Evaluating the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on perceived ability to work in breast cancer survivors during the first year post-treatment.

PURPOSE: To describe the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on breast cancer survivors' (BCS) perceived ability to work post-treatment. METHODS: The sample included 22 chemotherapy-treated (Ctx+) and 22 chemotherapy-naïve (Ctx-) female BCS. Data was collected at the following three time points: baseline (post-surgery, pre-chemotherapy), 1 month (1 M) post-chemotherapy, and approximately 1 year (1 Y) later. The presence, frequency, number, and severity of CIPN-sx were self-reported using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire (FACT/GOG-Ntx) version 4, a validated 11-item CIPN measure. Perceived ability to work was measured using an item from the Functional Well-Being subscale of the FACT/GOG-Ntx. RESULTS: At 1 Y, more than 50 % of Ctx+ reported discomfort, numbness, or tingling in their hands or feet; weakness; or difficulty feeling small objects. The presence, number, and severity of these symptoms were correlated with being less able to work for Ctx+ at 1 M but not 1 Y. Results of a regression analysis using CIPN-sx to predict work ability found that models combining (1) hand numbness and trouble feeling small objects, (2) trouble buttoning buttons and trouble feeling small objects, (3) foot numbness and foot pain, (4) foot numbness and trouble walking, and (5) trouble hearing and hand pain each predicted survivors who were "not at all" able to work at 1 M. CONCLUSIONS: Unresolved CIPN-sx may play a role in challenges working for BCS post-treatment. These findings highlight the need for research to explore the impact that CIPN-sx have on BCS' ability to work, as well as the development of interventions to improve work function in BCS with CIPN-sx.

Cerebral Perfusion and Gray Matter Changes Associated With Chemotherapy-Induced Peripheral Neuropathy.

PURPOSE: To investigate the longitudinal relationship between chemotherapy-induced peripheral neuropathy (CIPN) symptoms (sx) and brain perfusion changes in patients with breast cancer. Interaction of CIPN-sx perfusion effects with known chemotherapy-associated gray matter density decrease was also assessed to elucidate the relationship between CIPN and previously reported cancer treatment-related brain structural changes. METHODS: Patients with breast cancer treated with (n = 24) or without (n = 23) chemotherapy underwent clinical examination and brain magnetic resonance imaging at the following three time points: before treatment (baseline), 1 month after treatment completion, and 1 year after the 1-month assessment. CIPN-sx were evaluated with the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity four-item sensory-specific scale. Perfusion and gray matter density were assessed using voxel-based pulsed arterial spin labeling and morphometric analyses and tested for association with CIPN-sx in the patients who received chemotherapy. RESULTS: Patients who received chemotherapy reported significantly increased CIPN-sx from baseline to 1 month, with partial recovery by 1 year (P < .001). CIPN-sx increase from baseline to 1 month was significantly greater for patients who received chemotherapy compared with those who did not (P = .001). At 1 month, neuroimaging showed that for the group that received chemotherapy, CIPN-sx were positively associated with cerebral perfusion in the right superior frontal gyrus and cingulate gyrus, regions associated with pain processing (P < .001). Longitudinal magnetic resonance imaging analysis in the group receiving chemotherapy indicated that CIPN-sx and associated perfusion changes from baseline to 1 month were also positively correlated with gray matter density change (P < .005). CONCLUSION: Peripheral neuropathy symptoms after systemic chemotherapy for breast cancer are associated with changes in cerebral perfusion and gray matter. The specific mechanisms warrant further investigation given the potential diagnostic and therapeutic implications.

Altered cerebral blood flow one month after systemic chemotherapy for breast cancer: a prospective study using pulsed arterial spin labeling MRI perfusion.

Cerebral structural and functional alterations have been reported after chemotherapy for non-CNS cancers, yet the causative mechanism behind these changes remains unclear. This study employed a novel, non-invasive, MRI-based neuroimaging measure to provide the first direct longitudinal measurement of resting cerebral perfusion in breast cancer patients, which was tested for association with changes in cognitive function and gray matter density. Perfusion was measured using pulsed arterial spin labeling MRI in women with breast cancer treated with (N = 27) or without (N = 26) chemotherapy and matched healthy controls (N = 26) after surgery before other treatments (baseline), and one month after chemotherapy completion or yoked intervals. Voxel-based analysis was employed to assess perfusion in gray matter; changes were examined in relation to overall neuropsychological test performance and frontal gray matter density changes measured by structural MRI. Baseline perfusion was not significantly different across groups. Unlike control groups, chemotherapy-treated patients demonstrated significantly increased perfusion post-treatment relative to baseline, which was statistically significant relative to controls in the right precentral gyrus. This perfusion increase was negatively correlated with baseline overall neuropsychological performance, but was not associated with frontal gray matter density reduction. However, decreased frontal gray matter density was associated with decreased perfusion in bilateral frontal and parietal lobes in the chemotherapy-treated group. These findings indicate that chemotherapy is associated with alterations in cerebral perfusion which are both related to and independent of gray matter changes. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. Additionally, lower baseline cognitive function may be a risk factor for treatment-associated perfusion dysregulation. Future research is needed to clarify these mechanisms, identify individual differences in susceptibility to treatment-associated changes, and further examine perfusion change over time in survivors.

Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage.

Neuroimaging studies have begun to uncover the neural substrates of cancer and treatment-related cognitive dysfunction, but the time course of these changes in the years following chemotherapy is unclear. This study analyzed multimodality 3T MRI scans to examine the structural and functional effects of chemotherapy and post-chemotherapy interval (PCI) in a cohort of breast cancer survivors (BCS; n = 24; PCI mean 6, range 3-10 y) relative to age- and education-matched healthy controls (HC; n = 23). Assessments included voxel-based morphometry for gray matter density (GMD) and fMRI for activation profile during a 3-back working memory task. The relationships between brain regions associated with PCI and neuropsychological performance, self-reported cognition, and oxidative and direct DNA damage as measured in peripheral lymphocytes were assessed in secondary analyses. PCI was positively associated with GMD and activation on fMRI in the right anterior frontal region (Brodmann Areas 9 and 10) independent of participant age. GMD in this region was also positively correlated with global neuropsychological function. Memory dysfunction, cognitive complaints, and oxidative DNA damages were increased in BCS compared with HC. Imaging results indicated lower fMRI activation in several regions in the BCS group. BCS also had lower GMD than HC in several regions, and in these regions, GMD was inversely related to oxidative DNA damage and learning and memory neuropsychological domain scores. This is the first study to show structural and functional effects of PCI and to relate oxidative DNA damage to brain alterations in BCS. The relationship between neuroimaging and cognitive function indicates the potential clinical relevance of these findings. The relationship with oxidative DNA damage provides a mechanistic clue warranting further investigation.

Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: a replication and extension study.

Cognitive changes related to cancer and its treatment have been intensely studied, and neuroimaging has begun to demonstrate brain correlates. In the first prospective longitudinal neuroimaging study of breast cancer (BC) patients we recently reported decreased gray matter density one month after chemotherapy completion, particularly in frontal regions. These findings helped confirm a neural basis for previously reported cognitive symptoms, which most commonly involve executive and memory processes in which the frontal lobes are a critical component of underlying neural circuitry. Here we present data from an independent, larger, more demographically diverse cohort that is more generalizable to the BC population. BC patients treated with (N=27) and without (N=28) chemotherapy and matched healthy controls (N=24) were scanned at baseline (prior to systemic treatment) and one month following chemotherapy completion (or yoked intervals for non-chemotherapy and control groups) and APOE-genotyped. Voxel-based morphometry (VBM) showed decreased frontal gray matter density after chemotherapy, as observed in the prior cohort, which was accompanied by self-reported difficulties in executive functioning. Gray matter and executive symptom changes were not related to APOE ε4 status, though a somewhat greater percentage of BC patients who received chemotherapy were ε4 allele carriers than patients not treated with chemotherapy or healthy controls. These findings provide confirmatory evidence of frontal morphometric changes that may be a pathophysiological basis for cancer and treatment-related cognitive dysfunction. Further research into individual risk factors for such changes will be critical for development of treatment and prevention strategies.