Exploring neural correlates of chemotherapy-induced peripheral neurotoxicity (CIPN) and the impact of exercise: A URCC NCORP nationwide phase II randomized controlled trial (RCT).

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11023 Background: More than half of patients with cancer receiving neurotoxic chemotherapy (e.g., taxane, platinum, vinca alkaloid) develop CIPN, a dose-limiting, sometimes-debilitating condition characterized by numbness, tingling, and pain in the hands and feet. There are limited treatment options for CIPN partly due to limited understanding of CIPN pathophysiology. Methods: We conducted a phase II RCT examining the effect of exercise on CIPN via URCC NCORP Research Base. Patients who received neurotoxic chemotherapy within the past 9 months and report CIPN symptoms (rated ≥4 out of 10 at its worst in the past 2 weeks) were randomized 1:1 to usual care (UC) or virtually delivered Exercise for Cancer Patients (vEXCAP). vEXCAP is a 6-week personalized walking and resistance band exercise intervention. As part of our secondary aims, we investigated (1) whether CIPN symptoms are exacerbated by impairments in the brain’s descending pain modulation circuitry—quantified by functional connectivity between the dorsolateral prefrontal cortex (DLPFC) and 23 sensory-related brain regions—and (2) whether exercise can improve both CIPN and brain functional connectivity. We recruited 35 patients from 7 community oncology practices spanning 6 US states. Sensory CIPN severity was assessed using the patient-reported EORTC QLQ-CIPN20 sensory subscale and functional brain connectivity was measured via magnetic resonance imaging (MRI) at pre- and post-intervention. Results: An ANCOVA showed that exercise, compared to UC, reduced sensory CIPN severity (-7.66±3.05 (MCID is 4), effect size (ES) = -0.43, p = 0.158) (N = 35, 57 ± 10 yrs, 89% female, 60% breast cancer). At pre-intervention, correlation analysis revealed sensory CIPN severity was negatively correlated with functional connectivity between the left DLPFC and several brain areas, including the left anterior insula (r = -0.53, p = 0.001), left thalamus (r = -0.44, p = 0.009), and left precuneus (r = -0.32, p = 0.057). Participants who showed a decrease in sensory CIPN severity at post intervention had an increase in functional connectivity between the left DLPFC and left precuneus (r = -0.25, p = 0.152), and this increase in connectivity was greater in vEXCAP group (effect size (ES) = 0.2, p = 0.460). Conclusions: The association of sensory CIPN severity with lower brain connectivity with the left DLPFC may reflect impairment of descending pain inhibition pathways in the brain. vEXCAP may improve brain connectivity with the precuneus while lowering CIPN symptom severity. We believe that this line of research will ultimately inform better CIPN biomarkers and treatments. Funded by NCI UG1CA189956, UG1CA189861, UG1CA189805, UG1CA189961, K07CA221931, and R21CA256154. Clinical trial information: NCT04888988 .

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