Women with breast cancer who underwent CMF chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [5-FU]) scored lower on neuropsychological tests 20 years after treatment than women never treated for cancer, according to a study in the Journal of Clinical Oncology (doi:10.1200/JCO.2011.37.0189). The research team concluded that the regimen may be the cause of cognitive decline lasting 20 years post-treatment.
“The cognitive functions on which we saw differences resemble a lot of the cognitive domains that seem to be affected shortly after treatment, so we interpreted it as a sign some problems can be really long-lasting,” the principal investigator, Sanne B. Schagen, PhD, Group Leader in the Department of Psychosocial Research and Epidemiology at the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital in Amsterdam, said in a telephone interview.
The CMF regimen has been found to be associated with adverse short-term cognitive effects, but this is the first study of its size to suggest that those effects might continue long-term. “There are some studies looking 10 years after treatment, but this one has the largest interval between treatment,” she explained.
The researchers compared the neuropsychological examinations of a group of 196 women ages 50 to 80 who had received six cycles of CMF following surgery between 1976 and 1995, with a control group of 1,509 women in the same age range who had never been diagnosed with cancer. Despite the women's age, education, and depression scores, those who received the chemotherapy performed worse on all the tests, which covered learning, immediate and delayed verbal memory, information processing speed, inhibition, and psychomotor speed.
This research did not test for possible mechanisms behind the cognitive effects, but according to the report, explanations could include diminished cognitive reserve, stimulation of pro-inflammatory cytokines, and the effect of anesthetic drugs received for breast surgery. Further research needs to be done to identify the cause of these findings, but Schagen said it is likely there are many mechanisms at play here.
Additional tests will also be needed to determine if the same results will be seen in patients who received similar chemo regimens for other types of cancer, which Schagen said is likely. She explained that the team chose to study breast cancer patients because of their high survival ra-tes, thus assuring a large pool of candidates to study.
Another next step in this research will be to investigate whether other types of chemotherapy regimens may induce similar cognitive problems. The researchers chose to study the CMF combination, she said, because it was the first adjuvant treatment for breast cancer and was the standard of care used to treat thousands of breast cancer patients from the 1970s to mid-1990s.
In the time since, though, an anthracycline-based adjuvant regimen has replaced CMF, although two of the CMF agents (cyclophosphamide and 5-FU) are sometimes still incorporated in treatment.
Despite the results, Schagen emphasized: “By no means do these symptoms outweigh the advantages of chemotherapy. Nowadays patients can get more and more tailored advice on whether or not chemotherapy might benefit them, but I'm not at all convinced that this should be part of that discussion.” The advantages of the research are to inform patients of potential side effects, and to be able to correctly distinguish treatment symptoms from what may be other, serious health conditions.
Schagen said a much larger study is needed with a control group of breast cancer patients who did not receive chemotherapy, as opposed to the control group in this study who had never been diagnosed with breast cancer. “That's something we want to do in the near future to also see what the possible effects of breast cancer itself are,” she said.
Commenting in an ASCO news release, Sylvia Adams, MD, of NYU Langone Medical Center, a member of ASCO's Cancer Communications Committee, said that as the number of long-term breast cancer survivors continues to grow and age, patients and their health care providers need to be aware of possible long-term effects of past chemotherapy. “While there is currently no intervention to restore lost cognitive function, there are skills people can learn to help them manage their daily routines more easily.”