Abstract OT-05-01: Fine-sliced neurocognitive assessments and high-resolution neuroimaging biomarkers to diagnose cancer- and chemotherapy-induced cognitive deficits (CCICD) - a pilot study
Authors: Kanchna Ramchandran, Sneha Phadke, Sarah Mott, Grerk Sutamtewagul, Mark Karwal, Vince Magnotta
Journal: Cancer Research (2021)

Abstract Background: Significant progress has been made in cancer survival, however there is much room for improvement in supportive cancer care. “Chemo-brain” is the lay language that some patients use to describe a cognitive fog or mental fuzziness that they experience soon after chemotherapy (CT) and that can last more than a decade after CT has ended. In this study, we examine the notion of accelerated cognitive aging as a potential side effect of cytotoxic CT.While CCICD has been widely researched, its underlying biological mechanisms are yet to be sufficiently elucidated. The long-range goals of this study are to (a) yield clinically valid diagnostic criteria for CCICD by the identification of fine-sliced neurocognitive measures that can reliably capture within-subject, nuanced, cognitive changes pre/post CT; and (b) identify brain-based biomarkers that can leverage future systemic therapies or adjunctive medications that are neuroprotective. Trial design: The study takes advantage of greater clarity offered by high-resolution neuroimaging (7Tesla) to delve into biomarkers associated with the neurotoxic effects of the common chemotherapeutic agents doxorubicin, paclitaxel, docetaxel, and cyclophosphamide on brain metabolism and iron homeostasis, which may result in CCICD. We innovate by harnessing magnetic resonance spectroscopy (MRS) together with quantitative susceptibility mapping (QSM) and diffusion tensor imaging (DTI), a trio that has rarely been combined in 7T imaging, to uncover biomarkers related to CCICD. In this high-resolution imaging environment, we hope to individually isolate and track changes in key neuronal metabolites such as glutamate and glutamine using MRS (pre- and post-CT), in a prospective, longitudinal study. At these two time-points, we simultaneously use QSM to identify regions of increased iron deposits (associated with doxorubicin) in the brain along white matter tracts as well as DTI to assess white matter degeneration.We selected fine-sliced measurements of cognitive updating, mental flexibility and impulse control, the key executive function (EF) deficits associated with CCICD. These and other global EF measures are administered pre/post-CT (within a period of 4-6 months), while assessments of depression, anxiety, sleep, and pain will be administered via a weekly online questionnaire during CT.Eligibility criteria: Eligible patients are adults (age ≥18) with either early stage HER2 negative breast cancer or diffuse large B-cell lymphoma who will receive curative-intent combination CT, to include cyclophosphamide. Patients are excluded if they have a prior history of cancer diagnosis or treatment. Patients would have to be 7T MRI compatible.Specific Aims: To obtain preliminary estimates of the change in EF measures, brain metabolite, iron concentrations, and white matter degeneration in patients pre- and post-CT, to inform a subsequent larger trial.Statistical methods: The proposed sample (N=9) size achieves 74.8% power to detect a 1 SD change with a significance level of 0.05 using a two-sided, one-sample t-test for the pairwise difference. Estimates and 95% confidence intervals will be reported. Additionally, the relationship between executive function, brain metabolite, iron concentrations and white matter degeneration will be explored. Present and Target accrual: Accrual has thus far been delayed, partially due to due to COVID-19 restrictions on clinical research, beginning in March 2020. Target accrual is 9 patients.Contact information: Kanchna-ramchandran@uiowa.edu, Phone: 319-356-0535. Citation Format: Kanchna Ramchandran, Sneha Phadke, Sarah Mott, Grerk Sutamtewagul, Mark Karwal, Vince Magnotta. Fine-sliced neurocognitive assessments and high-resolution neuroimaging biomarkers to diagnose cancer- and chemotherapy-induced cognitive deficits (CCICD) - a pilot study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-05-01.