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

Abstract

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.

Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects

“…Cossor et al [115] conclude in their report the difference in OS against CRC among metformin use ( n = 84), without metformin ( n = 128), diabetes status ( n = 1854 without diabetes) in postmenopausal women are not significant [105]. In a substudy of randomized TOSCA trial in Italy, metformin intake among T2DM CRC patients treated with fluoropyrimidine-oxaliplatin adjuvant chemotherapy neither associated with OS nor relapse free survival (adjusted HR, 1.51; CI, 0.48–4.77; p = 0.4781 and HR, 1.56; CI, 0.69–3.54; p = 0.2881, respectively) [116]. Among the T2DM CRC metformin users (76 patients, 63.3%), 26 patients demonstrated CRC relapsed (21.7%) and 16 patients died (13.3%) after a median follow-up of 60.4 months.…”

Cytotoxicity of metformin against HT29 colon cancer cells contributes to mitochondrial Sirt3 upregulation

“…[ 11 ] Thus, it seems that some alterations of SIRT3 achieved by metformin as an antidiabetic agent could be searchable in cancer cells that are responsive to this agent. Metformin is an antidiabetic drug that has been determined to have anticancer effects on colon, [ 12,13 ] breast, [ 14 ] and pancreatic cancer. [ 15,16 ] Metformin in various models of colorectal cancer (CRC) has had the ability to cause upstream and downstream changes related to apoptosis, autophagy, cell cycle, oxidative stress, inflammation, metabolic homeostasis, and epigenetic regulation.…”

Novel combination of celecoxib and metformin improves the antitumor effect by inhibiting the growth of Hepatocellular Carcinoma

“…Recently, the therapeutic effect of metformin on tumors has attracted attention. Many studies have shown that metformin can also treat tumors, such as those found in lung, breast, colon and prostate 45 - 47 . Metformin may reduce the risk of HCC in patients with diabetes, implying that metformin may also have a therapeutic effect against HCC 48 .…”