Reference
Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Gundy C, Schagen SB. Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol. 2012;30(10):1080-1086.
Design
Case-cohort study
Participants
196 women (ages 50–80 in 2008) with a history of breast cancer treated with CMF (cyclophosphamide, methotrexate and fluorouracil, 6 cycles, average time since treatment=21.2 years) found through the registries of the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital and the Erasmus University Medical Center-Daniel den Hoed Cancer Center. Women who had relapsed disease or a secondary malignancy were not recruited. Exclusionary criteria included any history of adjuvant endocrine therapy use. The reference group used was taken from the the Rottingham Study, a population-based, prospective cohort study. The authors specifically used the Rottingham III subcohort, which they culled for women without any history of cancer who had undergone neuropsychological assessment between the ages of 50–80 years old. The reference group contained a total of 1,509 women.
Outcome Measures
Seven neuropsychological tests used in the Rottingham study were used to assess the following cognitive domains: processing speed, verbal learning, memory, inhibition and word fluency as elements of executive functioning, visual-spatial ability, and psychomotor speed. The Mini-Mental Status Exam (MMSE) was also included as a dementia screener.
Key Findings
Cognitive deficits more than 20 years after treatment with CMF are similar in pattern to those found shortly after receiving chemotherapy. Moreover, objective assessments showed that women who had received CMF in the distant past performed significantly worse than the reference group in immediate (P=0.015) and delayed verbal memory (P=0.002), processing speed (P<0.001), executive functioning (P=0.013), and psychomotor speed (P=0.001). Subjectively, those women who had received CMF reported more memory complaints, yet fewer symptoms of depression than the reference group (P<0.001).
Practice Implications
Many studies have shown chemotherapy related cognitive impairment (CRCI), otherwise known as “chemo brain,” is a sequela of chemotherapy in breast cancer survivors.1,2 This study is the first to demonstrate cognitive impairment can be significant 2 decades after receiving a chemotherapy regimen, in this case CMF. The permanence of these symptoms for some patients should prompt us to prioritize brain recovery after chemotherapy treatment.
Many patients will mention perceived cognitive deficits, or “chemo brain,” associated with their chemotherapy treatment. The existence of “chemo brain” has long been shrouded in doubt within the medical community. It has only been systematically studied and verified in the last decade.3 For this reason, our understanding of how to prevent and/or treat it is in its early stages. We now know, however, that the extent of effect cognitive deficits have on a patient’s quality of life can be debilitating and that mere acknowledgment of “chemo brain,” or CRCI, from medical practitioners has some therapeutic value.4
What can we do to protect and improve cognitive function in patients receiving chemotherapy? Unfortunately, clinical trial data on agents used for prevention and treatment is very limited to date. Stimulants such as methylphenidate (Ritalin®/Concerta®) and modafinil (Provigil®), as well as erythropoietin, had some positive effects on preventing long-term cognitive decline in pediatric populations.5 A small study (N=82) of women with breast cancer receiving chemotherapy showed less cognitive decline with the use of modafinil.6 Of course, these drugs come with risks and/or side effects, and finding ways of achieving protection and repair of the brain with minimal risk is ideal.
There is some data emerging that shows that physical activity may lessen CRCI. Rats exposed to 5-FU and oxaliplatin had less cognitive decline if they engaged in physical activity (wheel running) immediately after receiving the drugs.7 In a case series of 4 women, yoga was shown to lessen cognitive decline over the course of 12 weeks.8 Whether the therapeutic benefit from yoga may be from the meditative aspect or the physical is not discernible. Separately, meditation has been proposed as a means of preventing and alleviating the cognitive decline from chemo.9
Cognitive-behavioral therapies are also gaining some evidence of efficacy. An early pilot study, published in 2007 by Dr. Robert Furguson, showed a cognitive-behavioral therapy he dubbed "memory and attention adaptation training (MAAT)" benefited women with cognitive deficits they reported had onset 8 years prior with chemotherapy.10 A recent clinical trial by his group failed to show significant benefit of MAAT on self-report of daily cognitive complaints, but it did show improvement in verbal memory with MAAT.11
There is some data emerging that shows that physical activity may lessen CRCI.
One study of mice that demonstrated cognitive impairment with 5-FU suggested coadministration with glucose attenuated the cognitive damage from the drug.12 In this same study, in vitro experimentation showed that chemotherapy led to a dose-dependent decrease in neural stem cells, and that insulin countered this effect. This suggests that regulating blood glucose, specifically during the time of chemotherapy infusion, may have some protective benefit. Ingesting something with caloric value is a simple, risk-free recommendation that can be made to patients.
The pathophysiological mechanisms of CRCI are still being elucidated and may depend on the drug used. In general, rodent models suggest a role for hampered neurogenesis, high oxidative stress, immune system/(neuro) inflammation, hypothalamic-pituitary-adrenal (HPA) axis damage, and alterations in blood flow.13 Although clinical trial data on natural agents to address CRCI is lacking, using these proposed mechanisms as a guide, there are numerous lifestyle, botanical, and nutraceutical interventions that may benefit patients.
For example, the inflammatory reactions that have been proposed as a contributing factor in pathogenesis of CRCI include events that result in higher levels of tumor-necrosis factor αand interleukin 1β (IL-1β).14 If this is the case, then it stands to reason that anti-inflammatory foods and botanicals may be beneficial. Curcumin, a reliable natural anti-inflammatory agent, has shown some benefit in patients with Alzheimer’s disease,15 suggesting it crosses into the brain. Higher C-reactive protein (CRP) levels, which reflect systemic inflammation, are associated with lower overall and disease-free survival in women with a history of breast cancer.16 Therefore, in addition to its effects on the brain, curcumin may lower systemic inflammation, which may lead to improved survival. In theory other natural anti-inflammatory agents able to cross the blood brain barrier, such as omega-3 fatty acids, boswelia serrata, and bromelain, should also be therapeutic.
Addressing the role of oxidative damage, a diet high in antioxidant-rich foods should have therapeutic effect. There are certainly adequate health benefits from a plant-based diet to recommend this for all patients, regardless of the lack of evidence for CRCI specifically. In addition, integrative practitioners should address HPA-axis abnormalities that may be involved in the complex of fatigue, cognitive decline, and depression that can occur post treatment. Foundational measures such as exercise to maximize oxygenation of the brain and proper restful sleep should be encouraged. Ultimately, optimizing the patient’s overall health may improve cognitive symptomology, and this holistic approach can be recommended without any downside risk.
Limitations
This was a fairly small study, with only 196 cases used for comparison to the reference group. It was also isolated to 1 geographic area, which may or may not represent a more heterogeneous population. This study looked at the specific combination of 3 agents—cyclophosphamide, methotrexate, and fluorouricil—and the effects of that specific combination on cognition. The results cannot be generalized for other drug regimes. They also cannot be extrapolated to what women with breast cancer may expect with current chemotherapy treatment, as CMF is seldom if ever used in the adjuvant setting anymore.
