Sara Pusceddu1, Claudio Vernieri2, Massimo Di Maio3, Riccardo Marconcini4, Francesca Spada5, Sara Massironi6, Toni Ibrahim7, Maria Pia Brizzi8, Davide Campana9, Antongiulio Faggiano10, Dario Giuffrida11, Maria Rinzivillo12, Sara Cingarlini13, Francesca Aroldi14, Lorenzo Antonuzzo15, Rossana Berardi16, Laura Catena17, Chiara De Divitiis18, Paola Ermacora19, Vittorio Perfetti20, Annalisa Fontana21, Paola Razzore22, Carlo Carnaghi23, Maria Vittoria Davì24, Carolina Cauchi25, Marilina Duro26, Sergio Ricci4, Nicola Fazio5, Federica Cavalcoli6, Alberto Bongiovanni7, Anna La Salvia8, Nicole Brighi9, Annamaria Colao27, Ivana Puliafito11, Francesco Panzuto12, Silvia Ortolani13, Alberto Zaniboni14, Francesco Di Costanzo15, Mariangela Torniai16, Emilio Bajetta17, Salvatore Tafuto18, Silvio Ken Garattini19, Daniela Femia28, Natalie Prinzi28, Laura Concas28, Giuseppe Lo Russo29, Massimo Milione28, Luca Giacomelli30, Roberto Buzzoni28, Gianfranco Delle Fave12, Vincenzo Mazzaferro31, Filippo de Braud31. 1. Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy. Electronic address: sara.pusceddu@istitutotumori.mi.it. 2. Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy. 3. Dipartimento di Oncologia, Università degli Studi di Torino, A. O. Ordine Mauriziano, Turin, Italy. 4. Dipartimento di Oncologia, Santa Chiara Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 5. IEO - Istituto Europeo di Oncologia, ENETS Center of Excellence, Milan, Italy. 6. Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. 7. Centro di Osteoncologia e Tumori Rari, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 8. Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy. 9. Policlinico Sant'Orsola Malpighi, Bologna, Italy. 10. Unità di chirurgia tiroidea e paratiroidea, Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy. 11. IOM- Istituto Oncologico del Mediterraneo, Catania, Italy. 12. Azienda Ospedaliera Universitaria Sant'Andrea, ENETS Center of Excellence, Rome, Italy. 13. Azienda Ospedaliera Universitaria, Verona, Italy. 14. Fondazione Poliambulanza, Brescia, Italy. 15. A. O. U. Careggi, Firenze, Italy. 16. Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona, Italy. 17. Policlinico di Monza, Monza, Italy. 18. IRCCS Fondazione Pascale, ENETS Center of Excellence, Naples, Italy. 19. Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy. 20. Fondazione IRCCS Policlinico San Matteo, SC oncologia, Pavia, Italy. 21. Policlinico di Modena, Italy. 22. Unit of Endocrinology, Ospedale Mauriziano, Torino, Italy. 23. Istituto Clinico Humanitas, Rozzano, ENETS Center of Excellence, Italy. 24. Ospedale Policlinico Borgo Roma, Verona, Italy. 25. Ospedale S Croce e Carle, Cuneo, Italy. 26. Ospedale Valduce Como, Italy. 27. Endocrinology Section, Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy. 28. Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy. 29. Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Medical-Surgical Science and Traslational Medicine Departement, Sapienza University, Rome, Italy. 30. Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Italy. 31. Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Universita' degli Studi di Milano, Milan, Italy.
Abstract
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 < .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. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.
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 < .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. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.
Authors: Claudio Vernieri; Fabio Galli; Laura Ferrari; Paolo Marchetti; Sara Lonardi; Evaristo Maiello; Rosario V Iaffaioli; Maria G Zampino; Alberto Zaniboni; Sabino De Placido; Maria Banzi; Azzurra Damiani; Daris Ferrari; Gerardo Rosati; Roberto F Labianca; Paolo Bidoli; Giovanni L Frassineti; Mario Nicolini; Lorenzo Pavesi; Maria C Tronconi; Angela Buonadonna; Sabrina Ferrario; Giovanni Lo Re; Vincenzo Adamo; Emiliano Tamburini; Mario Clerico; Paolo Giordani; Francesco Leonardi; Sandro Barni; Andrea Ciarlo; Luigi Cavanna; Stefania Gori; Saverio Cinieri; Marina Faedi; Massimo Aglietta; Maria Antista; Katia F Dotti; Francesca Galli; Maria Di Bartolomeo Journal: Oncologist Date: 2019-01-03
Authors: Yael N Kusne; Heidi E Kosiorek; Matthew R Buras; Patricia M Verona; Kyle E Coppola; Kelley A Rone; Curtiss B Cook; Nina J Karlin Journal: Future Sci OA Date: 2021-02-15