417O - Metformin impact on progression-free survival in diabetic patients with advanced pancreatic neuroendocrine tumors (pNET) receiving everolimus and/o...

Date 10 October 2016
Event ESMO 2016 Congress
Session Endocrine and neuroendocrine tumours
Topics Neuroendocrine Tumours
Presenter Sara Pusceddu
Citation Annals of Oncology (2016) 27 (6): 136-148. 10.1093/annonc/mdw369
Authors S. Pusceddu1, R. Marconcini2, F. Spada3, S. Massironi4, A. Bongiovanni5, M.P. Brizzi6, N. Brighi7, A. Colao8, D. Giuffrida9, G. Delle Fave10, S. Cingarlini11, F. Aroldi12, L. Antonuzzo13, R. Berardi14, L. Catena15, C. de divitis16, P. Ermacora17, M. Di Maio18, R. Buzzoni1, F. de Braud19
  • 1Medical Oncology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milano/IT
  • 2U.o. Oncologia Medica 2 Universitaria, Azienda Ospedaliera Universitaria S.Chiara, 56100 - Pisa/IT
  • 3Medical Oncology, Istituto Europeo di Oncologia, Milano/IT
  • 4Gastroenterology Unit, IRCCS Ospedale Maggiore Policlinico, Milano/IT
  • 5Osteoncology And Rare Tumors Center, Istituto Tumori della Romagna I.R.S.T., 47014 - Meldola/IT
  • 6Divison Of Medical Oncology, Azienda Ospedaliero-Universitaria ASOU San Luigi Gonzaga, 10043 - Orbassano/IT
  • 7Pancreas Unit, Department Of Digestive System, Policlinico S. Orsola-Malpighi, Bologna/IT
  • 8Dipartimento Di Medicina Clinica E Chirurgia, Sezione Di Endocrinologia, Università Federico II, Napoli/IT
  • 9Oncologia, Istituto Oncologico del Mediterraneo, 95029 - Viagrande/IT
  • 10Digestive And Liver Disease, Azienda Ospedaliera St. Andrea - Roma, Roma/IT
  • 11Medical Oncology, Azienda Ospedaliera Universitaria Integrata AOUI, Verona/IT
  • 12Oncology Unit, Fondazione Poliambulanza, Brescia/IT
  • 13Oncology, Azienda Ospedaliera Careggi U.O. Medical Oncology, 50134 - Firenze/IT
  • 14Clinica Di Oncologia Medica, AOU Ospedali Riuniti Ancona Università Politecnica delle Marche, 60126 - Ancona/IT
  • 15Oncology Unit, Istituto di Oncologia del Policlinico di Monza, Monza/IT
  • 16Department Of Abdominal Oncology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Napoli/IT
  • 17Oncology Unit, Azienda Ospedaliera Universitaria-Udine Sta Maria della Misericordia, Udine/IT
  • 18Divison Of Medical Oncology, Azienda Ospedaliera Mauriziano Umberto I, Torino/IT
  • 19Oncology Department - University Of Milan, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milano/IT



In phase III trials, both everolimus (EVE), and somatostatin analogues (SA) have shown antitumor efficacy in pNETs. Some studies have identified diabetic patients (pts) as having increased risk for the development of cancer and have associated metformin (MET) treatment with a decrease of cancer risk. MET may have anti-proliferative activity due to its ability to decrease insulin and IGF1 levels; in addition, it promotes AMPK activation and TSC1-2/mTOR inhibition. This multicentric, retrospective study evaluates the impact of glycemic status (hyper vs normoglycemic pts) on progression-free survival (PFS); the impact of concomitant MET administered during EVE and/or SA therapy in diabetic pNETs is also assessed.


To obtain a 90% statistical power, with α error 0.05, and to detect an HR of progression (PD) of 0.67 for hyperglycemic vs normoglycemic pts, 267 events (PD or deaths without PD) were needed, and 445 pts were planned. With these numbers, 77% power was anticipated to detect HR 0.67 in each subgroup analysis (hyperglycemic pts on MET vs normoglycemic and hyperglycemic pts on INS vs normoglycemic pts).


Between 1999 and 2016, 445 pts (median age 59, range 49-69; 53.5% males), were treated with EVE and/or SA in 24 Italian Centers. In total, 112 (25.2%) diabetic pts received MET, 91 (20.4%) received INS and 33 (7.7%) received dietetic counseling; 209 (46.7%) pts were normoglycemic. In the overall population, median PFS was 23.4 months (mo) (95%CI 19.1–27.9); mPFS was 32.0 mo in diabetic pts and 15.1 mo in normoglycemic pts (HR 0.63, 95%CI 0.50-0.80; p = 0.0002). Median PFS was 20.8 mo (95%CI 15.6-36.3) in pts receving INS (HR vs normoglycemic pts 0.81, 95%CI 0.60-1.1, p = 0.18) and 44.2 mo (95%CI 36.4-61.9) in pts on MET (HR vs normoglycemic pts 0.45, 95%CI 0.32-0.62, p 


With the limitations of any retrospective analysis, the results of this large study may suggest that the addition of MET to EVE and /or SA can provide clinical benefits in advanced diabetic pNETs pts. Prospective evaluations are required to confirm these preliminary findings.

Clinical trial identification

Protocol number INT 85/15, approved by Ethical committee of Fondazione IRCCS Istituto tumori Milano on 15 June 2015.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale Tumori di Milano


Fondazione IRCCS Istituto Nazionale Tumori di Milano


S. Pusceddu: Ipsen, Novartis, Italfarmaco, Pfizer.

All other authors have declared no conflicts of interest.