Esophageal cancer is one of the major components of the global cancer burden. According to the Global Cancer Statistics 2020 report, in 2020, esophageal cancer ranked ninth in the world in incidence (604,100 new cases) and sixth in overall mortality (544,076 deaths). In China, esophageal cancer ranked fifth among cancer-related causes of death in 2020, with more than 90% of esophageal cancers being esophageal squamous cell carcinoma (ESCC). Until now, surgery-based comprehensive treatment has remained the main mode of treatment for patients with potentially curable localized esophageal cancer. However, despite efforts to advance treatment, the five-year survival rate for patients with esophageal cancer after surgery is still low, so it is important to identify prognosis-related factors.

Diabetes is a global health problem that has reached alarming levels. In 2019, nearly half a billion people worldwide (9.3% of adults aged 20-79 years) had diabetes, with approximately 20% in the age group aged 60-75 years (the main incidence group of esophageal cancer). Diabetes mellitus is a wasting systemic disease associated with poor outcomes across multiple disease processes and is one of the greatest challenges facing healthcare systems worldwide. For malignant tumors, diabetes is not only one of the causes but also one of the risk factors for low survival. Although other cancer specialties (eg, colon, pancreatic, breast) are associated with poor oncology outcomes, it may be due to decreased immunity and increased systemic inflammation in patients with diabetes. However, there is controversy regarding the prognostic role of diabetes mellitus in patients undergoing surgery for esophageal cancer. There is evidence that patients with diabetes have an increased risk of cancer recurrence and death after surgery compared with non-diabetic controls; However, some studies have shown no significant association between T2DM and postoperative complications, suggesting that diabetes is not an independent risk factor for survival.

Metformin, a member of the biguanide family, is commonly used as an oral antihyperglycemic agent that reduces cancer risk and improves prognosis for a variety of cancers. In recent years, the use of metformin has improved survival in patients with malignant tumors. For patients with esophageal squamous cell carcinoma (ESCC), several molecular mechanisms have been shown to inhibit tumor progression, for example, by inhibiting the growth of esophageal cancer cells. Metformin has also been shown to have a beneficial prognostic effect on some other tumors, such as colon, lung, and prostate cancers, in some studies. The association between metformin use and mortality in patients undergoing surgery for esophageal cancer has been analyzed with conflicting results. A study by Van De Voorde et al. showed that the use of metformin was associated with significantly better distant metastasis-free survival and overall survival. In contrast, the results of Spierings et al. showed that metformin use did not result in higher pathologic response rates or improved overall survival or disease-free survival. They believe that contrary to the assumptions of other tumor types, metformin may not have a beneficial effect on esophageal cancer.

Studies have shown that T2DM does not appear to have a significant effect on the long-term survival of esophageal cancer patients undergoing esophagectomy. In contrast, it may be more important to control blood glucose levels in patients with T2DM undergoing esophagectomy. At the same time, a large number of studies have confirmed that diabetic patients with poor glycemic control have a higher complication rate after esophageal cancer surgery, especially anastomotic leakage.

In summary, there is controversy as to whether type II diabetes mellitus will result in adverse short- and long-term outcomes for patients with esophageal squamous cell carcinoma undergoing minimally invasive esophagectomy. At the same time, to the best of our knowledge, the impact of metformin use and glycemic control on short- and long-term outcomes in this patient population is also controversial. Therefore, this study aims to test the hypothesis that diabetes mellitus is associated with reduced survival in patients with esophageal squamous cell carcinoma undergoing minimally invasive esophagectomy and that treatment with metformin and/or good glycemic control (HbA1c\<7.0%) is associated with improved survival.