PMID- 30606884 OWN - NLM STAT- MEDLINE DCOM- 20200603 LR - 20200603 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 24 IP - 3 DP - 2019 Mar TI - Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis. PG - 385-393 LID - 10.1634/theoncologist.2018-0442 [doi] AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. MATERIALS AND METHODS: This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. RESULTS: Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48-4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69-3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. CONCLUSIONS: Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. IMPLICATIONS FOR PRACTICE: The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival. CI - (c) AlphaMed Press 2019. FAU - Vernieri, Claudio AU - Vernieri C AD - Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy claudio.vernieri@istitutotumori.mi.it maria.dibartolomeo@istitutotumori.mi.it. AD - The Italian Foundation for Cancer Research Institute of Molecular Oncology, Milan, Italy. FAU - Galli, Fabio AU - Galli F AD - IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. FAU - Ferrari, Laura AU - Ferrari L AD - Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy. FAU - Marchetti, Paolo AU - Marchetti P AD - Sant'Andrea Hospital, Sapienza University of Rome and IRCCS Istituto Dermopatico dell'Immacolata, Rome, Italy. FAU - Lonardi, Sara AU - Lonardi S AD - IRCCS Istituto Oncologico Veneto, Padua, Italy. FAU - Maiello, Evaristo AU - Maiello E AD - Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. FAU - Iaffaioli, Rosario V AU - Iaffaioli RV AD - IRCCS Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy. FAU - Zampino, Maria G AU - Zampino MG AD - IRCCS Istituto Europeo di Oncologia, Milan, Italy. FAU - Zaniboni, Alberto AU - Zaniboni A AD - Fondazione Poliambulanza, Brescia, Italy. FAU - De Placido, Sabino AU - De Placido S AD - Universita Federico II, Naples, Italy. FAU - Banzi, Maria AU - Banzi M AD - IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. FAU - Damiani, Azzurra AU - Damiani A AD - IRCCS San Martino-IST, Genoa, Italy. FAU - Ferrari, Daris AU - Ferrari D AD - Azienda Ospedaliera San Paolo, Milan, Italy. FAU - Rosati, Gerardo AU - Rosati G AD - Ospedale San Carlo, Potenza, Italy. FAU - Labianca, Roberto F AU - Labianca RF AD - ASST Papa Giovanni XXIII, Bergamo, Italy. FAU - Bidoli, Paolo AU - Bidoli P AD - Ospedale San Gerardo dei Tintori, Monza, Italy. FAU - Frassineti, Giovanni L AU - Frassineti GL AD - IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy. FAU - Nicolini, Mario AU - Nicolini M AD - Azienda USL Romagna, Cattolica, Rimini, Italy. FAU - Pavesi, Lorenzo AU - Pavesi L AD - Fondazione Salvatore Maugeri, Pavia, Italy. FAU - Tronconi, Maria C AU - Tronconi MC AD - Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Buonadonna, Angela AU - Buonadonna A AD - Centro di Riferimento Oncologico, Aviano, Italy. FAU - Ferrario, Sabrina AU - Ferrario S AD - ASST Fatebenefratelli-Ospedale Luigi Sacco, Milan, Italy. FAU - Re, Giovanni Lo AU - Re GL AD - Azienda Ospedaliera S. Maria degli Angeli Pordenone, Pordenone, Italy. FAU - Adamo, Vincenzo AU - Adamo V AD - Dipartimento Universitario di Patologia Umana & Azienda Ospedaliera Papardo, Messina, Italy. FAU - Tamburini, Emiliano AU - Tamburini E AD - Ospedale degli Infermi, Rimini, Italy. FAU - Clerico, Mario AU - Clerico M AD - Ospedale degli Infermi, Biella, Italy. FAU - Giordani, Paolo AU - Giordani P AD - Ospedale San Salvatore, Pesaro, Italy. FAU - Leonardi, Francesco AU - Leonardi F AD - Azienda Ospedaliera Universitaria di Parma, Parma, Italy. FAU - Barni, Sandro AU - Barni S AD - Ospedale Treviglio Caravaggio Treviglio, Bergamo, Italy. FAU - Ciarlo, Andrea AU - Ciarlo A AD - USL4 Prato, Prato, Italy. FAU - Cavanna, Luigi AU - Cavanna L AD - Ospedale G. Da Saliceto, Piacenza, Italy. FAU - Gori, Stefania AU - Gori S AD - Ospedale Sacro Cuore Don Calabria, Verona, Italy. FAU - Cinieri, Saverio AU - Cinieri S AD - Presidio Ospedaliero Antonio Perrino, Brindisi, Italy. FAU - Faedi, Marina AU - Faedi M AD - Presidio Ospedaliero Bufalini, Cesena, Italy. FAU - Aglietta, Massimo AU - Aglietta M AD - Istituto di Candiolo IRCC, Candiolo Torin, Italy. FAU - Antista, Maria AU - Antista M AD - Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. FAU - Dotti, Katia F AU - Dotti KF AD - Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. FAU - Galli, Francesca AU - Galli F AD - IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. FAU - Di Bartolomeo, Maria AU - Di Bartolomeo M AD - Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy claudio.vernieri@istitutotumori.mi.it maria.dibartolomeo@istitutotumori.mi.it. CN - TOSCA (Three or Six Colon Adjuvant) Investigators LA - eng PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study DEP - 20190103 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Antineoplastic Agents) RN - 0 (Hypoglycemic Agents) RN - 04ZR38536J (Oxaliplatin) RN - 9100L32L2N (Metformin) RN - U3P01618RT (Fluorouracil) SB - IM MH - Aged MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - Chemotherapy, Adjuvant/*methods MH - Colonic Neoplasms/*drug therapy/pathology MH - Diabetes Mellitus, Type 2/*drug therapy/pathology MH - Female MH - Fluorouracil/*analogs & derivatives/pharmacology/*therapeutic use MH - Humans MH - Hypoglycemic Agents/pharmacology/*therapeutic use MH - Male MH - Metformin/pharmacology/*therapeutic use MH - Middle Aged MH - Oxaliplatin/pharmacology/*therapeutic use MH - Risk Factors PMC - PMC6519752 COIS- Disclosures of potential conflicts of interest may be found at the end of this article. EDAT- 2019/01/05 06:00 MHDA- 2020/06/04 06:00 PMCR- 2020/03/01 CRDT- 2019/01/05 06:00 PHST- 2018/07/23 00:00 [received] PHST- 2018/10/19 00:00 [accepted] PHST- 2019/01/05 06:00 [pubmed] PHST- 2020/06/04 06:00 [medline] PHST- 2019/01/05 06:00 [entrez] PHST- 2020/03/01 00:00 [pmc-release] AID - theoncologist.2018-0442 [pii] AID - ONCO12813 [pii] AID - 10.1634/theoncologist.2018-0442 [doi] PST - ppublish SO - Oncologist. 2019 Mar;24(3):385-393. doi: 10.1634/theoncologist.2018-0442. Epub 2019 Jan 3.