Chemotherapy Can Impair Cognition More than Two Decades Later
More than 20 years after treatment, breast cancer patients who received adjuvant chemotherapy exhibited cognitive deficits compared with women who were never diagnosed with cancer. The results, which appeared online February 27 in the Journal of Clinical Oncology, suggest that the phenomenon known as chemobrain can persist for decades after cancer treatment ends and may become more common as the number of cancer survivors grows.To investigate chemotherapy’s long-term effects on cognition, Dr. Vincent Koppelmans of Erasmus MC University Medical Center in Rotterdam, the Netherlands, and his colleagues identified 196 eligible breast cancer patients from two Dutch hospital registries and invited them to participate in tests that measured learning, memory, information processing, and psychomotor abilities.
All of the patients had received six cycles of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) on average 21 years earlier and were between 50 and 80 years old when recruited to the trial. Women who had experienced a relapse, second primary tumor, or distant metastases, and those who used adjuvant endocrine therapy were excluded from the study.
The 1,509 women in the reference group were selected from the Rotterdam Study, a population-based study also being conducted in the Netherlands. These women had no history of cancer and were also between 50 and 80 years old when they were tested.
Although the researchers observed no difference between the two groups in a dementia screening test, the breast cancer survivors performed worse on some tests of delayed verbal memory, processing speed, and psychomotor speed. The survivors also had more memory complaints but fewer symptoms of depression.
This pattern of deficits is similar to those from other trials conducted closer to the time patients finished chemotherapy. But it is unclear whether the results of this study are representative of the long-term effects of other chemotherapy regimens.
Although newer regimens are now available for women with early-stage breast cancer, the authors noted, “[CMF] was the standard regimen up to the 1990s... [and] cyclophosphamide and fluorouracil continue to be incorporated into currently used regimens.”
“This work is an important reminder that it is not enough to focus on the cure and control of cancer,” commented Dr. Julia Rowland, director of NCI’s Office of Cancer Survivorship. “We must also attend to the impact of therapy on the long-term health and function of our growing population of survivors.”
See also: “Delving Into Possible Mechanisms for Chemobrain”
Delving Into Possible Mechanisms for Chemobrain
After undergoing surgery, chemotherapy, and radiation therapy for stage II breast cancer, Lori (who asked to be identified only by her first name) was looking forward to getting back to her normal, busy life as a working mother of two.
This image of the human brain uses colors and shapes to show neurological differences between two people. The blurred front portion of the brain is associated with complex thought. (Image courtesy of Arthur Toga, University of California, Los Angeles)But within weeks of returning full-time to her job as a city planner, she knew something was wrong. “I couldn’t work, I couldn’t think,” she said. Before, multitasking had been second nature, but now it exhausted her. At home, she found that trying to do things like plan dinner for her family was more than she could cope with.
“My brain feels so heavy and tired...I can feel everything slowing down, getting cloudy,” she said.
Lori has the classic symptoms of chemobrain: cognitive changes associated with cancer or cancer treatment, most often experienced as difficulties with concentration, memory, multi-tasking, and planning ability. These changes usually first become apparent during chemotherapy (hence the name) and, in around 20 percent of survivors, persist well after treatment has ended.
A More Complicated Explanation
Although chemobrain was first identified and named by breast cancer survivors, research now suggests that the same constellation of symptoms also affects survivors of other cancers. Early studies of patients’ cognitive functioning after chemotherapy estimated that the number of survivors with chemotherapy-associated cognitive changes ranged from 17 percent to 75 percent.
When researchers began to measure cancer patients’ cognitive functioning both before and after chemotherapy, however, they were surprised to find that before undergoing chemotherapy, 20 to 30 percent of patients had lower cognitive performance than would be expected based on their age and education. Subsequent studies have consistently shown similar findings.
“This suggests that aspects of cancer biology may influence cognitive functioning, or that there are as-yet-unidentified shared risk factors for mild cognitive changes and the development of cancer,” said Dr. Tim Ahles, who studies chemobrain at Memorial Sloan-Kettering Cancer Center.
“It’s more complicated than chemotherapy,” added Dr. Ahles. “Almost no one who is treated for cancer receives only chemotherapy. Other aspects of treatment may be equally important to understanding changes in cognitive functioning.”
Increased Vulnerability
Evidence from animal and imaging studies suggests, for example, that the drug tamoxifen, widely used to treat hormone-receptor-positive breast cancer, may disrupt cognitive and other brain functions. In addition, some studies have found that hormonal agents such as goserelin and leuprolide may cause adverse cognitive effects in men who have prostate cancer.
Studies using functional magnetic resonance imaging have identified structural brain abnormalities in patients treated with chemotherapy. In a study using positron emission tomography imaging, breast cancer survivors who had received chemotherapy in the previous 5 to 10 years used more of their brains to perform a short-term memory task than control subjects who had never received chemotherapy, a sign that their brains are having to work harder to complete the task.
Findings from a preliminary study by Dr. Ahles and his colleagues at Dartmouth Medical School suggest that a form, or allele, of the APOE gene called ε4, which is associated with increased risk for Alzheimer’s disease, may be a genetic marker for increased vulnerability to chemobrain. In this study of 80 long-term survivors of breast cancer and lymphoma, participants with at least one ε4 allele had significantly lower scores on standard tests of visual memory and spatial ability and a tendency toward lower scores on psychomotor functioning than subjects who did not carry this allele.
Dr. Ahles and his team are currently analyzing the data from a larger study, looking at the role of genetic polymorphisms in the development of cancer-related cognitive changes. They are also investigating the hypothesis that patients whose cells have a reduced ability to repair the DNA damage caused by chemotherapy are at higher risk for chemobrain.
Dr. Patricia Ganz and her colleagues at UCLA’s Jonsson Comprehensive Cancer Center suspect that uncontrolled inflammation may be a cause of chemobrain. “Many of the patients in our breast cancer survivorship program who have cognitive complaints also have fatigue, sleep disturbance, or depression,” she said. “Our hypothesis is that polymorphisms in genes that regulate the immune system render some patients more vulnerable to this constellation of symptoms.”
Many cancer treatments, including surgery, radiation, chemotherapy, and immunotherapy, can increase inflammation, Dr. Ganz added, which may not resolve after treatment ends. “We have found that post-treatment fatigue is associated with specific single nucleotide polymorphisms in genes that code for interleukin-1 and interleukin-6, two cell-signaling molecules associated with both inflammation and cancer-related fatigue,” she explained. “Our research is examining whether disruption in immune regulation is also involved in the development of cognitive complaints.”
Treatment Studies
Research on treatments for chemobrain is still in its very early stages. Dr. Ganz is beginning a pilot study of rehabilitation strategies for affected breast cancer survivors. Some evidence suggests that medications that stimulate the central nervous system may moderate adverse cognitive effects.
Lori has obtained some improvement by taking the stimulant Adderall (dextroamphetamine and amphetamine). She also finds that exercise and getting a good night’s sleep help her feel more clear headed.
The most challenging aspect of chemobrain, she said, is its invisibility. “I look fine, so people think I’m well. But my brain still isn’t well.”
Dr. Julia Rowland, who directs NCI’s Office of Cancer Survivorship, is encouraged that this new body of research is bringing needed attention to and better scientific understanding of the cognitive problems that affect many survivors during and after treatment. “The very real challenges caused by cancer-related difficulties with memory and thinking have been poorly understood and are often dismissed when reported by survivors,” said Dr. Rowland. “Findings from these studies should empower survivors to ask their medical providers what can be done to help them improve their cognitive health, especially after treatment ends.”
– Eleanor Mayfield
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