Chemotherapy-related cognitive impairment: does integrating complementary medicine have something to add? Review of the literature
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- Avisar, A., River, Y., Schiff, E. et al. Breast Cancer Res Treat (2012) 136: 1. doi:10.1007/s10549-012-2211-5
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Chemotherapy-related cognitive impairment is a phenomenon of cognitive decline that some patients experience during and after chemotherapy. The prevalence of chemotherapy-related cognitive impairment in cancer survivors ranges from 14 to 85 %. Memory loss and lack of concentration are the most frequent symptoms, often resulting in deterioration of daily functioning and a decreased quality of life. Despite ongoing research on chemotherapy-related cognitive impairment, a clear understanding of the underlying mechanisms of the neurotoxicity induced by chemotherapy and the factors that determine a patient’s vulnerability are still lacking. We review current knowledge regarding the etiology of chemotherapy-related cognitive impairment, risk factors, conventional therapy, coping strategies, and potential complementary and integrative medicine treatments. Complementary and integrative medicine modalities that may improve chemotherapy-related cognitive impairment include mind–body techniques and acupuncture, as well as nutrition and herbal therapies. Studies on these modalities have not directly tested the hypothesis of modifying chemotherapy-related cognitive impairment and were done on different disorders of memory loss and lack of concentration. We recommend conducting further research on the potential role of complementary and integrative medicine modalities in the treatment and prevention of chemotherapy-related cognitive impairment.
KeywordsChemotherapy-related cognitive impairmentIntegrative medicineComplementary alternative medicineSupportive careCancer
Chemotherapy-related cognitive impairment is a phenomenon of cognitive decline that patients may experience during or after chemotherapy . Memory loss and lack of concentration and attention are the most frequent symptoms encountered . Other complaints include difficulties with multi-tasking , organizing and planning , as well as difficulty in thinking, and other subtle cognitive changes . These symptoms are mostly transient , but may persist for several years . Chemotherapy-related cognitive impairment was first described in the 1970s, but significant recognition of the phenomenon emerged only in the late 1990s [7, 8]. It is now one of the most common post-treatment symptoms reported by breast cancer survivors and may also represent the most troublesome symptom . Evidence suggests that chemotherapy-related cognitive impairment is of significant concern to patients  and has become a major quality-of-life issue for survivors [3, 5, 7] and estimates of its frequency range from 14 to 85 % of patients .
For some cancer survivors, the cognitive effects of chemotherapy linger on for years after treatment and even mild impairment may impact the survivors’ ability to function, both at home and at work [7, 9]. Subsequently, the impairment has a major deleterious effect on the economic, emotional, and interpersonal aspects of daily life . Due to the rise in the number of cancer survivors, chemotherapy-related cognitive impairment is expected to be encountered more frequently in the future . Currently, there are insufficient conventional therapeutic options available for chemotherapy-related cognitive impairment and limited data regarding its etiology, prevention, and treatment.
Etiology of chemotherapy-related cognitive impairment
Despite ongoing research on chemotherapy-related cognitive impairment, a clear understanding of the underlying mechanisms of the neurotoxicity induced by chemotherapy and the factors that determine a patient’s vulnerability are still lacking [2, 7]. The risk of chemotherapy-related cognitive impairment appears to be dose dependent [10, 11]. One of the main hypotheses is damage to the brain white matter microstructure through direct neurotoxicity or indirect effects such as oxidative stress or vascular damage [12, 13]. This hypothesis is supported by reports of patients who received high-dose chemotherapy leading to cerebral white matter damage . Recently, new data from a study done with breast cancer patients showed an association between longitudinal changes in cognitive functioning and cerebral white matter integrity, demonstrated by using magnetic resonance diffusion tensor imaging after chemotherapy treatment .
An association between chemotherapy-related cognitive impairment and specific chemotherapy agents has been described also. Intrathecal methotrexate may cause cognitive dysfunction in children with leukemia [15–17] and medulloblastoma . Methotrexate, cytarabine, and ifosfamide are primarily known for their central neurotoxic side effects, which include aseptic meningitis, cognitive deficits, hemiparesis, aphasia, and progressive dementia . Another chemotherapeutic agent that may induce serious neurological side effects is adriamycin. Patients treated with adriamycin may develop transient memory loss and an inability to handle complex tasks , and may complain of forgetfulness, lack of concentration, and dizziness . Significant increases in levels of protein oxidation and lipid peroxidation were measured in brains isolated from mice, 72 h post-injection of adriamycin [21, 22]. The systemic administration of adriamycin also induces tumor necrosis factor-alpha (TNF-alpha), which leads to production of reactive oxygen species and reactive nitrogen species in the brain. Circulating TNF also causes mitochondrial dysfunction, leading to the activation of apoptotic pathways in the brain . While adriamycin itself does not cross the blood–brain barrier, adriamycin induces peripheral increases in TNF-alpha which crosses the blood–brain barrier and leads to inflammation and oxidative stress in the brain; this is a likely contributing factor to the observed decline in cognition .
Another potential cognitive impairment-associated chemotherapy is 5-fluorouracil (5-FU) which readily crosses the blood–brain barrier. The neurologic toxicity of 5-FU, including an ataxic cerebellar syndrome, is well described . Mustafa et al.  reported that 5-FU caused marginal disruption in spatial working memory and significantly reduced brain-derived neurotrophic factor levels in the hippocampus, indicating alterations in neurotrophin levels and neurogenesis. Other studies utilizing brain imaging have demonstrated changes in brain metabolism in patients treated with chemotherapy [7, 26].
The etiology of chemotherapy-related cognitive impairment may be caused by many cancer-related factors as well (e.g., disease site, stage, paraneoplastic phenomenon, elevated levels of pro-inflammatory cytokines), or patient-related factors such as affective distress and social support [8, 27, 28]. The possible development of chemotherapy-related cognitive impairment may be attributed to age, education, intelligence quotient, debilitating symptoms of advanced cancer or chemotherapy side effects (e.g., fatigue, depression, anxiety), co-morbidities (e.g., menopausal symptoms induced by chemotherapy or oophorectomy ), impact of surgery and anesthesia, and supportive care medications .
Saykin et al.  studied patients with breast cancer and reported preliminary results of disrupted pattern of brain activation with less overall activity in bilateral prefrontal regions 1 month after chemotherapy. This finding may be related to the role of frontal and prefrontal activation in regulating recall, executive functions, attention, and motor planning. In another study, Silverman et al.  found that women who received chemotherapy had a lower resting brain metabolism compared to women with breast cancer who had never had chemotherapy or healthy control subjects. In this study, women received a delayed-recall memory test while brain metabolic activity was observed through positron emission tomography imaging. The researchers found that questions activated a larger portion of the frontal cortex in the group of women who had persistent memory problems following chemotherapy compared to untreated women. This is indicative of central nervous system dysfunction necessitating the need to recruit a larger number of neuronal networks to perform the memory recall task.
In recent study reporting a 3-year longitudinal comparison of breast cancer survivors treated with chemotherapy or radiotherapy to non-cancer controls, significant differences were seen in some of the cognitive functions between the two treatment groups compared to the controls that lasted even after 3 years of follow-up. Interestingly, the ability to improve cognitive functions over time was low, not only just in the chemotherapy group, but also in the radiotherapy-only group, indicating mechanisms other than chemotherapy that may damage cognitive functions. In this study, hormone therapy was not associated with changes in cognitive functions over time .
Possible treatment and coping strategies
Current proposed chemotherapy-related cognitive impairment therapeutics is based merely on hypothesized mechanisms of its etiology. Proposed interventions include pharmacological treatment, rich antioxidant nutrition, and various cognitive techniques.
The pharmacological approach involves giving a mild stimulant to patients who have just completed chemotherapy. A pilot study by Kohli et al. on 68 participants who complained of memory problems 2 years after breast cancer chemotherapy indicates that modafinil, a medication approved for fatigue-related to sleep apnea, improves short-term memory in these patients. Women who received modafinil showed modest but statistically significant improvement in cognitive testing, compared with controls .
Antioxidant intervention may prevent cognitive dysfunction originating from oxidative stress induced in the brain by some chemotherapy agents . A recent study was designed to test the hypothesis that, by elevating brain levels of glutathione, the brain would be protected against oxidative stress in adriamycin-injected mice. Gamma-glutamyl cysteine ethyl ester (GCEE), a precursor of glutathione, injected i.p. 4 h prior to injection of adriamycin led to significantly decreased protein oxidation and lipid peroxidation in subsequently isolated mice brains compared with brains isolated from adriamycin-injected mice without GCEE. These results indicate a potential pharmacological prevention measure of brain cognitive dysfunction in patients receiving adriamycin chemotherapy . However, it is necessary to consider the potential clinical interaction between antioxidants and chemotherapy-dependant agents.
Until now, few efforts have been made to study ways of providing cognitive rehabilitation for those suffering from chemotherapy-related cognitive impairment [4, 33]. Nowadays, support for patients who are concerned about or experiencing chemotherapy-related cognitive impairment may be provided by support groups, neuropsychologists, and cognitive retraining programs . Cognitive rehabilitation was tested in a pilot study by Ferguson et al., with 29 breast cancer survivors with lingering memory problems. The team used “an old behavioral technique called ‘self-instructional training’” which involves talking through a set of instructions. The researchers modified the technique and renamed it Memory and Attention Adaptation Training. The patients’ scores improved during the study, and they rated the technique as helpful in compensating for memory problems .
An in-depth qualitative study of 74 breast cancer survivors aimed at a better understanding of the survivors’ own coping strategies. Some women tried to counteract the effects of chemotherapy by keeping their minds active, while others more-or-less accepted the limitations that cognitive impairment placed on their lives and resigned themselves to having a diminished cognitive capacity . Participants used a variety of coping strategies that included journals to record everything they needed to do (“writing everything down”) [5, 34]. Others trained themselves to put daily-life objects, such as keys, in specific places .
Recent interventional studies examined whether a regular exercise program can improve cognitive functioning following chemotherapy in cancer survivors (http://clinicaltrials.gov/ct2/home).
Potential role of complementary and integrative medicine in chemotherapy-related cognitive impairment
In the past decade, complementary/integrative medicine has been included more frequently in conventional clinical and academic institution services and is regarded as integrative medicine. The Consortium of Academic Health Centers for Integrative Medicine in North America defined complementary/integrative medicine as “the practice of medicine that reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, healthcare professionals and disciplines to achieve optimal health and healing” (http://www.ahc.umn.edu/cahcim/about/home.html).
In this review, we summarize the potential beneficial effects of some complementary/integrative medicine modalities in the prevention and treatment of chemotherapy-related cognitive impairment. There is limited data about the prevention and treatment of cognitive disorders among patients with cancer with complementary/integrative medicine currently. Preliminary data suggest that acupuncture may be helpful in a range of psychoneurological issues in patients with chemotherapy-related cognitive impairment . Clues for this potential can be found in several studies. Acupuncture combined with point-injection therapy may improve cranial nerve function as well as traumatic brain injury symptoms in individuals with post-traumatic coma . Scalp acupuncture combined with language therapy may have a positive effect on language development in children with autism . In vivo studies on cerebral multi-infarction rats suggest that acupuncture improves cognitive impairment [38, 39], prevents oxidative stress, and exerts beneficial effects on spatial memory . Also, acupuncture improved cognitive deficits and regulated the brain cell proliferation of senescence-accelerated mouse prone 8 (SAMP8) mice .
Another complementary/integrative medicine modality with a potential chemotherapy-related cognitive impairment role is herbal medicine, one of the common practices in patients with dementia and MCI  but never tested in chemotherapy-related cognitive impairment. A traditional Chinese herbal formula, Ba Wei Di Huang Wan, was found to significantly improve cognitive functioning as assessed by the Mini-Mental State Examination (MMSE) in patients with dementia , although MMSE results were unchanged after treatment with the Chinese herbal medicine Yi-Gan San . An extract from the leaves of Gotu Kola (Centella asiatica) has been used as an alternative medicine for memory improvement in the Indian ayurvedic system of medicine for a long time, and may improve memory impairment in patients with Alzheimer’s disease . The Japanese herbal remedies, kami-untan-to and hachimi-jiou-gan, have been shown to be beneficial for Alzheimer’s disease treatment in some pilot studies . Another promising herbal preparation is the antioxidant flavonoid Pycnogenol which may improve working memory among healthy elderly .
Ginkgo biloba, a traditional Chinese-driven herb that gained popularity in the West in relation to the treatment of dementia, may improve neurologic symptoms in patients with Alzheimer’s disease  and dementia [47, 48]. Of note in this population, Ginkgo may increase bleeding risk with coumadin and high-dose aspirin intake [49–51]. Clinical indicators of a beneficial response include memory, information processing, and activities of daily living . However, Ginkgo did not prevent dementia in elderly people [52–54], and no beneficial cognitive effect of Ginkgo treatment was found in a randomized control trial in patients with dementia [55, 56]. Ginkgo may have a role in treating impairment in memory and cognitive speed associated with traumatic brain injury . Ginkgo is widely used to alleviate or delay the progress of age-related cognitive impairment , and showed a positive effect in the treatment of memory and information processing impairments associated with normal aging . Preliminary evidence suggests that there are responders and non-responders to the cognitive effects of Ginkgo among healthy subjects . However, a positive effect of Ginkgo on cognition is not proven by data from rigorous clinical trials [55–57]. Likewise, no convincing evidence from a randomized control trial for a positive effect of Ginkgo ingestion was found on cognitive function in healthy young people .
Meditation may have neuroprotective effects [60–62] and reduce age-related cognitive decline [61, 62]. Potential mind–body techniques include mindfulness meditation training, which may improve behavioral and neurocognitive impairments as well as anxiety and depressive symptoms in adults and adolescents with ADHD . The Flexyx Neurotherapy System, which combines biofeedback and photic stimulation, may produce improvements in cognitive functioning, depression, and fatigue in subjects with traumatic brain injuries .
A specific form of manual therapy, named haptotherapy, was found to improve both perceived cognitive and social functioning and general quality of life of patients with cancer treated with chemotherapy in day care centers .
The co-morbidity of chemotherapy-related cognitive impairment with emotional distress and potential emotional-induced chemotherapy-related cognitive impairment are other fields for potential intervention. It is imperative to screen patients for anxiety, depression, fatigue, and insomnia and to treat them appropriately [4, 9]. There is well-documented evidence for the increasingly widespread use of complementary/integrative medicine in the treatment of psychiatric symptoms . Beneficial complementary/integrative medicine therapies in the treatment of potential distress-derived chemotherapy-related cognitive impairment may be acupuncture , massage therapy, and mind–body techniques such as meditation, relaxation, and biofeedback . Literature reviews have found preliminary data to support the efficacy of acupuncture in the treatment of anxiety [68, 69]. Meditation programs have been shown to reduce stress and to improve mood and sleep quality in patients with cancer . Hypnosis is useful in the treatment of post-traumatic stress disorder  and in reducing emotional distress associated with medical procedures [71–74]. Relaxation training proved to reduce depression, anxiety, and hostility in cancer patients in acute medical treatment  and was found to be a beneficial treatment for anxiety [76, 77], panic disorders , emotional eating , and dental fear . Herbal and nutritional supplements that may improve depression include omega-3 fatty acids  and St John’s wort (Hypericum perforatum) [48, 66]. Nevertheless, serious concerns exist about St. John’s wort and its interactions with several conventional drugs , including chemotherapy [80, 81]. Serious safety concerns also exist about kava kava (Piper methysticum) [48, 66], one of the extensively studied herbs regarding anxiety treatment . Severe kava-related adverse events include dermatological reactions, neurological complications, elevated liver enzymes, and liver failure. A possible interaction between kava and benzodiazepines has also been reported .
Safety of complementary/integrative medicine treatments
In recent years, the medical community has become more aware of the importance of data concerning complementary/integrative medicine safety, relating to toxicity, adverse effects, and potential interactions with drugs, herbs, and nutritional supplements. A large number of complementary/integrative medicine therapies (e.g., acupuncture, mind–body techniques) do not include pharmacological substances which may potentially interact with conventional drugs as well as chemotherapy. Nevertheless, using herbal medicine may be associated with adverse events or drug interactions. Many herbal and biological preparations are not regulated by government agencies, such as the Food and Drug Administration . The use of complementary/integrative medicine supplements by patients with cancer, who frequently purchase these medications without seeking medical advice, imposes the risk of drug interactions . Prevalent self-administered complementary/integrative medicine use among adults was also reported in patients with common neurological conditions , patients admitted for elective surgery , and in patients with dementia and MCI . A call for better communication with patients and complementary/integrative medicine providers in order to secure safety and decrease drug–herb interactions is being promoted by increasing numbers of complementary/integrative medicine physicians [88, 89].
Complementary/integrative medicine therapies may have a potential role in chemotherapy-related cognitive impairment treatment and should be considered for further robust research. There is a need for adequately powered randomized controlled studies, especially in the field of mind–body, herbal medicine, and acupuncture. Research should probably include multi-modality complementary/integrative medicine therapies or a combination of appropriate conventional treatment and complementary/integrative medicine. Although these studies are needed, the possibility of their being planned is low. They can be established only with public interest by an organization such as the US National Center for Complementary and Alternative Medicine, but utilization of complementary and alternative treatments by the general public is relatively low.
The authors thank Prof. Aaron Polliack for his contribution to the manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.