Exercise volume, skeletal muscle maintenance, and plasma IL-6/IL-6R in patients with PDAC

Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by debilitating muscle wasting, which is associated with reduced treatment tolerance and survival. IL-6 and IL-6 receptor (IL-6R) have been implicated in cancer-associated muscle loss and as exercise-responsive myokines, though variable results have made the roles of IL-6 and IL-6R in muscle wasting unclear. This study investigated the relationship between skeletal muscle, plasma IL-6/IL-6R levels, and exercise in PDAC patients undergoing neoadjuvant therapy. The PancFit randomized controlled trial (NCT03187951) included a usual care and an exercise intervention arm in which patients with borderline resectable PDAC were asked to perform > 150 minutes/week of moderate intensity aerobic exercise and > 2 strength training sessions per week during the time of neoadjuvant treatment. Physical activity was monitored by Fitbits and self-reported by Godin-Leisure Questionnaire. Skeletal Muscle Index (SMI) was measured by CT images obtained at study enrollment (baseline) and at pre-operative re-staging (end of neoadjuvant therapy and intervention) in 112 patients. Plasma IL-6 and IL-6R were measured by ELISA at the same timepoints in 26 patients. Due to variability in quantity of exercise in both arms, we performed post hoc analysis in which all patients were pooled, then regrouped based on average weekly strength sessions (≥2 vs. <2 sessions/week) or average very active minutes (VAM, by Fitbit/ week). Spearman rank correlations or student's t-test were used for analysis. Patients who completed <2 strength training sessions / week had an average SMI loss of -3.9% + 8.9 SD from enrollment to pre-operative staging, while those who performed > 2 strength training sessions per week had an average SMI maintenance of +0.35% + 9.5 SD (p = 0.03). There was no correlation between VAM and SMI. There were no significant correlations between the change in SMI from baseline to pre-op and plasma IL-6 at baseline, IL-6 at pre-operative restaging, or in the change in IL-6 between timepoints. However, there was a significant negative correlation between the change in SMI and plasma IL-6R at baseline (p=0.002, r = -0.5), pre-operative restaging (p <0.0001, r = -0.67), and in the change in IL-6R over time (p=0.03, r = -0.38), and between SMI and IL-6R at pre-operative restaging (p=0.02, r =-0.41). No correlations were observed between VAM and plasma IL-6 or IL-6R at any timepoint. Strength training may be one method to maintain SMI for patients with PDAC undergoing neoadjuvant therapy. Plasma IL-6R, but not IL-6, may be a blood biomarker of SMI. A future randomized controlled trial focusing on strength training is needed to further understand these relationships.