Journal of the National Cancer Institute Advance Access originally published online on January 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(3):162-169; doi:10.1093/jnci/djn007
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© Oxford University Press 2008.
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Chemobrain Is Real but May Need New Name
Cancer patients know that chemobrain is real. The nearly ubiquitous experience of foggy thinking immediately after chemotherapy treatment has even inspired T-shirts and buttons emblazoned with "My Name is Chemo Brain." For some cancer survivors, the cognitive effects of chemotherapy such as lack of concentration and short-term memory loss linger for years after treatment, but little is known about who is most likely to suffer a long-term deficit or how to guard against it. Confounding factors such as fatigue and depression—as well as widely divergent patient experiences—have made studying the cognitive consequences of chemotherapy problematic. That obstacle has led to a disconnect between patient experiences and physician attention to the issue.
"I think it's probably true that there's still a fair amount of skepticism amongst some people about how real of a phenomenon this is," says Tim Ahles, Ph.D., a cognitive psychologist at Memorial Sloan-Kettering Cancer Center in New York. "Even though patients have been talking about this for years, really since the 1970s, it's only the last 10 years that anyone has been doing systematic research."
Now a series of studies that combine neuropsychological testing with sophisticated brain imaging and molecular analyses has allowed investigators to get a handle on what had previously been seen as an indescribable phenomenon. And several research studies focusing on treatment are beginning to yield new strategies to mitigate some of the quality-of-life issues that accompany short-term memory loss after chemotherapy.
In the first study of its kind, Daniel Silverman, M.D., Ph.D., associate professor of molecular and medical pharmacology at UCLA's David Geffen School of Medicine, and his colleagues conducted positron emission tomography imaging studies of 16 long-term breast cancer survivors with persistent memory problems, eight former breast cancer patients who had never had chemotherapy, and 10 healthy control subjects. The researchers, who were blinded, administered a delayed-recall memory test while observing brain metabolic activity.
The studies demonstrated that the women who had received chemotherapy had a lower resting brain metabolism, and the questions activated a larger portion of their frontal cortex than that in untreated women. "The more impaired they were in performing the memory task, the lower the resting metabolism was in that area of the brain," Silverman said. "That same part of the brain, the inferior frontal cortex, is less metabolically active to begin with, so ... to perform the same cognitive task, [the subjects have] to work that part of the brain that much harder to get up to the level that they would have if they had not been impaired."
Complementary functional magnetic resonance imaging studies have yielded similar results. Andrew Saykin, Psy.D., director of Indiana University's center for neuroimaging, and his colleagues are studying breast cancer patients before and after chemotherapy, breast cancer patients who did not receive chemotherapy, and healthy control subjects. Preliminary results, presented at the annual meeting of the Organization for Human Brain Mapping in June 2007, show a disrupted pattern of brain activation 1 month after chemotherapy, with less overall activity in bilateral prefrontal regions. Saykin said that the group will repeat the imaging 1 year after the women finish chemotherapy before publishing the dataset.
Should It Be "Cancer Brain"?
However, other studies suggest that blaming cognitive problems solely on chemotherapy is too limiting. Ahles and his colleagues recently published a neuropsychological study of 132 newly diagnosed breast cancer patients and 45 healthy control subjects that concluded patients with stage I–III invasive disease had statistically significantly lower cognitive performance before treatment than that of patients with noninvasive disease or no disease, although both sets of patients scored within what is considered the "normal" reference range. Ahles suggests that other factors associated with invasive cancer, such as elevated levels of proinflammatory cytokines or DNA damage, may contribute to poorer baseline cognitive performance.
Previous studies have established the deleterious effects of cytokines on cognitive function. Janette Vardy, M.D., Ph.D., a medical oncologist at the University of Sydney in Australia, is collaborating with Ian Tannock, M.D., Ph.D., of Princess Margaret Hospital in Toronto, on a study of cytokine levels and functional magnetic resonance imaging results in 120 breast cancer patients. The goal is to associate cytokine levels with levels of fatigue and cognitive impairment. Preliminary data suggest that cytokine levels are elevated in all cancer patients compared with those in control subjects, but with the current sample size no conclusions can be drawn, Vardy said.
Other factors may also be involved that point to issues besides chemotherapy. "One of the first things we ought to do is rename ‘chemobrain,’" Ahles said. "... For most women with breast cancer, they also receive hormonal intervention like tamoxifen or aromatase inhibitors. There are issues like age, stress, anxiety, [and] depression that can factor in. If anything, it has become more complicated than we realized."
Organizing the Field
The recent convergence of data suggesting a biological basis for chemobrain has sparked an international effort to standardize research methods and to prioritize future research directions. The International Cognition and Cancer Task Force, formed during the October 2006 international cognitive workshop in Venice, Italy, is creating a Web site that will serve both physicians and patients seeking assistance with managing cognitive symptoms associated with cancer treatment, according to Vardy, cochair of the group.
"There are groups of us around the world that are trying to study this problem," Ahles said. "One of the things we found when we get together is that everybody is using different sets of tests, different inclusion and exclusion criteria for their studies, and different statistical analysis plans. We are trying to come up with a core of common measures so that we can be comparing across studies."
Indeed, the methodological problems with early studies on cognitive impairment in cancer patients are well known (see J Natl Cancer Inst 2003;95:190–7). Also, most studies on cognitive changes have been small and have included few older patients, even though most cancer patients and cancer survivors are elderly, Ahles said. According to a 2007 Institute of Medicine report on cancer in the elderly, 60% of all cancer survivors are older than 65 years.
Andrea Bial, M.D., a geriatrician at the University of Chicago, published a review in Critical Reviews in Oncology/Hematology in which she pointed out that only 17% of studies on cognition included cancer patients whose mean age was more than 65 years. "There is an obvious and unmet need to look specifically at cognitive issues in older folks," Bial said. "It is a complicated issue because being elderly is an independent risk factor for cognitive impairment. It is important that future studies include a sufficient number of elderly patients in their trials so that oncologists have enough information to advise elderly patients about potential deleterious effects of chemotherapy on cognition."
Lessening the Effects
While researchers are working to identify who is most at risk for long-term cognitive problems, others are turning their attention to mitigating its effects. One recent approach involves giving a mild stimulant to patients who have just completed chemotherapy. At the 2007 American Society for Clinical Oncology meeting, Sadhna Kohli, Ph.D., a professor at the University of Rochester, presented data showing that modafinil, a medication approved for sleep apnea, improved short-term memory in breast cancer patients. In the study, 68 women who complained of memory problems 2 years after breast cancer chemotherapy were given modafinil for 4 weeks. For the next 4 weeks, half the women continued to receive the drug, while the others were given a placebo. Women who received modafinil showed modest but statistically significant improvement in cognitive testing, according to Kohli. The pilot study was sponsored by the maker of modafinil and by a grant from the National Cancer Institute.
Others are concentrating on cognitive rehabilitation and coping strategies to improve working memory. "If you treat the brain as a mental muscle and exercise it, these functions will improve," said Robert Ferguson, Ph.D., of the department of rehabilitative medicine at Eastern Maine Medical Center in Bangor. Ferguson is leading a team working with patients, using "an old behavioral technique called ‘self-instructional training.’" The technique, which involves talking through a set of instructions "as if you were a sports announcer doing a play-by-play," originates from students with reading comprehension problems who alternate reading the same passage aloud and then silently. Ferguson modified the technique and renamed it Memory and Attention Adaptation Training.
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He has tested this approach in a pilot study of 29 breast cancer survivors who were on average 8 years out from chemotherapy and had lingering memory problems. The participants received a workbook and attended four monthly sessions, with telephone follow-up between sessions. Investigators compared self-reported cognitive function and results of pre- and posttest cognitive examinations with those of control subjects participating in a larger study using the same tests. The patients scores improved during the study, and they rated Memory and Attention Adaptation Training as helpful in compensating for memory problems, according to the report published in the August 2007 issue of Psycho-Oncology.
"We think this is a good approach, given that we don’t know the etiology of the chemotherapy effect on memory," he said. "If we can improve quality of life and function with compensatory memory strategies in daily life and improve stress management in dealing with the consequences of these memory problems in a practical way, we are doing something good, even if we are not improving memory per se."
Other research teams are trying to mitigate memory problems through moderate exercise and even meditation. Patients may have to rely on such techniques, their strength of spirit, and their sense of humor until the researchers studying causes can catch up.
Survey Points to Doctor–Patient Miscommunication in Chemobrain Research
Defining what it means to have chemobrain is difficult, but getting a handle on the prevalence and effect of cognitive changes resulting from systemic chemotherapy treatment has been even harder to pin down. Estimates of how many cancer patients are affected range from 14% to 85%. Patient advocacy groups say that no matter how many are affected, it's time to focus on chemobrain as a major quality-of-life issue for survivors.
"I’m hearing from a lot of patients that their doctors don’t believe them or they don’t think it's important," said Janet Colantuono, executive director of Hurricane Voices Breast Cancer Foundation. "They think it's age- or hormone-related, anything other than being an impact from the cancer treatment. So we identified this gap between the patient and the physician, and we wanted to do something that would help close that gap."
Working with Ian Tannock, M.D., Ph.D., of Princess Margaret Hospital in Toronto and Janette Vardy, M.D., Ph.D., of the University of Sydney, the advocacy group conducted the first survey to gather information from cancer survivors about their experience with chemotherapy-related cognitive changes. A self-selected group of 471 men and women diagnosed with any type of cancer participated. Colantuono said that the survey was not meant to be scientific but rather to give an overall picture of what experiences patients had and how it affected their ability to function in daily life. Highlights of the survey included the following:
- Most respondents indicated an effect on their functioning and relationships at home (62%) and in employment outside the home (62%). The effects rangeed from taking longer to do ordinary jobs around the house to having to change careers or stop working.
- Of the 102 respondents 5 or more years out from treatment, 92% were still affected by cognitive changes—61% at the same level they first experienced after treatment. Only 8% reported that their symptoms had gone away.
- Most patients reported that medical professionals do not help them cope with cognitive changes. Sixty-three percent of patients conferred with their doctors, but only 10% felt that they were provided information and support to manage their symptoms.
As the number of survivors continues to grow, cognitive deficits will become a critical quality-of-life concern for millions of cancer patients, the report concludes. Colantuono said the survey results indicate that cancer care teams need to better incorporate cognitive changes into the array of side effects discussed and monitored throughout treatment and afterward.
—Karyn Hede
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