Esophageal squamous cell carcinoma : opportunities for prevention

Abstract: 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. 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. 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. 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. 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. 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.