Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy.
Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
Gastroenterology. 2018 Aug;155(2):479-489.e7. doi: 10.1053/j.gastro.2018.04.010. Epub 2018 Apr 13.
BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time.
We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake.
PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results.
In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.
二甲双胍似乎具有抗癌作用。然而，目前尚不清楚血糖和二甲双胍的使用是否会影响晚期胰腺神经内分泌肿瘤（pNET）患者的预后。我们研究了血糖水平与接受依维莫司和/或生长抑素类似物治疗的 pNET 患者的无进展生存期（PFS）之间的关系，以及二甲双胍使用与 PFS 时间之间的关系。
我们对意大利 24 个医疗中心于 1999 年至 2015 年期间收治的 445 例晚期 pNET 患者进行了回顾性分析。在诊断为 pNET 时、治疗开始前以及使用依维莫司（联合或不联合生长抑素类似物）、奥曲肽或兰瑞肽期间，收集血糖水平的数据。糖尿病的定义为使用血糖控制药物和/或空腹血糖水平≥126mg/dL、糖化血红蛋白≥6.5%（48mmol/L）或随机血糖样本≥200mg/dL（11.1mmol/L），伴有高血糖的典型症状或高血糖危象，或报告有高血糖症。根据抗肿瘤治疗前或治疗期间是否诊断为糖尿病，将患者分为两组。比较有糖尿病和无糖尿病患者的 PFS。在有糖尿病的患者中，评估二甲双胍使用与 PFS 的关系。我们进行了敏感性和基准分析，以排除在接受癌症治疗期间发生糖尿病的患者，并排除与二甲双胍摄入相关的潜在不朽时间偏倚。
有糖尿病的患者 PFS 明显长于无糖尿病的患者（中位数，32.0 个月比 15.1 个月）（有糖尿病与无糖尿病患者的危险比，0.63；95%置信区间，0.50-0.80；P=0.0002）。接受二甲双胍治疗的患者的 PFS 明显长于无糖尿病的患者（有糖尿病接受二甲双胍治疗的患者与无糖尿病患者的生存危险比，0.45；95%置信区间，0.32-0.62；P<0.00001），也长于接受其他治疗的有糖尿病的患者（中位数 PFS，20.8 个月；危险比，0.49；95%置信区间，0.34-0.69；P<0.0001）。在多变量分析中，调整了与结局相关的其他因素后，二甲双胍与较长的 PFS 相关，但血糖水平无相关性。二甲双胍与接受生长抑素类似物治疗的患者和接受依维莫司治疗的患者（联合或不联合生长抑素类似物）的 PFS 延长相关。敏感性和基准分析得出了类似的结果。
在一项对 pNET 患者的回顾性研究中，我们发现二甲双胍的使用与较长的 PFS 之间存在显著关联。
