Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial

The Lancet Oncology

Volumn 17, Issue 4, 2016, Pages 475-483

  Higurashi, Takuma ^a   Hosono, Kunihiro ^a   Takahashi, Hirokazu ^a   Komiya, Yasuhiko ^a   Umezawa, Shotaro ^a   Sakai, Eiji ^a   Uchiyama, Takashi ^b   Taniguchi, Leo ^b   Hata, Yasuo ^b   Uchiyama, Shiori ^c   Hattori, Akiko ^c   Nagase, Hajime ^c   Kessoku, Takaomi ^d   Arimoto, Jun ^d   Matsuhashi, Nobuyuki ^e   Inayama, Yoshiaki ^f   Yamanaka, Shoji ^f   Taguri, Masataka ^a   Nakajima, Atsushi ^a  

^a YOKOHAMA CITY UNIVERSITY   (Japan)

^b CHIGASAKI MUNICIPAL HOSPITAL   (Japan)

^c YOKOHAMA ROSAI HOSPITAL   (Japan)

^d Hiratsuka City Hospital   (Japan)

^e Sapporo Medical Center   (Japan)

^f YOKOHAMA CITY UNIVERSITY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

METFORMIN; PLACEBO;

ABDOMINAL PAIN; ADULT; AGED; ALOPECIA; ARTICLE; CANCER RECURRENCE; CHEMOPROPHYLAXIS; COLONOSCOPY; COLORECTAL ADENOMA; COLORECTAL POLYP; CONSTIPATION; CONTROLLED STUDY; DIARRHEA; DOUBLE BLIND PROCEDURE; DRUG WITHDRAWAL; ENDOSCOPIC SURGERY; FEMALE; FOLLOW UP; HIGH RISK PATIENT; HUMAN; JAPAN; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; OUTCOME ASSESSMENT; PHASE 3 CLINICAL TRIAL; POLYPECTOMY; PREVALENCE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RASH; RECURRENCE RISK; VERY ELDERLY; ADENOMA; CLINICAL TRIAL; COLONIC POLYPS; COLORECTAL NEOPLASMS; MIDDLE AGED; NEOPLASMS, SECOND PRIMARY; PATHOLOGY; TUMOR RECURRENCE;

ADENOMA; ADULT; AGED; AGED, 80 AND OVER; CHEMOPREVENTION; COLONIC POLYPS; COLONOSCOPY; COLORECTAL NEOPLASMS; DOUBLE-BLIND METHOD; FEMALE; HUMANS; JAPAN; MALE; METFORMIN; MIDDLE AGED; NEOPLASM RECURRENCE, LOCAL; NEOPLASMS, SECOND PRIMARY;

EID: 84959298298     PISSN: 14702045     EISSN: 14745488     Source Type: Journal    
DOI: 10.1016/S1470-2045(15)00565-3     Document Type: Article

References (32)

1. 1 Torre, LA, Bray, F, Siegel, RL, Ferlay, J, Lortet-Tieulent, J, Jemal, A, Global cancer statistics, 2012. CA Cancer J Clin 65 (2015), 87–108.
2. 2 Winawer, SJ, Zauber, AG, Ho, MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 329 (1993), 1977–1981.
3. 3 Imperiale, TF, Glowinski, EA, Lin-Cooper, C, Larkin, GN, Rogge, JD, Ransohoff, DF, Five-year risk of colorectal neoplasia after negative screening colonoscopy. N Engl J Med 359 (2008), 1218–1224.
4. 4 Das, D, Arber, N, Jankowski, JA, Chemoprevention of colorectal cancer. Digestion 76 (2007), 51–67.
5. 5 Drazen, JM, COX-2 inhibitors—a lesson in unexpected problems. N Engl J Med 352 (2005), 1131–1132.
6. 6 Zell, JA, Pelot, D, Chen, WP, McLaren, CE, Gerner, EW, Meyskens, FL, Risk of cardiovascular events in a randomized placebo-controlled, double-blind trial of difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas. Cancer Prev Res 2 (2009), 209–212.
7. 7 Limburg, PJ, Vierkant, RA, Fredericksen, ZS, et al. Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am J Gastroenterol 101 (2006), 1872–1879.
8. 8 Frezza, EE, Wachtel, MS, Chiriva-Internati, M, Influence of obesity on the risk of developing colon cancer. Gut 55 (2006), 285–291.
9. 9 Balsells, M, Garcia-Patterson, A, Sola, I, Roque, M, Gich, I, Corcoy, R, Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ, 350, 2015, h102.
10. 10 Duca, FA, Cote, CD, Rasmussen, BA, et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med 21 (2015), 506–511.
11. 11 Shaw, RJ, Lamia, KA, Vasquez, D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310 (2005), 1642–1646.
12. 12 Hawley, SA, Ross, FA, Chevtzoff, C, et al. Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11 (2010), 554–565.
13. 13 Libby, G, Donnelly, LA, Donnan, PT, Alessi, DR, Morris, AD, Evans, JM, New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32 (2009), 1620–1625.
14. 14 Tomimoto, A, Endo, H, Sugiyama, M, et al. Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci 99 (2008), 2136–2141.
15. 15 Hosono, K, Endo, H, Takahashi, H, et al. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog 49 (2010), 662–671.
16. 16 Hosono, K, Endo, H, Takahashi, H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res 3 (2010), 1077–1083.
17. 17 Takayama, T, Katsuki, S, Takahashi, Y, et al. Aberrant crypt foci of the colon as precursors of adenoma and cancer. N Engl J Med 339 (1998), 1277–1284.
18. 18 Higurashi, T, Takahashi, H, Endo, H, et al. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial. BMC Cancer, 12, 2012, 118.
19. 19 Wallace, TM, Levy, JC, Matthews, DR, Use and abuse of HOMA modeling. Diabetes Care 27 (2004), 1487–1495.
20. 20 Atkins, L, Hunkeler, EM, Jensen, CD, et al. Factors influencing variation in physician adenoma detection rates: a theory-based approach for performance improvement. Gastrointest Endosc, 2015, 10.1016/j.gie.2015.08.075 published online Sept 11.
21. 21 Takayama, T, Nagashima, H, Maeda, M, et al. Randomized double-blind trial of sulindac and etodolac to eradicate aberrant crypt foci and to prevent sporadic colorectal polyps. Clin Cancer Res 17 (2011), 3803–3811.
22. 22 Taniguchi, L, Higurashi, T, Uchiyama, T, et al. Metabolic factors accelerate colorectal adenoma recurrence. BMC Gastroenterol, 14, 2014, 187.
23. 23 Ishikawa, H, Mutoh, M, Suzuki, S, et al. The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial. Gut 63 (2014), 1755–1759.
24. 24 Pierotti, MA, Berrino, F, Gariboldi, M, et al. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 32 (2013), 1475–1487.
25. 25 Zakikhani, M, Dowling, R, Fantus, IG, Sonenberg, N, Pollak, M, Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66 (2006), 10269–10273.
26. 26 Algire, C, Amrein, L, Zakikhani, M, Panasci, L, Pollak, M, Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer 17 (2010), 351–360.
27. 27 Suissa, S, Azoulay, L, Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 35 (2012), 2665–2673.
28. 28 Tsilidis, KK, Capothanassi, D, Allen, NE, et al. Metformin does not affect cancer risk: a cohort study in the U.K. Clinical Practice Research Datalink analyzed like an intention-to-treat trial. Diabetes Care 37 (2014), 2522–2532.
29. 29 Stevens, RJ, Ali, R, Bankhead, CR, et al. Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia 55 (2012), 2593–2603.
30. 30 Sehdev, A, Shih, YC, Vekhter, B, Bissonnette, MB, Olopade, OI, Polite, BN, Metformin for primary colorectal cancer prevention in patients with diabetes: a case-control study in a US population. Cancer 121 (2015), 1071–1078.
31. 18F-FDG bowel uptake in patients treated with metformin. Eur J Nucl Med Mol Imaging 35 (2008), 95–99.
32. 32 Lieberman, DA, Rex, DK, Winawer, SJ, Giardiello, FM, Johnson, DA, Levin, TR, Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 143 (2012), 844–857.