Effect of ketorolac on serum GDF-15 and IL-8 in patients with pancreatic cancer with cachexia.

Abstract

713 Background: Cancer cachexia deteriorates the quality of life, chemotherapy tolerance and survivability of pancreatic cancer (PC) patients. Although a prevalent condition affecting PC patients, there are no approved therapies for cachexia and its mechanism of action is poorly understood. Elevated growth differentiation factor 15 (GDF-15), a stress-induced cytokine, has been associated with the pathogenesis of cachexia. Similarly, prior studies have displayed positive correlations between the proinflammatory factor interleukin-8 (IL-8) and PC cachexia. This abstract focuses on the exploratory endpoints (serum GDF-15 and IL-8 levels) of a feasibility trial on ketorolac as a treatment for PC cachexia. Methods: Patients took ketorolac 10 mg PO QID for 5 consecutive days, with weights measured on Day 1 (D1) and Day 6 (D6). Serum cytokines were drawn on D1 and D6. IL-8 was measured using a HDF15 assay (Eve Technologies). GDF-15 was measured using a human R-plex GDF-15 assay. Activity (e.g., number of steps) was measured via Fitbit. Differences in weight, activity, GDF-15, and IL-8 were analyzed using two-sample paired t-tests. Results: Twenty-nine patients were enrolled, of which 19 were evaluable. Median age was 70, 47.4% (9/19) were female, and 94.7% (18/19) were adherent with ketorolac. Statistically significant increases in both weight per baseline BMI and activity were observed from D1 to D6 (0.0716±0.1079 kg/BMI, p=0.012; 1423±2477 steps, p=0.0221). Of the 19 evaluable patients, 16 patients provided complete D1 and D6 pairs of serum cytokines. From D1 to D6, the mean GDF-15 level decreased by 277.5 pg/mL (p=0.529) and mean IL-8 decreased by 65.13 pg/mL (p=0.103). In all patients who gained weight (n=14), a trend toward reduced IL-8 from D1 to D6 was observed (79.57±39.57 pg/mL, p=0.065). Similarly, for patients who gained ≥ 1-kg from D1 to D6 (n=10), a trend toward reduced GDF-15 was observed (951.2±482.3 pg/mL, p=0.080). Patients with increased activity from D1 to D6 (n=12) had mean reductions of 157.7 pg/mL (p=0.643) and 70.17 pg/mL (p=0.179) in GDF-15 and IL-8, respectively. Conclusions: Given the growing literature suggesting associations between inflammatory cytokines and cancer cachexia, it is critical to investigate treatments that may possibly alter cytokine levels. Although our findings suggest that ketorolac aids in weight gain and increased activity, larger sample sizes are needed to determine whether these differences are related to reductions of specific serum cytokines. However, given reductions that trended towards significance for both GDF-15 and IL-8 serum levels within subsets of patients that gained weight on ketorolac, further studies investigating these cytokines are warranted to hopefully provide insight on the mechanistic action of ketorolac in cachexia. Clinical trial information: NCT05336266 .