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Original Investigation |

Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors

Shelli R. Kesler, PhD1; Douglas W. Blayney, MD2
[+] Author Affiliations
1Department of Neuro-oncology, University of Texas MD Anderson Cancer Center, Houston
2Division of Medical Oncology, Stanford University School of Medicine, Stanford, California
JAMA Oncol. 2016;2(2):185-192. doi:10.1001/jamaoncol.2015.4333.
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Published online

Importance  Chemotherapy exposure is a known risk factor for cancer-related cognitive impairments. Anthracycline-based regimens are commonly used chemotherapies that have been shown to be associated with cognitive impairment and brain changes in clinical studies.

Objective  To directly compare the effects of anthracycline and nonanthracycline regimens on cognitive status and functional brain connectivity.

Design, Setting, and Participants  In this observational study, we retrospectively examined cognitive and resting state functional magnetic resonance imaging data acquired from 62 primary breast cancer survivors (mean [SD] age, 54.7 [8.5] years) who were more than 2 years off-therapy, on average. Twenty of these women received anthracycline-based chemotherapy as part of their primary treatment, 19 received nonanthracycline regimens, and 23 did not receive any chemotherapy. Participants were enrolled at a single academic institution (Stanford University) from 2008 to 2014, and the study analyses were performed at this time.

Main Outcomes and Measures  Cognitive status was measured using standardized neuropsychological tests, and functional brain connectivity was evaluated using resting state functional magnetic resonance imaging with a focus on the brain’s default mode network.

Results  The anthracycline group demonstrated significantly lower verbal memory performance including immediate recall (F = 3.73; P = .03) and delayed recall (F = 11.11; P < .001) as well as lower left precuneus connectivity (F = 7.48; P = .001) compared with the other 2 groups. Patient-reported outcomes related to cognitive dysfunction (F = 7.27; P = .002) and psychological distress (F = 5.64; P = .006) were similarly elevated in both chemotherapy groups compared with the non–chemotherapy-treated controls.

Conclusions and Relevance  These results suggest that anthracyclines may have greater negative effects than nonanthracycline regimens on particular cognitive domains and brain network connections. Both anthracycline and nonanthracycline regimens may have nonspecific effects on other cognitive domains as well as certain patient reported outcomes. Further research is needed to identify potential methods for protecting the brain against the effects of various chemotherapeutic agents.

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Default Mode Network Connectivity

A, The group treated with anthracycline demonstrated significantly lower intrinsic functional connectivity between the left precuneus (LPCN) and several other default mode network regions compared with the nonanthracycline group. B, The anthracycline group also showed lower connectivity in these regions compared with the no-chemotherapy (no-CT) group. C, The nonanthracycline group showed lower connectivity between LPCN and right middle cingulate (RMCG) compared with the no-chemotherapy group. Color bars indicate effect size; LMEF, left medial frontal; LLP, left lateral parietal; RHIP, right hippocampus; RPCG, right posterior cingulate; RSFG, right superior frontal gyrus. Connectivity data are shown overlaid on a smoothed Montreal Neurological Institute space anatomic template using BrainNet Viewer.75

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