Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer



      Observational and preclinical studies have suggested that metformin has antitumor effects in solid tumors, including colorectal cancer (CRC). However, the effects of metformin in CRC have not been tested in clinical trials.

      Patients and Methods

      This was a single-center, single-arm phase 2 clinical trial where histologically confirmed CRC patients with measurable and progressing metastatic disease previously treated with 5-fluorouracil (5-FU), irinotecan, oxaliplatin, and an anti–epidermal growth factor receptor (if the tumor was RAS wild type) were enrolled to receive metformin 850 mg orally continuously 2 times a day plus 5-FU 425 mg/m2 and leucovorin 50 mg intravenously weekly until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was disease control rate at 8 weeks.


      Among 50 patients included, 11 (22%) met the primary end point. The median progression-free survival was 1.8 months and the median overall survival 7.9 months. Analyzing only the 11 patients who experienced disease control at 8 weeks, their median progression-free survival was 5.6 months and their median overall survival was 16.2 months. There was a trend for prolonged median survival for obese patients (12.4 vs. 5.8 months) and those longer off 5-FU. The treatment was well tolerated; the main adverse effects were diarrhea, nausea, vomiting, and myelotoxicity.


      Metformin and 5-FU showed an overall modest but intriguing activity in patients with refractory CRC in this phase 2 study. Some patients experienced long-term disease control. Further trials are needed to confirm these results, particularly in obese patients with CRC.


      To read this article in full you will need to make a payment


      Subscribe to Clinical Colorectal Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Miranda V.C.
        • Barroso-Sousa R.
        • Glasberg J.
        • et al.
        Exploring the role of metformin in anticancer treatments: a systematic review.
        Drugs Today (Barc). 2014; 50: 623-640
        • Lee J.H.
        • Kim T.I.
        • Jeon S.M.
        • et al.
        The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus.
        Int J Cancer. 2012; 131: 752-759
        • Garrett C.R.
        • Hassabo H.M.
        • Bhadkamkar N.A.
        • et al.
        Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer.
        Br J Cancer. 2012; 106: 1374-1378
        • Tseng C.H.
        Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan.
        Eur J Endocrinol. 2012; 167: 409-416
        • Zhang Z.J.
        • Zheng Z.J.
        • Kan H.
        • et al.
        Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis.
        Diabetes Care. 2011; 34: 2323-2328
        • Belfiore A.
        • Frasca F.
        IGF and insulin receptor signaling in breast cancer.
        J Mammary Gland Biol Neoplasia. 2008; 13: 381-406
        • Frasca F.
        • Pandini G.
        • Sciacca L.
        • et al.
        The role of insulin receptors and IGF-I receptors in cancer and other diseases.
        Arch Physiol Biochem. 2008; 114: 23-37
        • Dowling R.J.
        • Zakikhani M.
        • Fantus I.G.
        • et al.
        Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.
        Cancer Res. 2007; 67: 10804-10812
        • Inoki K.
        • Zhu T.
        • Guan K.L.
        TSC2 mediates cellular energy response to control cell growth and survival.
        Cell. 2003; 115: 577-590
        • Sui X.
        • Xu Y.
        • Yang J.
        • et al.
        Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation.
        PLoS One. 2014; 9: e97781
        • Ling S.
        • Tian Y.
        • Zhang H.
        • et al.
        Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells.
        Mol Med Rep. 2014; 10: 2891-2897
        • Simon R.
        Optimal two-stage designs for phase II clinical trials.
        Control Clin Trials. 1989; 10: 1-10
        • Grothey A.
        • Van Cutsem E.
        • Sobrero A.
        • et al.
        Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
        Lancet. 2013; 381: 303-312
        • Mayer R.J.
        • Van Cutsem E.
        • Falcone A.
        • et al.
        Randomized trial of TAS-102 for refractory metastatic colorectal cancer.
        N Engl J Med. 2015; 372: 1909-1919
        • Mills K.T.
        • Bellows C.F.
        • Hoffman A.E.
        • et al.
        Diabetes mellitus and colorectal cancer prognosis: a meta-analysis.
        Dis Colon Rectum. 2013; 56: 1304-1319
        • Sandhu M.S.
        • Dunger D.B.
        • Giovannucci E.L.
        Insulin, insulin-like growth factor-I(IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer.
        J Natl Cancer Inst. 2002; 94: 972-980
        • Moghaddam A.A.
        • Woodward M.
        • Huxley R.
        Obesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 events.
        Cancer Epidemiol Biomarkers Prev. 2007; 16: 2533-2547
        • Haydon A.M.
        • Macinnis R.J.
        • English D.R.
        • et al.
        Effect of physical activity and body size on survival after diagnosis with colorectal cancer.
        Gut. 2006; 55: 62-67
        • Wu S.
        • Liu J.
        • Wang X.
        • et al.
        Association of obesity and overweight with overall survival in colorectal cancer patients: a meta-analysis of 29 studies.
        Cancer Causes Control. 2014; 25: 1489-1502
        • de Gramont Lesparre A.H.
        • Chibaudel B.
        • Bourges O.
        • et al.
        Definition of oxaliplatin sensitivity in patients with advanced colorectal cancer previously treated with oxaliplatin-based therapy.
        J Clin Oncol. 2009; 27 (abstract 4024)
        • Yang M.
        • Liu P.
        • Huang P.
        Cancer stem cells, metabolism, and therapeutic significance.
        Tumour Biol. 2016; 37: 5735-5742
        • Denise C.
        • Paoli P.
        • Calvani M.
        • et al.
        5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits.
        Oncotarget. 2015; 6: 41706-41721
        • Braghiroli M.I.
        • de Celis Ferrari A.C.
        • Pfiffer T.E.
        • et al.
        Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas.
        Ecancermedicalscience. 2015; 9: 563
        • Joseph S.J.
        • Osborne T.
        • Word B.
        • et al.
        Metformin upregulates hENT1 expression and enhances gemcitabine efficacy in pancreatic cancer cells.
        Cancer Res. 2015; 75 (abstract 4436)
        • Kordes S.
        • Pollak M.N.
        • Zwinderman A.H.
        • et al.
        Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial.
        Lancet Oncol. 2015; 16: 839-847
        • Guinney J.
        • Dienstmann R.
        • Wang X.
        • et al.
        The consensus molecular subtypes of colorectal cancer.
        Nat Med. 2015; 21: 1350-1356
        • Son J.
        • Lyssiotis C.A.
        • Ying H.
        • et al.
        Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
        Nature. 2013; 496: 101-105