Cancer is challenging to treat. Despite recent advances in earlier diagnostics and targeted therapy, radiotherapy and chemotherapy remain the mainstream treatments to complement surgery.
Chemotherapy is an umbrella term referring to multiple aggressive drugs administered to cancer patients. What unites them is the way they work by targeting fast dividing cells in the body. The therapy can reduce the size of tumors and/or patient’s symptoms. In some cases, chemotherapy can even destroy all cancer cells in the body and lead to complete recovery. But despite its relative efficiency, chemotherapy is associated with a large number of undesirable and often severe side effects. Cancer cells are not the only fast dividing cells in the body, and the lack of specificity associated with the use of chemotherapeutic agents means that normal non-cancerous cells can also be targeted and killed by these drugs.
The most affected tissues include bone marrow, hair follicles, the cells of gastrointestinal tract and reproductive cells. But other organs and tissues such as the brain can also become affected by chemotherapy.
It is well know that chemotherapy can cause decline in cognitive functions. There is a term used for that cognitive impairment – chemobrain. The condition is characterized by reduced cognitive abilities, impaired motor functions, loss of memory, and weaker attention. At least some symptoms of cognitive decline are often observed after chemotherapy and can cause severe problems for patients.
The exact mechanisms behind the chemobrain phenomenon are poorly studied. Researchers believe that genetic factors play some role in cognitive decline after chemotherapy. These genetic risk factors may include weaker mechanisms of DNA repair, lower capacity for repairing neurons, and lower activity of neurotransmitters in the brain.
Impairment of cognitive functions can be expected in a short period after chemotherapy, but in most cases it disappears quickly. However, in some cases the impairment persists and can last for a long period of time. In one recent study, a mouse model was used to test the effects of chemotherapy on the cognitive functions in a longer run (three months in this particular case). The results clearly show that animals subjected to chemotherapy agents learned new tasks much slower. Their neurons lived a shorter period of time and differentiated more slowly. This study was designed to test the effects of drugs given to post-menopausal women undergoing chemotherapy treatment for breast cancer. The study also provided evidence that omega-3 fatty acids do not have any positive effect on reducing the symptoms of cognitive impairment after chemotherapy.
Another study that was also conducted using laboratory animals focused on the changes in level of neurotransmitters, especially dopamine and serotonin in the brain. Researchers used fast-scan cyclic voltammetry to detect levels of the neuromediators. They compared the levels of these neurotransmitters in the brains of mice which were receiving chemotherapy, and in the brains of the control group of mice that did not receive chemotherapy. The results demonstrated that the release of serotonin and dopamine is impaired after chemotherapy.
Human studies of chemobrain focused mostly on breast cancer sufferers, and the data described below were gathered on this group of patients. There are good reasons to believe that the results will be similar for other types of cancer too.
One study compared the total brain volume in individuals with breast cancer that used chemotherapy and the total brain volume in the control group without cancer. The study was important as it examined the long-term consequences of chemotherapy on human brain volume. Researchers measured the total brain volume 21 years after chemotherapy. Their results show a significant loss of total brain volume and a loss of grey brain matter. The white matter remained mainly unaffected. The scientists think that this loss of total brain volume and grey matter may lead to the development of cognitive impairment.
A similar research study was conducted on another group of patients with breast cancer. The study mainly focused on the changes in the brain’s white and grey matter after chemotherapy. The measurements were done 9 years after the chemotherapy. Multimodal magnetic resonance imaging was used to detect any changes. The findings show that there is a link between chemotherapy and changes in the structure of the human brain. Chemotherapy causes damage to white matter, specifically axonal degeneration and demyelination, but also it is harmful for the grey matter.
Another study was conducted on almost 200 female breast cancer patients that had chemotherapy 20 years ago. Researchers used neuropsychological tests to determine the level of cognition among these patients and in a cancer-free control group. The results showed significantly worse scores in the chemotherapy group compared to the control group. The cancer patients had problems with verbal memory and psychomotor speed and functioning. These problems are the same as those occurring shortly after chemotherapy. This indicates that the patterns of cognitive impairment do not change even after a long period of time post-chemotherapy.
A very recent study compared the integrity of white matter in females with breast cancer before and after chemotherapy. Scientists assessed and compared the cognition scores before and after the treatment. Also, they performed the same tests on a group of females with breast cancer which did not undergo chemotherapy. The findings show significantly weaker test results in the chemotherapy group. In this group, there were notable changes in the white matter in frontal, parietal, and occipital tracts.
Although cancer chemotherapy does work very well for many cancer patients, most certainly it can also cause dangerous and permanent brain damage. Chemotherapy can change how the brain works through changing the level of neurotransmitters. It can even change the structure of the brain, reducing its volume and reducing grey matter in the brain. Eventually this leads to cognition impairment which is strongest shortly after finishing the chemotherapy but can persist for decades after.
References
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Deprez, S., Amant, F., Smeets, A., Peeters, R., Leemans, A., et al. (2012) Longitudinal Assessment of Chemotherapy-Induced Structural Changes in Cerebral White Matter and Its Correlation With Impaired Cognitive Functioning. JCO, 30(3): 274-281. doi: 10.1200/JCO.2011.36.8571
de Ruiter, M. B., Reneman, L., Boogerd, W., Veltman, D. J., Caan, M., et al. (2012) Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: Converging results from multimodal magnetic resonance imaging. Hum. Brain Mapp., 33: 2971–2983. doi:10.1002/hbm.21422
Kaplan, S. V., Limbocker, R. A., Gehringer, R. C., Divis, J. L., Osterhaus, G. L., et al. (2016) Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin. ACS Chem. Neurosci., 7 (6): 689–699. DOI: 10.1021/acschemneuro.5b00029
Koppelmans, V., Breteler, M. M. B., Boogerd, W., Seynaeve, C., Gundy, C. and Schagen, S. B. ( 2012) Neuropsychological Performance in Survivors of Breast Cancer More Than 20 Years After Adjuvant Chemotherapy. JCO, 30(10): 1080-1086. doi: 10.1200/JCO.2011.37.0189
Koppelmans, V., de Ruiter, M.B., van der Lijn, F. et al. (2012) Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. Breast Cancer Res Treat, 132: 1099. doi:10.1007/s10549-011-1888-1
Rendeiroa, C., Sheriffa, A., Bhattacharyaa, T. K., Gogolaa, J.V., Baxterd, J.H., et al. (2016) Long-lasting impairments in adult neurogenesis, spatial learning and memory from a standard chemotherapy regimen used to treat breast cancer. Behavioural Brain Research, 315: 10-22. doi: 10.1016/j.bbr.2016.07.043
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