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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.
OBJECTIVE: 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
CONCLUSIONS: 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.
摘要：
背景：大多数晚期胰腺神经内分泌肿瘤（pNETs）患者因肿瘤进展而死亡。因此,确定低毒性和良好耐受性的新疗法与已建立的pNET治疗同时使用是相关的。从这个角度来看,二甲双胍正在成为一种感兴趣的分子。回顾性研究描述了二甲双胍，一种广泛用于治疗2型糖尿病（T2DM）患者的药物，有效调节不同的肿瘤相关事件，包括癌症发病率，通过抑制mTOR磷酸化复发和存活。本系统评价了T2DM和二甲双胍在pNET患者发病和治疗后转归中的作用。
目的：系统分析和总结2型糖尿病和二甲双胍在预测pNET预防和治疗后结局方面的诊断和预后价值。
方法：对已发表的文献进行了系统综述，重点探讨2型糖尿病和二甲双胍在pNET发病和预后中的作用,通过无瘤生存率（TFS）的结果来衡量，总生存期和无进展生存期。
结果：本综述共纳入13项研究（5674例患者）。对来自5项回顾性研究的809例pNET病例进行分析（研究异质性低，I²=0％），证实了T2DM与pNET预防之间的相关性（OR=2.13，95CI=1.56-4.55；P<0.001）。来自1174名pNET患者的汇总数据显示，T2DM与pNET患者治疗后TFS之间存在相关性（风险比=1.84，95CI=0.78-2.90；P<0.001）。研究的异质性是中等程度的，I²=51%。一些研究限制了在二甲双胍的背景下进行汇总分析的可能性；因此，结果是异质的，与该药物在pNET诊断和预后中的应用无统计学相关性。
结论：T2DM是pNET发病的危险因素，也是pNET患者治疗后TFS不良的重要预测因子。不幸的是,一些结果不一致的研究限制了探索二甲双胍在pNET诊断和预后中的作用的可能性。
目的：系统分析和总结2型糖尿病和二甲双胍在预测pNET预防和治疗后结局方面的诊断和预后价值。
方法：对已发表的文献进行了系统综述，重点探讨2型糖尿病和二甲双胍在pNET发病和预后中的作用,通过无瘤生存率（TFS）的结果来衡量，总生存期和无进展生存期。
结果：本综述共纳入13项研究（5674例患者）。对来自5项回顾性研究的809例pNET病例进行分析（研究异质性低，I²=0％），证实了T2DM与pNET预防之间的相关性（OR=2.13，95CI=1.56-4.55；P<0.001）。来自1174名pNET患者的汇总数据显示，T2DM与pNET患者治疗后TFS之间存在相关性（风险比=1.84，95CI=0.78-2.90；P<0.001）。研究的异质性是中等程度的，I²=51%。一些研究限制了在二甲双胍的背景下进行汇总分析的可能性；因此，结果是异质的，与该药物在pNET诊断和预后中的应用无统计学相关性。
结论：T2DM是pNET发病的危险因素，也是pNET患者治疗后TFS不良的重要预测因子。不幸的是,一些结果不一致的研究限制了探索二甲双胍在pNET诊断和预后中的作用的可能性。
