HPB P10 Evaluation of the prognostic role of aspirin and metformin in the ESPAC 4 randomised trial of adjuvant gemcitabine versus gemcitabine plus capecitabine in patients with resected pancreatic cancer
Authors: Ponweera Arachchige , Robinson Matthew , Jackson Richard , Halloran Chris , Palmer Dan , Hackert Thilo , Costello Eithne , Greenhalf Bill , Bϋchler Markus , Neoptolemos John , Ghaneh Paula 
Published: December 2022

Abstract

Background
Pancreatic cancer is currently the world's seventh most common cancer with it's incidence being equivalent to it's mortality. It is the fourth most common cause of cancer-related mortality and is set to be the second most common by 2030. 5-year overall survival of pancreatic cancer is set at just below 10%, with only approximately 15% - 20% of diagnosed patients being eligible for resection. Patients eligible for resection have a 5-year overall survival improvement of up to 30% over recent years following the combination of resection and adjuvant therapy. The prognostic effects of chemo-preventive agents such as metformin and aspirin have been investigated previously in pancreatic cancer (PC) with variable results. ESPAC-4 was a phase-3 randomised controlled trial which recruited patients with resectable pancreatic cancer and examined the survival benefit between adjuvant monotherapy gemcitabine therapy and adjuvant gemcitabine-capecitabine (GEMCAP) combination therapy. This study aims to evaluate the prognostic impact of aspirin and metformin on survival among PC patients in the ESPAC 4 randomised trial.

Methods
Concomitant medication data was identified from ESPAC-4 trial database. Primary and secondaryoutcome measures were overall survival (OS) and disease-free survival (DFS) respectively for users and non-users of aspirin and metformin. Survival data was analysed using multivariate and univariate Cox-proportional hazard models and log-rank testing.The primary and secondary outcome was to investigate overall survival (OS) and Relapse-Free Survival (RFS) time respectively, between users and non- users of aspirin and metformin in either treatment arm.

Results
We identified 86 patients using aspirin and 55 patients using metformin out of 730 randomised trial patients at baseline . Aspirin usage led to a median OS of 30 months versus 26 months with non-users and a hazard ratio of 0.91 (95% CI:0.68–1.2; p=0.499). Median DFS with and without aspirin usage was 17.9 months versus 13.1 months respectively with a hazard ratio of 0.76 (95% CI: 0.58–0.99, p=0.044). Gemcitabine treatment amongst aspirin users demonstrated a median OS of 42.4 months compared to 24.7 months in non-aspirin users and a hazard ratio of 1.69 with non-users (95% CI:1.06–2.67; p=0.026). Aspirin users randomised to gemcitabine had a median DFS of 37.2 months, compared to non-aspirin users with 11.9 months and a hazard ratio of 2.01 (95% CI:1.31–3.08; p=0.001). Metformin usage resulted in a median OS of 23.8 months versus 27.7 months in non-users with a hazard ratio of 0.95 (95% CI:0.65–1.4; p=0.819). Median DFS with and without metformin usage was 14.7 months versus 12.5 months respectively, with a hazard ratio of 0.88 (95% CI:0.61–1.27; p=0.498). Metformin usage in either treatment arm did not demonstrate a significant survival difference

Conclusions
Though numbers are small, gemcitabine therapy and aspirin usage demonstrated a prognostic benefit in OS and DFS in this study. Further in vivo studies exploring the mechanism of this interaction would be beneficial. There was no survival benefit observed with metformin usage. Standardisation of dosages in chemopreventive agents such as metformin and aspirin in future trials could yield further standardised results.