Impact of diabetes mellitus on treatment efficacy in patients with advanced pancreatic cancer: the Italian, multicenter, observational PANCAKE study

Background: Diabetes mellitus (DM) is a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Preclinical evidence suggests higher glucose levels may enhance chemotherapy injury to PDAC cells. Clinical evidence of DM's impact in patients with PDAC receiving palliative treatment remains conflicting, however. Materials and methods: PANCAKE, an Italian multicenter observational study, assessed the impact of DM and blood glucose levels on progression-free survival during first-line treatment and overall survival (OS) in patients with advanced PDAC. Results: Among 663 patients with available baseline and on-treatment glycemic values, DM was confirmed in 193 patients (29.1%). Pre-existing DM was associated with a modest but significant OS benefit [median OS 11.6 versus 10.3 months, adjusted hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-0.99; P = 0.036]. This benefit was significantly associated with the chemotherapy regimen: it was observed only in patients treated with first-line gemcitabine–nab-paclitaxel, but not with FOLFIRINOX. A longitudinal, Bayesian joint modelling approach accounting for the concomitant use of glucose-lowering medications confirmed a statistically significant, but clinically modest prognostic effect of glycemic trends, as a 10 mg/dl-point increase from baseline blood glucose values resulted associated with a 4% reduction in the risk of death (HR for OS 0.9967, 95% CI 0.9939-0.9995). Conclusions: DM and higher blood glucose levels show a statistically significant, though clinically modest, impact on the OS of patients affected by advanced PDAC, which may be differential according to the chemotherapy regimen. This evidence lays the foundations to guide future studies on pharmacological and dietary approaches targeting tumor metabolism in this setting.