that changes in attention and verbal memory
correlated with mean regional fractional anisotropy changes in the chemotherapy
Previous research indicated that cancer-treatment induced cognitive
dysfunction may last up to 2 years; however, findings published recently in the
Journal of Clinical Oncology indicate these issues can persist much
In a case-cohort study, Sanne B. Schagen, PhD, of the Netherlands
Cancer Institute/Antoni van Leeuwenhoek Hospital in Amsterdam, evaluated the
cognitive performance of patients with breast cancer who were treated with a
regimen of cyclophosphamide, methotrexate and fluorouracil (CMF) chemotherapy.
Although the CMF combination is no longer widely used, two agents —
cyclophosphamide and fluorouracil — are used often in current breast
cancer regimens, Schagen told HemOnc Today.
Schagen and colleagues evaluated 196 patients with breast cancer, and
the average time since treatment was 21 years. The researchers compared these
women with a population-based sample of 1,509 women who were never diagnosed
The results showed that the chemotherapy group performed significantly
worse on cognitive tests of immediate and delayed verbal memory, processing
speed, executive functioning and psychomotor speed.
“It is the first study that shows that many years after completion
of chemotherapy for breast cancer, subtle differences between former patients
with breast cancer treated with chemotherapy and women without a history of
cancer in cognitive performance are still present,” Schagen said.
Many questions about cognitive dysfunction after cancer treatment
For example, researchers do not know how many patients are affected. The
best estimates are that about 20% of patients have lasting cognitive deficits
“Estimates range widely because different studies have used
different populations and different approaches to measuring and defining
cognitive impairment,” said Lynne I. Wagner, PhD, associate
professor in the department of medical social sciences and a member of the
Robert H. Lurie Comprehensive Cancer Center at the Northwestern University
Feinberg School of Medicine in Chicago.
It is not clear which patients are most at risk, Ganz said.
“We know that more intensely treated patients — those who
undergo bone marrow transplant, high-dose chemotherapy and whole-body radiation
— probably are at higher risk,” Ganz said.
Older women, as well as those who were less physically and mentally
active before their diagnosis, are much more vulnerable to the effects of
chemotherapy, Kesler said.
Researchers also are trying to determine what causes cognitive
impairment after cancer treatment.
“The causes are not known,” Ganz said. “Some of the
chemotherapy treatments may get into the brain and cross the blood-brain
Chemotherapy can be extremely toxic to neural stem cells, Kesler said.
“If even a small amount gets in, that can likely do quite a bit of
damage,” she said.
There also is a possibility that cancer treatment may stimulate an
inflammatory response in the body that causes problems with memory and
concentration, Ganz said.
She is studying the pattern of single nucleotide polymorphisms in the
promoter region of the tumor necrosis factor (TNF)-alpha gene (TNF-alpha 308)
to determine whether some individuals may be predisposed to develop
post-treatment increases in pro-inflammatory cytokines and associated symptoms.
“These are not genes that cause brain damage,” she said.
“They’re just genes that are involved in inflammation, and people who
may have one variant or another may have more inflammation.”
Lynne I. Wagner
Increased blood levels of TNF-alpha, as well as other pro-inflammatory
cytokines, can lead to fatigue and other symptoms that, in animal models, are
called “sickness behavior,” which causes loss of interest in usual
activities, Ganz said. This is similar to how a person feels when they have the
flu or a bad cold.
“We can see elevations of this in patients who get cancer
therapies,” she said. “This might be one of the mechanisms by which
patients are having fatigue and these cognitive complaints.”
Inflammation also is increased simply by having a tumor, Kesler said.
“There are several things that are probably playing a role, with
the chemotherapy being a toxin that gets into the brain and does some
damage,” she said.
Genetics may affect the development of cognitive issues. Some research
has been done on apolipoprotein E-4 gene, a genetic SNP linked to
“There is some concern that patients with that polymorphism may be
more susceptible to this,” Ganz said.
Other factors such as fatigue and secondary medical conditions could
negatively influence cognitive function.
“It’s a complicated picture,” Wagner said. “When
someone is going through chemotherapy, they have a lot of other symptoms
related to treatment, fatigue being most common.
“We must evaluate the patient to see if there are any medications
that are compromising cognitive function and, if so, whether they are
necessary,” Wagner said. “Can other medications be used? Or perhaps,
if it’s a short-term medication, then everybody understands that once
you’re off this medicine, things should get better.”
Other medical conditions that could lead to cognitive impairment, such
as anemia, should be ruled out or treated if present, Wagner said.
“Anemia is commonly associated with chemotherapy,” she said.
“We have an abundance of research in patients with end-stage renal disease
demonstrating that anemia is associated with significant impairment of
Diagnosing cognitive dysfunction is difficult because the standard
neurological tests available are not sensitive enough to detect the cognitive
“One of the problems is, we’re talking about subtle
changes,” Ganz said.
“The first challenge is finding a good measure that can be used in
the clinic easily that can discriminate between who has it and who
doesn’t,” Kesler said. “The standard psychological testing is
not super-practical in the clinic because it takes multiple hours and you have
to have a specialist [administer it], and it’s not always sensitive. The
biggest challenge is to develop some measure that correlates with brain
function and also with outcomes that occur several years down the road.”
There currently are no reliable pharmacologic treatments for cancer
therapy-induced cognitive impairment.
The narcolepsy treatment modafinil (Provigil, Cephalon) appears
promising, but there have been no large randomized clinical trials
demonstrating its effectiveness, Wagner said.
“Modafinil has been studied for cancer-related fatigue,”
Wagner said. “In that study, [the researchers] looked at cognitive
function as a secondary endpoint and they found that some patients improved on
only a few subscales out of many on cognitive function. It may be that
modafinil, in improving fatigue, may improve cognitive function, but we
don’t have a solid evidence base yet.”
Researchers at Wake Forest University have studied whether donepezil
(Aricept, Eisai) would improve cognitive function in patients with primary
brain tumors or brain metastases, Wagner said.
“In their early phase trials, they have found that the drugs we use
for Alzheimer’s may play a role, but this is in a different population
than your breast cancer survivor who is post-treatment and has no evidence of
cancer,” Wagner said.
Some small studies have been done on attention-deficit/hyperactivity
disorder drugs, but no drug has stood out as a good option, Ganz said.
A few studies have examined erythropoietin, which is typically used to
treat anemia. Erythropoietin had some moderate effects but also reduced
survival, Kesler said.
“Finding the right pharmacology is going to be challenging,”
Currently, the most exciting research is being conducted on nondrug
strategies such as cognitive behavioral therapy, Wagner said.
Robert J. Ferguson, PhD, a clinical health psychologist at the
Eastern Maine Medical Center in Bangor, Maine, and colleagues are studying a
cognitive rehabilitation tool called Memory and Attention Adaptation Training
(MAAT), which they designed specifically for mild cancer treatment-related
Robert J. Ferguson
Unlike typical cognitive rehabilitation, in which the patient performs a
repetitive task to recreate brain circuitry, this approach emphasizes the
acquisition of new behaviors and cognition to compensate for the impairment.
“Our approach is more behaviorally adaptive,” Ferguson said.
“We probably aren’t going to improve memory functioning per se, but
[we will] help the person improve behaviors in daily performance for which
memory is used.”
With MAAT, the patient practices compensatory strategies, such as
keeping a daily planner and verbal rehearsals. They also practice
self-instruction training, which requires them to talk through a task to
improve attention and procedural performance. Patients can use that skill in
the event of a memory failure.
Results of a single-arm pilot study in patients with breast cancer
yielded high patient satisfaction and improvements in verbal memory.
A subsequent randomized trial included patients with breast cancer who
were 5 to 7 years post-chemotherapy. The researchers randomly assigned patients
to a waitlist group, with normal follow-up cancer care, or the treatment group.
Both groups’ pretreatment and post-treatment testing occurred at the same
The results showed a robust effect in verbal memory performance.
“We weren’t expecting that,” Ferguson said.
There also was an increase in quality of life as measured by a spiritual
“We were kind of puzzled by that, but when we looked at the items
in that spiritual scale, it has a lot to do with optimism and acceptance of
cancer survivorship and the problems,” Ferguson said.
In the end, the best way for physicians to treat cognitive dysfunction
in cancer survivors is to recognize it.
“Know that it is real,” Kesler said. “There is a
neurobiological mechanism that is associated with the complaints patients have.
Currently, the best treatment plan is to get a referral to neuropsychology for
an evaluation and recommendations for dealing with cognitive
difficulties.” – by Colleen Owens
Does chemotherapy have a direct, organic effect on the brain that
causes cognitive dysfunction?
We do not know the answer yet.
Ian F. Tannock
Some patients have reported that they are unable to think and function
as well when they have chemotherapy. For a small portion of them, the problems
persist for quite some time after the chemotherapy is stopped.
These complaints led to investigations of cognitive function.
Essentially, those investigations found that the cancer diagnosis itself is
associated with cognitive deficits. The chemotherapy may add to that in a small
portion of patients.
There is not a very strong relationship between the people who
self-report cognitive dysfunction and their formal testing. That may be because
the tests are not sensitive enough to pick up subtle differences in cognition.
It may be that patients are initially high functioning and, even though that
level of function decreases and is noticeable to them, it is still within
normal range. It also may be that people feel very anxious, and they report
changes that perhaps are not real.
There clearly are patients who both immediately and long term
demonstrate deficits in cognitive functioning. Documented changes in brain
imaging, both on PET and MRI, lend support to this being a real phenomenon.
It has taken some time for these cognitive impairments to be recognized.
In the early days of chemotherapy, the overwhelming problems were things like
nausea, vomiting, fatigue and infection. Those acute effects were so dominant;
they tended to mask the rather subtle cognitive changes that we now recognize.
Only since the beginning of the last decade have well-designed studies
begun to investigate this area, and most studies have shown an effect.
The early studies were not well controlled. You cannot ethically do a
randomized trial to compare chemotherapy with no chemotherapy. These trials
require two types of controls. First, it is necessary to have a control group
of healthy people. Second, researchers must compare chemotherapy-treated
patients with people who have cancer but who do not receive chemotherapy.
We have done this in a very large study of colorectal patients, which
includes both men and women. We have not published these data yet, but, at
least initially, we found an effect of the cancer itself to cause cognitive
dysfunction. There was not a big difference between the chemotherapy group and
the non-chemotherapy group.
Ian F. Tannock, MD, PhD, DSc, is Daniel E. Bergsagel Professor
of Medical Oncology at Princess Margaret Hospital in Toronto.
Disclosure: Dr. Tannock reports no relevant financial disclosures.
There is no proof that chemotherapy leads to cognitive impairments.
Daniel F. Hayes
One theory is that chemotherapy may have a direct organic effect on the
brain and, therefore, lead to cognitive dysfunction. A second theory, supported
in part by data from our own institution, is that cognitive dysfunction may be
the result of the conflict and confusion the patient experiences.
Bernadine Cimprich, PhD, RN, FAAN, of the University of Michigan School
of Nursing, has performed functional MRI and cognitive functioning testing in
women at the time of diagnosis — before they received treatment — and
compared them to otherwise normal controls who have not been told they have
breast cancer. She found cognitive function drops dramatically in women
diagnosed with cancer.
It makes perfect sense to me. If you are told you have had some major
catastrophe in your life, your ability to concentrate takes a hit.
It is easy to blame a decline in cognitive functioning on treatment
when, in fact, it may be related to everything else going on in the
The trouble is that most of the research has been a cross-sectional
analysis of a population without serial follow-up or without proper controls.
Researchers in Canada, as well as Dr. Cimprich, have been monitoring a
cohort of chemotherapy-treated patients vs. a control group of patients who did
not receive chemotherapy. They have found that the cognitive function of
chemotherapy-treated women drops while they are getting treatment. In the
studies I have seen, their cognitive function usually returns to baseline
within a few months of stopping chemotherapy.
That could be a now-resolved direct organic effect of the chemotherapy
on the brain, or it could be that chemotherapy is tough to take. Patients
experience fatigue, nausea, vomiting and hair loss. If they have breast cancer,
they may have had a mastectomy. A number of things are going on, all of which
could affect cognitive function.
I do not want women to perceive that chemotherapy will cause long-term
cognitive dysfunction and, therefore, walk away from potentially life-saving
therapies. Breast cancer mortality has plummeted over the last 30 years. Part
of the decline is due to screening, but a lot of it is from widespread
application of adjuvant and systemic therapies, chemotherapy, anti-estrogen
therapy and anti-HER-2 therapy.
We need good studies with proper controls to determine whether women who
undergo chemotherapy really have persistent cognitive dysfunction and whether
chemotherapy is an organic cause. I want to be sure we apply good scientific
principles to this to find out what is wrong. We need to prove the mechanism
first before we start treating a presumed mechanism.
Daniel F. Hayes, MD, is clinical director of the breast cancer
oncology program and Stuart B. Padnos Professor in Breast Cancer at the
University of Michigan Comprehensive Cancer Center in Ann Arbor, Mich.
Disclosure: Dr. Hayes reports no relevant financial disclosures.
- Deprez S. J Clin Oncol. 2012;30:274-281.
- Kesler SR. Arch Neurol. 2011;68:1447-1453.
- Koppelmans V. J Clin Oncol. 2012;30:1080-1086.
- Drs. Ferguson, Ganz, Kesler, Schagen and Wagner report no relevant