Metformin and pancreatic neuroendocrine tumors: A systematic review and meta-analysis

Abstract

BACKGROUND

Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant. In this perspective, metformin is emerging as a molecule of interest. Retrospective studies have described metformin, a widely used agent for the treatment of patients with type 2 diabetes mellitus (T2DM), to be effective in modulating different tumor-related events, including cancer incidence, recurrence and survival by inhibiting mTOR phosphorylation. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.

AIM

To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNET.

METHODS

A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), overall survival and progression-free survival.

RESULTS

A total of 13 studies (5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with I² = 0%) confirms the correlation between T2DM and insurgence of pNET (OR = 2.13, 95%CI = 1.56-4.55; P < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; P < 0.001). The study heterogeneity was intermediate, with I² = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.

CONCLUSION

T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Keywords: Pancreatic neuroendocrine tumors; Type 2 diabetes mellitus; Prognosis; Treatment; Metformin

Core Tip: Pancreatic neuroendocrine tumors (pNETs) are a challenge to diagnose and treat. Often curative treatments are not possible and additional therapy aimed at symptom relief and tumor cell growth inhibition is warranted. Unfortunately, a significant number of pNET patients do not respond to the above-mentioned medical treatments or show resistance. Therefore, exploring the risk factors and additional therapeutics is of importance. This systematic review and meta-analysis showed that in patients with type 2 diabetes mellitus (T2DM), the risk for pNET insurgence was significantly increased. In addition, T2DM was a significant predictor of poor tumor free survival. Results on the role of metformin in the setting of diagnosis and prognosis of pNET due to paucity of data and data heterogeneity failed to show statistical relevance of its use, although there are indices that it might positively impact the progression free survival.