Post-chemotherapy cognitive impairment
Post-chemotherapy cognitive impairment (PCCI) (also known as chemotherapy-induced cognitive dysfunction or impairment, chemo brain, or chemo fog) describes the cognitive impairment that can result from chemotherapy treatment. Approximately 20–30% of people who undergo chemotherapy experience some level of post-chemotherapy cognitive impairment. The phenomenon first came to light because of the large number of breast cancer survivors who complained of changes in memory, fluency, and other cognitive abilities that impeded their ability to function as they had pre-chemotherapy.
Although the causes and existence of post-chemotherapy cognitive impairment have been a subject of debate, recent studies have confirmed that post-chemotherapy cognitive impairment is a real, measurable side effect of chemotherapy that appears in some patients. While any cancer patient may experience temporary cognitive impairment while undergoing chemotherapy, patients with PCCI continue to experience these symptoms long after chemotherapy has been completed. PCCI is often seen in patients treated for breast cancer, ovarian cancer, prostate cancer, and other reproductive cancers, as well as other types of cancers requiring aggressive treatment with chemotherapy.
The clinical relevance of PCCI is significant, considering the increasing number of long-term cancer survivors in the population, many of whom may have been treated with aggressive dosing of chemotherapeutic agents, or with chemotherapy as an adjuvant to other forms of treatment. In some patients, fear of PCCI can impact treatment decisions. The magnitude of chemotherapy-related cognitive changes and their impact on the activities of daily living are uncertain.
It generally affects about 10–40% of breast cancer patients, with higher rates among pre-menopausal women and patients who receive high-dose chemotherapy.
The systems of the body most affected by chemotherapy drugs include visual and semantic memory, attention and motor coordination. These effects can impair a chemotherapy patient's ability to understand and make decisions regarding treatment, perform in school or employment and can reduce quality of life. Survivors often report difficulty multitasking, comprehending what they have just read, following the thread of a conversation, and retrieving words.
Breast cancer survivors who were treated with chemotherapy may find it harder to perform tasks than survivors whose treatment was surgical. One study demonstrated that, a year after treatment, the brains of cancer survivors treated with chemotherapy had physically shrunk while those of people not treated surgically had not.
Post-chemotherapy cognitive impairment comes as a surprise to many cancer survivors. Often, survivors think their lives will return to normal when the cancer is gone, only to find that the lingering effects of post-chemotherapy cognitive impairment impede their efforts. Working, connecting with loved ones, carrying out day-to-day tasks—all can be very challenging for an impaired brain. Although post-chemotherapy cognitive impairment appears to be temporary, it can be quite long-lived, with some cases lasting 10 years or more.
The details of PCCI's causes and boundaries are not well known. Two major theories have been advanced: the direct effect of chemotherapy drugs on the brain, and the role of hormones in nervous system health.
PCCI is complex and factors other than the chemotherapeutic agents may impact cognitive functioning. Menopause, the biological impact of a surgical procedure with anesthesia, medications prescribed in addition to the chemotherapy, genetic predisposition, hormone therapy, emotional states (including anxiety, depression and fatigue), comorbid conditions and paraneoplastic syndrome may all co-occur and act as confounding factors in the study or experience of PCCI. Chemotherapy drugs thalidomide, the epothilones such as ixabepilone, the vinca alkaloids vincristine and vinblastine, the taxanes paclitaxel and docetaxel, the proteasome inhibitors such as bortezomib, and the platinum-based drugs cisplatin, oxaliplatin and carboplatin often cause chemotherapy-induced peripheral neuropathy, a progressive and enduring tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs. In most cases there is no known way of reducing the effects of chemotherapeutic agents related to taxanes, thalidomide and platinum-based compounds (oxaliplatin is a notable exception to the latter category—though it does cause PCCI its effects can be buffered by infusion of calcium and thought related to PCCI include the ability of the nerves to repair themselves, the ability of cells to excrete compounds, permeability of the blood–brain barrier, damage done to DNA including shortening of telomeres and cellular oxidative stress.
The importance of hormones, particularly estrogen, on cognitive function is underscored by the presence of cognitive impairment in breast cancer patients before chemotherapy is begun, the similarity of the cognitive impairments to several menopausal symptoms, the increased rate of PCCI in pre-menopausal women, and the fact that the symptoms can frequently be reversed by taking estrogen.
Fifty-six of the 132 chemotherapy agents approved by the FDA have been reported to induce oxidative stress. The drug doxorubicin (adriamycin) has been investigated as a PCCI-causing agent due to its production of reactive oxygen species. It has been investigated in an animal model with mice.
Research has revealed that neural progenitor cells are particularly vulnerable to the cytotoxic effects of chemotherapy agents. 5-fluorouracil has been demonstrated to reduce the viability of neural progenitor cells by 55-70% at concentrations of 1 μM, whereas cancer cell lines exposed to 1 μM of 5-fluorouracil were unaffected. Other chemotherapy agents such as BCNU, cisplatin, and cytarabine also displayed toxicity to progenitor cells in vivo and in vitro. This is a concern because neural progenitor cells are the major dividing cell population in the brain, giving rise to neurons and glia.
Due to the critical role the hippocampus plays in memory, it has been the focus of various studies involving post-chemotherapy cognitive impairment. The hippocampus is one of the rare areas of the brain that exhibits neurogenesis. These new neurons created by the hippocampus are important for memory and learning and require a brain-derived neurotrophic factor (BDNF) to form. 5-fluorouracil, a commonly used chemotherapy agent, has been shown to significantly reduce the levels of BDNF in the hippocampus of the rat. Methotrexate, an agent widely used in the chemotherapy treatment of breast cancer, has also displayed a long-lasting dose dependent decrease in hippocampal cell proliferation in the rat following a single intravenous injection of the drug. This evidence suggests that chemotherapy agent toxicity to cells in the hippocampus may be partially responsible for the memory declines experienced by some patients.
Deficits in visuo-spatial, visual-motor, and visual memory functions are among the symptoms seen in post-chemotherapy patients. There is evidence that this may be due to damage to the visual system rather than caused by cognitive deficits. In one study, 5-flouracil caused ocular toxicity in 25-38% of patients treated with the drug. Methotrexate also caused ocular toxicity in 25% of patients within 2–7 days of initial chemotherapy regimen with the drug. This evidence suggests that some of the visual-based cognitive deficits experienced by cancer survivors may be due to damage at the ocular level rather than cognitive processing, but most likely it is due to a synergistic effect on both systems.
Hypothesized treatment options include the use of antioxidants, cognitive behavior therapy, erythropoietin and stimulant drugs such as methylphenidate, though as the mechanism of PCCI is not well understood the potential treatment options are equally theoretical.
Modafinil, approved for narcolepsy, has been used off-label in trials with people with symptoms of PCCI. Modafinil is a wakefulness-promoting agent that can improve alertness and concentration, and studies have shown it to be effective at least among women treated for breast cancer.
While estrogen hormone supplementation may reverse the symptoms of PCCI in women treated for breast cancer, this carries health risks, including possibly promoting the proliferation of estrogen-responsive breast cancer cells.
Research on PCCI is limited, and studies on the subject have often been conflicting in results, in part due to differing means of assessing and defining the phenomenon, which makes comparison and synthesis difficult. Most studies have involved small samples, making generalization difficult. There has been a focus on PCCI in younger cancer patients. This makes it difficult to draw conclusions about PCCI in the elderly.
Several recent studies have advanced the field using neuroimaging techniques. In 2005, Dr. Masatoshi Inagaki used magnetic resonance imaging (MRI) to measure differences in brain volume between breast cancer patients exposed to chemotherapy and subjects unexposed. Subjects were tested at two periods: one year after surgery, and again at three years post-surgery. Results from the first year study found smaller volumes of gray and white matter in patients exposed to chemotherapy. However, in the three-year study, both groups of breast cancer survivors were observed to have similar gray and white matter volumes. Altered brain structure in chemotherapy patients provides explanation for cognitive impairment.
Another study in 2007 investigated the differences in brain structure between two adult, monozygotic twin females. One underwent chemotherapy treatment for breast cancer, while the other did not have cancer and was not treated with chemotherapy. MRI scans were taken of both twins' brain while taking part in a working memory task. Results found that twin A (exposed to chemotherapy) experienced a broader spatial extent of activation in her brain than twin B (not exposed to chemotherapy). Twin A also reported a greater difficulty than twin B in completing the memory activity. The authors of this study declare that commonly chemotherapy patients will self-report cognitive complaints, although they perform within normal limits on neuropsychological tasks. MRI scans may provide evidence for this occurrence. Chemotherapy patients may require greater volume of neural circuitry to complete neuropsychological tasks compared to others.
Positron Emission Tomography (PET) is also used to study post-chemotherapy cognitive impairment. In one study in 2007, scans were taken of patients exposed to adjuvant chemotherapy. Significantly altered blood flow in the brain was found, most notably in the frontal cortex and cerebellum. The most significant difference of blood flow was found in the inferior frontal gyrus. Authors report resting metabolism in this area is associated with performance on short term memory tasks.
While post-treatment studies suggest significant negative side effects of chemotherapy on cognition, other studies have indicated that there may be baseline vulnerability factors which could contribute to cognitive impairment development. Such factors may include menopausal status, surgery/anesthesia, stress, genetics and fatigue, among other suspected confounding variables.    
While frustrating, the ultimate outcome is very good: symptoms typically disappear in about four years.
The symptoms of PCCI were recognized by researchers in the 1980s, who typically described it as mild cognitive impairment subsequent to successful cancer treatment. Some authors say that it was identified primarily in breast cancer survivor and support groups as affecting a subset of individuals treated with chemotherapy, who attributed it to the effects of the medication taken to treat their cancers.
The term chemobrain appears in publications at least as early as 1997.
- Tannock IF, Ahles TA, Ganz PA, Van Dam FS (2004). "Cognitive impairment associated with chemotherapy for cancer: report of a workshop". J. Clin. Oncol. 22 (11): 2233–9. doi:10.1200/JCO.2004.08.094. PMID 15169812.
- Hede K (2008). "Chemobrain is real but may need new name". J. Natl. Cancer Inst. 100 (3): 162–3, 169. doi:10.1093/jnci/djn007. PMID 18230787.
- Matsuda T, Takayama T, Tashiro M, Nakamura Y, Ohashi Y, Shimozuma K (2005). "Mild cognitive impairment after adjuvant chemotherapy in breast cancer patients--evaluation of appropriate research design and methodology to measure symptoms". Breast Cancer 12 (4): 279–87. doi:10.2325/jbcs.12.279. PMID 16286908.
- Ness KK, Gurney JG. (2007). "Adverse late effects of childhood cancer and its treatment on health and performance.". Annu Rev Public Health. 28: 278–302. doi:10.1146/annurev.publhealth.28.021406.144049. PMID 17367288.
- Baudino B, et al. (December 2012). "The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients.". Q J Nucl Med Mol Imaging. 56 (6): 559–568. PMID 23172518.
- Taillibert S, Voillery D, Bernard-Marty C (November 2007). "Chemobrain: is systemic chemotherapy neurotoxic?". Curr Opin Oncol 19 (6): 623–7. doi:10.1097/CCO.0b013e3282f0e224. PMID 17906463.
- Hurria A, Somlo G, Ahles T (September 2007). "Renaming "chemobrain"". Cancer Invest. 25 (6): 373–7. doi:10.1080/07357900701506672. PMID 17882646.
- Kannarkat G, Lasher EE, Schiff D (December 2007). "Neurologic complications of chemotherapy agents". Curr. Opin. Neurol. 20 (6): 719–25. doi:10.1097/WCO.0b013e3282f1a06e. PMID 17992096. Retrieved 2008-04-24.
- Nelson CJ, Nandy N, Roth AJ (September 2007). "Chemotherapy and cognitive deficits: mechanisms, findings, and potential interventions". Palliat Support Care 5 (3): 273–80. PMID 17969831.
- Book: "Your Brain After Chemo: A Practical Guide to Lifting the Fog and Getting Back Your Focus" by Dan Silverman, MD, PhD and Idelle Davidson (Da Capo Lifelong Books, 2009). 
- Inagaki M, Yoshikawa E, Matsuoka Y, et al. (2007). "Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy". Cancer 109 (1): 146–56. doi:10.1002/cncr.22368. PMID 17131349.
- Silverman DH, Dy CJ, Castellon SA, et al. (2007). "Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy". Breast Cancer Res. Treat. 103 (3): 303–11. doi:10.1007/s10549-006-9380-z. PMID 17009108.
- del Pino BM. Chemotherapy-induced Peripheral Neuropathy. NCI Cancer Bulletin. Feb 23, 2010;7(4):6.
- Grisold W, Oberndorfer S, Windebank AJ. Chemotherapy and polyneuropathies. European Association of Neurooncology Magazine. 2012;12(1).
- Myers, J. S., Pierce, J., & Pazdernik, T. 2008. "Neurotoxicology of chemotherapy in relation to cyotkine release, the blood brain barrier, and cognitive impairment." "Oncology Nursing Forum", 35 (6): 916-920.
- Joshi G, Hardas S, Sultana R, St Clair DK, Vore M, Butterfield DA (February 2007). "Glutathione elevation by gamma-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin: Implication for chemobrain". J. Neurosci. Res. 85 (3): 497–503. doi:10.1002/jnr.21158. PMID 17171703.
- Tangpong J, Cole MP, Sultana R, et al. (January 2007). "Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain". J. Neurochem. 100 (1): 191–201. doi:10.1111/j.1471-4159.2006.04179.x. PMID 17227439.
- Han,R., Dietrich, J., Luebke, A., et al. 2008. "Systematic 5-flouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system." "Journal of Biology", 7 (4): 12.
- Dietrich, J., Ruolan, H., Yang, Y., Margot, M. P., Noble, M. 2006. "CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo." "Journal of Biology", 5 (7): 22.
- Mustafa, S., Walker, A., Bennett, G., & Wigmore, P. M. (2008). "5-flouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus." "The European Journal of Neuroscience", 28 (2): 323-330.
- Seigers, R., Schagen, S. B., Beerling, W., Boogerd, W., et al. 2008. "Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat." "Behavioral Brain Research", 186 (2): 168-175.
- Raffa, R. B. & Tallarida. 2010. "Effects on the visual system might contribute to some of the cognitive deficits of cancer chemotherapy-induced ‘chemo-fog’." "Journal of Clinical Pharmacy and Therapeutics", 35 (3): 249-255.
- Khaw P. T., Sherwood M. B., MacKay S. L., Rossi M. J. & Schultz G. 1992. "Five-minute treatments with ﬂuorouracil, ﬂoxuridine, and mitomycin have long-term effects on human Tenon’s capsule ﬁbroblasts." "Archives of Ophthalmology, 110: 1150-115.
- Al-Tweigeri T, Nabholtz J. M., & Mackey J. R. 1996. "Ocular toxicity and cancer chemotherapy." "Cancer", 78: 1359-1373.
- Doctors are finding it harder to deny "Chemobrain" The Virginian-Pilot October 2, 2007
- Modafinil Relieves Cognitive Chemotherapy Side Effects Psychiatric News, Stephanie Whyche, August 3, 2007 Volume 42 Number 15, page 31
- Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., et al. (2006). Smaller Regional Volumes of Brain Gray and White Matter Demonstrated in Breast Cancer Survivors Exposed to Adjuvant Chemotherapy. Cancer, 109 (1): 146-156.
- Ferguson, R. J., McDonald, B. C., Saykin, A. J. & Ahles, T. A. (2007). Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. Journal of Clinical Oncology, 25: 3866-3870.
- Silverman, D. H., Dy C. J., Castellon, S. A. (2007). Altered frontocortical cerebellar, and basal ganglia activity in adjuvant treated breast cancer survivors 5-10 years after chemotherapy. Breast Cancer Research and Treatment, 103 (3), 303-311.
- Cimprich B., Reuter-Lorenz P, Nelson J, Clark PM, Therrien B, Normolle D, Berman M, Hayes DF, Noll DC, Peltier S, Welsh RC. (2009). Pre-chemotherapy alterations in brain function in women with breast cancer. Journal of Clinical and Experimental Neuropsychology. 29, 1-8.
- Scherling C, Collins B, Mackenzie J, Bielajew C, Smith A. (2011) Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an FMRI study. Front Hum Neurosci. 2011 Nov 1;5:122. doi: 10.3389/fnhum.2011.00122.
- Scherling C, Collins B, Mackenzie J, Bielajew C, Smith A. (2012)Prechemotherapy differences in response inhibition in breast cancer patients compared to controls: a functional magnetic resonance imaging study. J Clin Exp Neuropsychol., 34(5),543-60. doi: 10.1080/13803395.2012.666227
- Scherling C, Collins B, Mackenzie J, Lepage C., Bielajew C, Smith A. (2012) Structural Brain Differences in Breast Cancer Patients Compared to Matched Controls Prior to Chemotherapy International Journal of Biology, 4(2). doi: 10.5539/ijb.v4n2p3
- Scherling, C.S.; Smith, A. Opening up the Window into “Chemobrain”: A Neuroimaging Review. Sensors 2013, 13, 3169-3203.
- "Chemo Brain". American Cancer Society. April 15, 2014. Retrieved November 27, 2015.
- Mayo Clinic Staff (February 2, 2013). "Chemo Brain". Mayo Clinic. Retrieved November 27, 2015.
- Brody, Jane (August 3, 2009). "The Fog That Follows Chemotherapy". Personal Health (column). The New York Times. p. D7. Retrieved November 27, 2015.