Esophageal squamous cell carcinoma : opportunities for prevention

<p>Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer, a highly fatal malignant neoplasm. Most ESCC patients are diagnosed at a late stage when tumors are unresectable or have metastasized. The median survival is less than one year, highlighting a great need for early diagnosis and preventive measures. The overall aim of the thesis is to provide a better knowledge of how ESCC can be prevented.</p><p>Study I is an incidence study based on the data collected directly from 30 cancer registries in 20 countries for 1970-2015. Cross-sectional analyses of the year 2012 showed that the highest incidence rate of ESCC was in Japan (9.7/100,000 person-years). The incidence had decreased continuously in men globally but slightly increased in women from Japan, the Netherlands, New Zealand, Norway, and Switzerland. Age-period-cohort analyses revealed that birth-cohort effects were strong determinants for the incidence trends.</p><p>Study II is a systematic review and meta-analysis assessing tobacco smoking cessation and risk of ESCC. We found 41 relevant studies from 15,009 publications. The random-effects model was applied to estimate pooled risk ratios (RRs) with 95% confidence intervals (CIs). Compared with current smokers, those who stopped smoking 5-9 years earlier had a decreased risk of ESCC (RR 0.59, 95% CI 0.47-0.75), and the risk reduction was stronger in those who had stopped smoking 10-20 years earlier and reached almost the level of nonsmokers in those who had stopped smoking >20 years ago (RR 0.34, 95% CI 0.25-0.47). Thus, smoking cessation seems to reduce the risk of ESCC strongly.</p><p>Study III is a Swedish nationwide population-based cohort study in 2005-2015. Among 8.4 million participants, we identified 411,603 metformin users for the study who were compared with ten times as many age- and sex-matched nonusers of metformin. Hazard ratios (HRs) were estimated using multivariable cause-specific proportional hazards modeling. The ESCC incidence rate was 3.5/100,000 person-years in metformin users and 5.3/100,000 person-years in nonusers. Compared with nonusers, ever-users of metformin had an HR of 0.68 (95% CI 0.54-0.85) and new metformin users had an HR of 0.44 (95% CI 0.28-0.64). Thus, metformin use may prevent ESCC.</p><p>Study IV is a Swedish nationwide case-control study in 1995-1997, including 167 ESCC cases and 820 randomly selected control participants who were all personally interviewed.A risk prediction model was developed based on the predictors: age, sex, smoking, alcohol use, education, duration of the partnership, and childhood residence. The area under the receiver operating characteristic curve was 0.81 (95% CI 0.77-0.84). With these predictors, an individual’s absolute risk of ESCC within the next five years can be predicted.</p><p>In summary, this thesis indicates that ESCC remains common cancer globally, that prevention of this tumor may be possible by smoking cessation and metformin use, and those high-risk individuals can be identified by a risk prediction model, which may enable earlier tumor detection.</p><h3>List of scientific papers</h3><p>I. Wang QL, Xie SH, Wahlin K, Lagergren J. Global time trends in the incidence of esophageal squamous cell carcinoma. Clinical Epidemiology. 2018;10:717-728. <br><a href="https://doi.org/10.2147/CLEP.S166078">https://doi.org/10.2147/CLEP.S166078</a><br><br> </p><p>II. Wang QL, Xie SH, Li WT, Lagergren J. Smoking cessation and risk of esophageal cancer by histological type: systematic review and meta-analysis. Journal of the National Cancer Institute. 2017;109(12). <br><a href="https://doi.org/10.1093/jnci/djx115">https://doi.org/10.1093/jnci/djx115</a><br><br> </p><p>III. Wang QL, Santoni G, Ness-Jensen E, Lagergren J, Xie SH. Association between metformin use and risk of esophageal squamous cell carcinoma in a population-based cohort study. American Journal of Gastroenterology. 2020;115(1):73-78. <br><a href="https://doi.org/10.14309/ajg.0000000000000478">https://doi.org/10.14309/ajg.0000000000000478</a><br><br> </p><p>IV. Wang QL, Lagergren J, Xie SH. Prediction of individuals at high absolute risk of esophageal squamous cell carcinoma. Gastrointestinal Endoscopy. 2019;89(4):726-732. <br><a href="https://doi.org/10.1016/j.gie.2018.10.025">https://doi.org/10.1016/j.gie.2018.10.025</a><br><br> </p>