Cancer's Toll on the Brain

When she was treated for breast cancer in 2003, Janet B. suffered the typical side effects of chemotherapy: nausea, fatigue, and hair loss. Subsequent radiation treatments barely fazed her, apart from causing some additional fatigue. But after her cancer treatment ended, when she was struggling to regain her strength, she noticed another problem.

Her short-term memory was shot. "I'd always been a little absent-minded," she says, " that got a lot worse. If I start a load of laundry and the phone rings, I'll forget I was doing laundry and I'll go do something else." Janet also finds it harder to concentrate now. "I'm more distractible," she explains. "It's like suddenly I have attention deficit disorder."

Janet's sense of direction is no longer reliable. Nor can she plot a driving route in her head anymore. "Sometimes when driving in a familiar area, I get a little disoriented and can't visualize what landmarks are coming next," she says. "It's not like I'm totally lost, but I have to think about it more."

Despite the side effects, Janet is delighted with the success of her cancer treatment. But patients, physicians, and biomedical researchers are increasingly asking what price patients pay for beating cancer with this type of treatment.

Chemotherapy, though life-saving, may itself cause cancer later in life. The treatment may also cause other persistent problems such as hearing loss, heart damage, and infertility. And evidence is building that chemotherapy can lead to difficulties with memory and concentration, much like those Janet has experienced.

Known informally as chemobrain or chemofog, this condition can make it hard to find the right word during a conversation or to learn new material. People suffering from chemobrain may "have to read the same page of material over and over again," according to Tim A. Ahles, a psychologist who is a professor of psychiatry and program director of the Center for Psycho-Oncology Research at Dartmouth Medical School. They may have difficulty finding their keys or remembering what they meant to buy at a store. The speed at which they process information may drop.

Compared with the cognitive effects of conditions such as Alzheimer's disease, Ahles notes, the mental changes accompanying chemobrain "are relatively subtle. But they still can be very disruptive and interfere with achieving work or educational goals."

The changes that characterize chemobrain have proven hard to spot in standardized tests of memory and attention. Patients who experience cognitive changes after chemotherapy often score in the normal range in these tests. Unfortunately, such tests are usually administered only after chemotherapy treatment, so changes in an individual's test results are rarely determined. Even when pretreatment tests are conducted, however, it's not easy to interpret the results because the period prior to treatment is so stressful.

Christina A. Meyers, a neuropsychologist at the University of Texas M. D. Anderson Cancer Center, is one of the few researchers who have collected data on patients prior to treatment. She has found evidence that patients with hematologic, lung, or breast cancer showed learning and memory problems before starting chemotherapy. Among the breast cancer patients, chemotherapy nearly doubled the pretreatment percentage of patients suffering from cognitive difficulties, though half of them improved within a year of treatment.

It's possible that an inflammatory immune response caused by cancer itself and/or by cancer treatment may be responsible for some of these cases of chemobrain, according to Meyers. The immune system is regulated by proteins known as cytokines, which are secreted by immune cells. Cytokines are activated in response to infection or injury and cause brain-mediated symptoms, including fatigue, lack of motivation and appetite, sleep disturbance, and problems with concentration. "Certain cancers and cancer treatments secrete or induce cytokines, which may be one mechanism by which cancer-related symptoms, including cognitive impairment, develop," Meyers says.

For instance, Meyers found that patients with acute leukemia had elevated levels of certain cytokines circulating in their blood, which correlated with the extent of their cognitive impairment and fatigue. This finding lends some support to the hypothesis that chemobrain may be due at least in part to cytokine activation of the immune system, Meyers says. Conceivably, anti-inflammatory drugs might be useful as an antidote to the harmful activity of cytokines, she adds. Cytokine antagonists-which prevent the binding of cytokines to their target cells in the immune system and elsewhere-are under development and may also help. Such treatments would have to be used with caution so as not to suppress beneficial immune activity.

Several other factors can contribute to cognitive difficulties experienced by chemotherapy patients. During chemotherapy and shortly thereafter, "almost everybody reports having problems with memory and concentration," Ahles says. Patients are "anemic, they're nauseous, they're taking medications that are sedating, and they're not sleeping well. There's a whole lot of reasons why they could be experiencing cognitive problems."

Some people continue to experience fatigue or sleep disruption after chemotherapy. Others battle depression and anxiety. Some patients continue to take medication after chemotherapy, either to hold cancer at bay or to treat other conditions. "If you treat the fatigue or depression or you change the dose of a sedating medication, very often the cognitive problems will resolve," Ahles said during a June 2004 workshop on chemobrain. The workshop was hosted by CancerCare, an organization that provides counseling and educational services related to cancer.

Other potentially reversible sources of cognitive problems include vitamin B-12 and folic acid deficiency or an underactive thyroid, according to Stewart Fleishman, another workshop speaker. Fleishman is director of cancer supportive services at Continuum Cancer Centers of New York: Beth Israel Medical Center. Hormonal changes that can occur with cancer or its treatment can also play a role, he added.

As breast cancer patient Janet, who was 51 when she had cancer treatment two years ago, sums it up: "I can see lots of differences in cognitive processes since chemo. It's hard to know what is chemo related and what is just to be expected at this age."

Whatever the basis for their cognitive difficulties, most patients report a gradual improvement within six months to a year or two after treatment. "However, there is a group of people who say they improve to a certain extent and then hit a plateau and never improve after that," Ahles says. “We don't know how big that group is, but it's probably in the 20-25% range.”

Furthermore, the source of their ongoing cognitive problems is uncertain. Chemotherapy may affect the brain directly, or it may alter some other aspect of human biology. "Those are the kinds of things that we are intensively trying to study right now," Ahles says. "If we can understand the cause of chemobrain, then hopefully we can come up with ways of either treating it or, ideally, preventing the problem."

One fundamental question that needs to be answered is whether chemotherapy drugs get into the brain. Traditionally, passage of chemotherapy drugs into the brain was believed to be blocked by the blood-brain barrier, according to the Mayo Clinic. But some researchers now suspect that some of these drugs slip past.

Once they're in the brain, chemotherapy drugs could cause atrophy of gray matter and demyelination of white matter fibers, Ahles says. The compounds may also alter neurotransmitter levels.

Another hypothesis is that chemotherapy drugs cause vascular injury in the brain and perhaps elsewhere. It's also possible that the free radicals produced by chemotherapy to kill cancer cells also harm membranes and DNA of normal cells.

There are still many unknowns, according to the Mayo Clinic. Which chemotherapy drugs are more likely to cause memory changes? Do higher doses pose a bigger risk than do smaller ones? And who is more likely to suffer from cognitive impairment after chemotherapy?

The answer to that last question is likely to be multifaceted, but genetics might be involved. For instance, Ahles suspects that a gene associated with Alzheimer's disease may increase a patient's vulnerability to chemobrain. He has collected preliminary data showing that patients who have the 4 allele of the apolipoprotein E (APOE) gene score worse on cognitive tests than patients with other forms of the gene. Ahles is now conducting a more in-depth study of APOE and other genetic markers "to see if we can begin to predict who might be at higher risk for developing some of these cognitive problems."

Two factors may explain the 4 allele's influence: It diminishes the body's ability to repair the vascular and nervous systems after they have been damaged, and it is associated with a smaller than average hippocampus, a brain region involved in memory and concentration.

Another population that may be particularly vulnerable to the negative consequences of chemotherapy comprises children, adolescents, and young adults, because their brains are still developing.

The Children's Oncology Group, a cancer research organization, notes that high doses of both methotrexate and cytarabine are associated with cognitive deficits such as diminished IQ, processing speed, and memory when administered to girls under the age of three. Methotrexate and cytarabine are both antimetabolites, compounds that block enzymes that cancer cells need to survive. An antimetabolite prevents the cancer cells' growth and eventually causes them to die.

But these two compounds-in addition to others such as carmustine and cisplatin-can cause toxic leukoencephalopathy, in which myelin in cerebral white matter is damaged, according to Robert E. Smith, codirector of the South Carolina Cancer Center (J. Support. Oncol. 2004, 2, 39).

While research is ongoing into the causes of chemobrain, scientists are also hunting for potential treatments.

For instance, three weeks of treatment with Ritalin (methylphenidate hydrochloride) has been shown to help children who develop attention and learning problems as a result of chemotherapy, Raymond K. Mulhern and colleagues reported last December (J. Clin. Oncol. 2004, 22, 4795). Mulhern, who died this year, was chief of behavioral medicine at St. Jude Children's Research Hospital. Ritalin is usually prescribed for the treatment of children with attention deficit hyperactivity disorder (ADHD). The drug is a central nervous system stimulant that blocks reuptake of the neurotransmitters norepinephrine and dopamine.

Meanwhile, Fleishman has been involved in a recent multicenter trial of the Celgene drug Focalin, which is dexmethylphenidate, the R,R enantiomer of racemic Ritalin. Adult patients enrolled in the trial had received chemotherapy ending at least two months before their participation in the study began. They had to have fatigue and problems with memory or concentration but not have anemia. The patients given Focalin-who had been treated for breast or ovarian cancer-showed improvements in memory and fatigue compared with patients who received a placebo. The results of this study were presented at the American Society of Clinical Oncology meeting this June.

Other medications that may be useful to assess include anti-inflammatory drugs and antidepressants such as Zoloft (sertraline hydrochloride) and Prozac (fluoxetine hydrochloride), according to Fleishman.

Other drugs that are being considered include erythropoietic agents, which have traditionally been used to combat the anemia and associated fatigue that are common in cancer patients. Like the natural hormone erythropoietin, these agents bind to receptors on the surface of erythroid progenitor cells, which then mature into red blood cells. Researchers have discovered, however, that erythropoietin receptors can be found on other cells, including neuronal cells, Smith says. Furthermore, erythropoietin demonstrates neuroprotective abilities, possibly by increasing production of antiapoptotic proteins.

These findings may explain why some evidence suggests that erythropoietic agents have cognitive benefits. For instance, a pilot study showed that treatment with epoetin alfa during anthracycline-based chemotherapy eased cognitive impairment in breast cancer patients, according to Baylor University oncologist Joyce A. O'Shaughnessy and colleagues (Clin. Breast Cancer 2005, 5, 439).

It's not yet clear whether neuroprotection or enhanced tissue oxygenation resulting from increased blood cell production is responsible for the cognitive improvement that results from treatment with erythropoietic agents, Smith notes. These agents will have to be studied carefully because they may contribute to tumor growth.

Patients can also turn to a number of nonpharmacological approaches to manage chemobrain, Meyers notes. Options include exercise, behavioral interventions such as relaxation therapy, and compensatory strategies such as making to-do lists.

Cancer therapy has evolved to a point where patients and physicians can increasingly take into account the nature of life after treatment. Both physicians and researchers are working to lessen the burden of surviving cancer. As Meyers puts it, "Optimizing the quality of life of cancer patients is possible, essential, and should be on equal footing with anticancer therapy."