Esophageal squamous cell carcinoma (ESCC) represents the predominant histologic type of esophageal cancer worldwide.1,2 Alcohol and smoking remain the most common risk factors, especially in the United States (US) and Western Europe.3 Once diagnosed with ESCC, the clinical outcomes are relatively poor with an overall 5-year survival rate of less than 20%.4 Therefore, there is great research interest in evaluating certain medications that could be used as part of a preventive care strategy in conjunction with improving patient education on smoking and alcohol cessation.

One such medication that has been postulated to have an impact on ESCC is metformin (MFM).  MFM has traditionally been used to treat patients with type 2 diabetes and polycystic ovarian syndrome.5 There has been some observational data proposing that MFM could be implicated in reducing the risk for certain gastrointestinal cancers such as colon, stomach, and esophageal cancer.6 The exact mechanism to explain this potential effect has not yet been fully elucidated but could include deactivation of the mitogen-activated protein-kinase or phosphoinositide 3-kinase pathway leading to reduced protein synthesis and cell proliferation.7 MFM can also activate the 5’adenosine monophosphate-activated protein kinase pathway, which has been associated with mediating the tumor suppressor liver kinase B1.7,8

Many esophageal cancer studies have not yet distinguished the impact of MFM on ESCC compared with esophageal adenocarcinoma (EAC).9 Therefore, a group of researchers led by Wang, Qiao-Li, MD, of upper gastrointestinal surgery, department of molecular medicine and surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; conducted a study specifically evaluating the effect of MFM on ESCC incidence and published the results in the American Journal of Gastroenterology

The researchers conducted a population-based prospective cohort study in Sweden between 2005 and 2015 using a nationwide database.8 A total of 8.4 million patients were included in the Swedish Prescribed Drugs and Health (SPREDH) database. The study population included only patients 18 years or older without any prior cancer diagnosis except for nonmelanoma skin cancer.  


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A total of 411,603 patients (5%) were identified as receiving MFM during the study time period. Patients who did not receive MFM during the first year of the study (July 1, 2005 to June 30, 2006) were considered “new” users of MFM.  All MFM users were matched 10:1 with controls without exposure to MFM. Baseline demographics between the 2 groups were similar, including smoking and alcohol overconsumption. However, MFM users were more likely to be receiving nonsteroidal anti-inflammatory drugs (NSAIDS), including aspirin (48.6% vs 35.6%, respectively and statins (51.7% vs 20.1%, respectively) compared with non-users.  

A total of 1352 ESCC cases were identified, of which 86 (0.02%) were in the MFM group compared with 1266 (0.03%) in the control group. This equates to incidence rates of ESCC of 3.5 per 100,000 person-years in the MFM group compared with 5.3 per 100,000 person-years in the non-MFM group. MFM use was associated with a decreased adjusted hazard ratio (aHR) of 0.67 (95% CI 0.54-0.84). When the effect of statins and NSAIDs were adjusted for, the decreased aHR remained similar at 0.68 (95% CI 0.54-0.85). “New” users of MFM had overall lower aHRs (0.46, 95% CI 0.31-0.67). The aHRs remained intact when controlling for potential confounders.  

Both men (aHR 0.70, 95% CI 0.54-0.90) and women (aHR 0.62, 95% CI 0.39-0.97) receiving MFM had decreased risk for ESCC. Of note, only patients receiving MFM aged 60 to 69 (HR 0.45, 95% CI 0.31-0.66) had statistically significant decreases in HR, while patients age <59 years or ≥70 years did not. There were no statistically significant differences found between low, intermediate, or high cumulative doses. It was found that adherence to MFM was close to 80% each year during follow-up.  

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The investigators concluded that MFM users had a decreased risk for ESCC compared with nonusers. The study had multiple strengths including its relatively large sample size, focus on ESCC specifically, and prospective nature. It was interesting that no specific dose response was found, although the actual small number of ESCC cases could have precluded the appropriate power numbers needed to show this effect. It may be reasonable to conclude that even a low dose of MFM contributed to a lower risk for ESCC.  

A study limitation is that it was conducted only in Swedish patients. Future randomized controlled clinical trials could aim to further evaluate the impact of MFM on the prevention of ESCC in certain high-risk populations in certain parts of Asia and individuals with an extensive prior smoking and alcohol history. It will be interesting to see if future studies eventually do detect an inflection point with respect to cumulative dosing or duration.  

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.

2. Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 2015;64:381-387.

3. Pandeya N, Williams G, Green AC, Webb PM, Whiteman DC; Australian Cancer Study. Alcohol consumption and the risks of adenocarcinoma and squamous cell carcinoma of the esophagus. Gastroenterology. 2009:136(4):1215-1224.

4. Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet. 2017;390:2383-2396.

5. Metformin [package insert]. Whitehouse Station, NJ: Merck & Co., Inc., 2017.

6. Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: A representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11:20.

7. Joo MK, Park JJ, Chun HJ. Additional benefits of routine drugs on gastrointestinal cancer: Statins, metformin, and proton pump inhibitors. Dig Dis. 2018;36:1-14.

8. Wang QL, Santoni G1, Ness-Jensen E, Lagergren J, Xie SH.  Association between metformin use and risk of esophageal squamous cell carcinoma in a population-based cohort studyAm J Gastroenterol.  2020;115(1):73-78.

9. Becker C, Meier CR, Jick SS, Bodmer M. Case-control analysis on metformin and cancer of the esophagus. Cancer Causes Control. 2013;24:1763-1770.