Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues

TY - JOUR

T1 - Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues

AU - Pusceddu, S.

AU - Vernieri, C.

AU - Di Maio, M.

AU - Marconcini, R.

AU - Spada, F.

AU - Massironi, S.

AU - Ibrahim, T.

AU - Brizzi, M.P.

AU - Campana, D.

AU - Faggiano, A.

AU - Giuffrida, D.

AU - Rinzivillo, M.

AU - Cingarlini, S.

AU - Aroldi, F.

AU - Antonuzzo, L.

AU - Berardi, R.

AU - Catena, L.

AU - De Divitiis, C.

AU - Ermacora, P.

AU - Perfetti, V.

AU - Fontana, A.

AU - Razzore, P.

AU - Carnaghi, C.

AU - Davì, M.V.

AU - Cauchi, C.

AU - Duro, M.

AU - Ricci, S.

AU - Fazio, N.

AU - Cavalcoli, F.

AU - Bongiovanni, A.

AU - La Salvia, A.

AU - Brighi, N.

AU - Colao, A.

AU - Puliafito, I.

AU - Panzuto, F.

AU - Ortolani, S.

AU - Zaniboni, A.

AU - Di Costanzo, F.

AU - Torniai, M.

AU - Bajetta, E.

AU - Tafuto, S.

AU - Garattini, S.K.

AU - Femia, D.

AU - Prinzi, N.

AU - Concas, L.

AU - Lo Russo, G.

AU - Milione, M.

AU - Giacomelli, L.

AU - Buzzoni, R.

AU - Delle Fave, G.

AU - Mazzaferro, V.

AU - de Braud, F.

N1 - Cited By :3 Export Date: 5 February 2019 CODEN: GASTA Correspondence Address: Pusceddu, S.; Department of Medical Oncology Unit-1, Fondazione IRCCS Istituto Nazionale dei Tumori and ENETS Center of Excellence, Via Venezian 1, 20133, Italy; email: sara.pusceddu@istitutotumori.mi.it Chemicals/CAS: angiopeptin, 113294-82-9; everolimus, 159351-69-6; glucose, 50-99-7, 84778-64-3; hemoglobin A1c, 62572-11-6; insulin, 9004-10-8; metformin, 1115-70-4, 657-24-9; octreotide, 83150-76-9, 1607842-55-6; somatostatin, 38916-34-6, 51110-01-1; Antineoplastic Agents; Everolimus; Hypoglycemic Agents; Metformin; Somatostatin References: Hallet, J., Law, C.H., Cukier, M., Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes (2015) Cancer, 121, pp. 589-597; Yao, J.C., Lagunes, D.R., Kulke, M.H., Targeted therapies in neuroendocrine tumors (NET): clinical trial challenges and lessons learned (2013) Oncologist, 18, pp. 525-532; Fendrich, V., Waldmann, J., Bartsch, D.K., Surgical management of pancreatic endocrine tumors (2009) Nat Rev Clin Oncol, 6, pp. 419-428; Halfdanarson, T.R., Rabe, K.G., Rubin, J., Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival (2008) Ann Oncol, 19, pp. 1727-1733; Yao, J.C., Shah, M.H., Ito, T., Everolimus for advanced pancreatic neuroendocrine tumors (2011) New Engl J Med, 364, pp. 514-523; Raymond, E., Dahan, L., Raoul, J.L., Sunitinib malate for the treatment of pancreatic neuroendocrine tumors (2011) New Engl J Med, 364, pp. 501-513; Strosberg, J., El-Haddad, G., Wolin, E., Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors (2017) N Engl J Med, 376, pp. 125-135; Caplin, M.E., Pavel, M., Cwikla, J.B., Lanreotide in metastatic enteropancreatic neuroendocrine tumors (2014) New Engl J Med, 371, pp. 224-233; Leoncini, E., Carioli, G., La Vecchia, C., Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis (2016) Ann Oncol, 27, pp. 68-81; Haugvik, S.P., Hedenstrom, P., Korsaeth, E., Diabetes, smoking, alcohol use, and family history of cancer as risk factors for pancreatic neuroendocrine tumors: a systematic review and meta-analysis (2015) Neuroendocrinology, 101, pp. 133-142; Vander Heiden, M.G., Cantley, L.C., Thompson, C.B., Understanding the Warburg effect: the metabolic requirements of cell proliferation (2009) Science, 324, pp. 1029-1033; Godsland, I.F., Insulin resistance and hyperinsulinaemia in the development and progression of cancer (2009) Clin Science, 118, pp. 315-329; Vernieri, C., Casola, S., Foiani, M., Targeting cancer metabolism: dietary and pharmacologic interventions (2016) Cancer Discover, 6, pp. 1315-1333; Han, X., Wang, D., Kuang, T., Glucagonoma syndrome: report of one case (2016) Transl Gastroenterol Hepatol, 1, p. 70; Struyvenberg, M.R., Fong, Z.V., Martin, C.R., Impact of treatments on diabetic control and gastrointestinal symptoms after total pancreatectomy (2017) Pancreas, 46, pp. 1188-1195; Beger, H.G., Poch, B., Mayer, B., Siech, M., New onset of diabetes and pancreatic exocrine insufficiency after pancreaticoduodenectomy for benign and malignant tumors: a systematic review and meta-analysis of long-term results (2018) Ann Surg, 267, pp. 259-270; Vergès, B., Cariou, B., mTOR inhibitors and diabetes (2015) Diabetes Res Clin Pract, 110, pp. 101-108; Steffin, B., Gutt, B., Bidlingmaier, M., Effects of the long-acting somatostatin analogue Lanreotide Autogel on glucose tolerance and insulin resistance in acromegaly (2006) Eur J Endocrinol, 155, pp. 73-78; Libby, G., Donnelly, L.A., Donnan, P.T., New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes (2009) Diabetes Care, 32, pp. 1620-1625; Pierotti, M.A., Berrino, F., Gariboldi, M., Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects (2013) Oncogene, 32, pp. 1475-1487; Sonnenblick, A., Agbor-Tarh, D., Bradbury, I., Impact of diabetes, insulin, and metformin use on the outcome of patients with human epidermal growth factor receptor 2-positive primary breast cancer: analysis from the ALTTO phase III randomized trial (2017) J Clin Oncol, 35, pp. 1421-1429; Klubo-Gwiezdzinska, J., Costello, J., Jr., Patel, A., Treatment with metformin is associated with higher remission rate in diabetic patients with thyroid cancer (2013) J Clin Endocrinol Metab, 98, pp. 3269-3279; Meng, F., Song, L., Wang, W., Metformin improves overall survival of colorectal cancer patients with diabetes: a meta-analysis (2017) J Diabetes Res, 2017, p. 5063239; Shackelford, D.B., Shaw, R.J., The LKB1-AMPK pathway: metabolism and growth control in tumour suppression (2009) Nat Rev Cancer, 9, pp. 563-575; Pusceddu, S., Buzzoni, R., Vernieri, C., Metformin with everolimus and octreotide in pancreatic neuroendocrine tumor patients with diabetes (2016) Future Oncol, 12, pp. 1251-1260; Lloyd, R.V., Osamura, R.Y., Klöppel, G., Rosai, J., Neoplasms of the neuroendocrine pancreas (2017) WHO classification of tumours of endocrine organs. WHO/IARC classification of tumours, 10, pp. 209-239. , 4th ed. R.V. Lloyd R.Y. Osamura G. Klöppel J. Rosai World Health Organization Geneva; Diagnosis and classification of diabetes mellitus (2017) Diabetes Care, 40, pp. S12-S13; Eisenhauer, E.A., Therasse, P., Bogaerts, J., New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) (2009) Eur J Cancer, 45, pp. 228-247; Yin, M., Zhou, J., Gorak, E.J., Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis (2013) Oncologist, 18, pp. 1248-1255; Kordes, S., Pollak, M.N., Zwinderman, A.H., Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial (2015) Lancet Oncol, 16, pp. 839-847; Braghiroli, M.I., de Celis Ferrari, A.C., Pfiffer, T.E., Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas (2015) Ecancermedicalscience, 9, p. 563; Reni, M., Dugnani, E., Cereda, S., (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase II trial (2016) Clin Cancer Res, 22, pp. 1076-1085; Ding, X.Z., Fehsenfeld, D.M., Murphy, L.O., Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression (2000) Pancreas, 21, pp. 310-320

PY - 2018

Y1 - 2018

N2 - 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. Methods: 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. Results: 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

AB - 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. Methods: 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. Results: 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

KW - Chemoprevention

KW - Drug

KW - Insulin Resistance

KW - Pancreas

KW - angiopeptin

KW - everolimus

KW - glucose

KW - hemoglobin A1c

KW - insulin

KW - metformin

KW - octreotide

KW - somatostatin derivative

KW - antidiabetic agent

KW - antineoplastic agent

KW - somatostatin

KW - adolescent

KW - adult

KW - aged

KW - Article

KW - cancer prognosis

KW - child

KW - clinical outcome

KW - confidence interval

KW - controlled study

KW - correlation analysis

KW - diabetic patient

KW - dose response

KW - drug effect

KW - drug megadose

KW - female

KW - glucose blood level

KW - glycemic control

KW - hazard ratio

KW - human

KW - hyperglycemia

KW - lifestyle

KW - low drug dose

KW - major clinical study

KW - male

KW - multicenter study

KW - multivariate analysis

KW - non insulin dependent diabetes mellitus

KW - outcome assessment

KW - overall survival

KW - pancreas islet cell tumor

KW - priority journal

KW - progression free survival

KW - retrospective study

KW - sensitivity analysis

KW - statistical analysis

KW - analogs and derivatives

KW - clinical trial

KW - comparative study

KW - disease free survival

KW - epidemiology

KW - Italy

KW - Kaplan Meier method

KW - middle aged

KW - mortality

KW - neuroendocrine tumor

KW - pancreas tumor

KW - pathology

KW - time factor

KW - treatment outcome

KW - very elderly

KW - young adult

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents

KW - Child

KW - Diabetes Mellitus, Type 2

KW - Disease-Free Survival

KW - Everolimus

KW - Female

KW - Humans

KW - Hypoglycemic Agents

KW - Kaplan-Meier Estimate

KW - Male

KW - Metformin

KW - Middle Aged

KW - Neuroendocrine Tumors

KW - Pancreatic Neoplasms

KW - Retrospective Studies

KW - Somatostatin

KW - Time Factors

KW - Treatment Outcome

KW - Young Adult

U2 - 10.1053/j.gastro.2018.04.010

DO - 10.1053/j.gastro.2018.04.010

M3 - Article

VL - 155

SP - 479

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -