Risk of dementia in colorectal cancer patients receiving chemotherapy: A nationwide cohort study

1

Introduction

With advances in treatments, a growing number of patients survive cancer, but treatments can be toxic to the central nervous system [1] . Many cancer patients experience cognitive impairment during or following chemotherapy [2] , known as “chemobrain” or “chemofog.” Among patients with non-central nervous system cancers, 65–75% showed worsening of cognitive function when chemotherapy was finished, and 35% continued to have cognitive impairment after that [3] . Chemotherapy-induced cognitive impairment affects not only memory, information processing, and executive function [2] but also the quality of life [4] . The mechanisms of chemobrain remain uncertain; the molecular mechanisms of neuroinflammation and neurodegeneration may be involved [5] . A genetic predisposition, such as the apolipoprotein E4 allele, the most prominent genetic risk factor for Alzheimer’s disease (AD), has a detrimental cognitive effect on those undergoing chemotherapy [6] . Psychological distress and health factors (i.e., age and cognitive reserve) may also contribute to chemobrain [7] . Therefore, the etiologies of chemobrain may be multifactorial and not limited to chemotherapy itself.

Although the chemobrain effect tends to become attenuated after the discontinuation of chemotherapy, whether chemotherapy leads to dementia in later life remains unclear. There are perplexing relationships between cancer and dementia. Several epidemiological studies demonstrated an inverse association between cancer and dementia [8] . A meta-analysis of these studies confirmed a weak inverse association existed, but survival bias remained an explanation for the observed association [9] . In contrast, a population-based prospective cohort study in the Netherlands demonstrated that mild cognitive impairment increased cancer risk [10] .

Several studies examined the role of chemotherapy in dementia using the cancer registry data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. In one study, diagnoses of dementia in the long term were more common among women with breast cancer who had undergone chemotherapy [11] . However, two other studies demonstrated that the dementia risk was not increased (or was even reduced) by chemotherapy in breast cancer patients [1213] . Regarding colorectal cancer (CRC), a study conducted by Du et al. determined that patients receiving chemotherapy had a higher risk of drug-induced dementia in those without mood disorders, but chemotherapy reduced the risks of AD, vascular dementia (VaD), and other types of dementia [14] . Another study by Akushevich et al. demonstrated that chemotherapy reduced the risks of AD, AD-related diseases, dementia (permanent mental disorder), and senile dementia in patients with CRC; in contrast, chemotherapy increased the risk of cerebral degeneration (excluding AD) [15] .

CRC is the most common cancer among male individuals and the second-most common cancer among female individuals in Taiwan; it is also the third-leading cause of cancer-related death 161718 . The long-term cognitive effect of chemotherapy on Taiwanese CRC patients has never been studied. Although the above studies using SEER-Medicare database provide insight into this question, whether their findings based on the multiethnic cohorts could be applied to Asians is unknown. In this study, we used a national healthcare computerized database and cancer registry of Taiwan to test the hypothesis: whether the risk of all-cause dementia was higher among Taiwanese patients with CRC who had received chemotherapy than among those who had not.