To evaluate the efficacy of endoscopic screening on esophageal cancer (EC) and determine the most cost-effective strategy of endoscopic screening in high risk population in China, 668 villages of Hua county, a high risk area of esophageal cancer, were randomized into screening arm and control arm in a ratio of 1:1 and the total sample size is over 32,000 (~16,000 per group). Participants in the screening arm will accept standard chromoendoscopy examination to detect early esophageal cancer and no screening were designed in the control arm. The incidence of advanced EC, EC-specific mortality and all-cause mortality will be compared within the two groups to test the hypothesis that endoscopic screening would alter the natural history of lesions in esophagus and the incidence of advanced stage EC, EC-specific mortality and all-cause mortality in the screening arm will be lower than the control group. Cost-effectiveness analysis will also be conducted to find the most cost-effective strategy of endoscopic screening in rural China.

BACKGROUND Esophageal cancer (EC) is one of the most common cancers in the world, and is a leading cause of cancer death, with more than 450,000 new cases and 400,000 deaths in 2012.Nearly half of the new cases of EC worldwide are found in China, and esophageal squamous cell carcinoma (ESCC) is the predominant histologic type. A series of etiologic factors for ESCC have been proposed in previous studies conducted in high prevalence regions of China, including age, family history of ESCC, poor nutritional status, smoking and drinking, chemical carcinogen exposure, and human papillomavirus (HPV) infection. But the main etiologic factors have not been definitively identified.

Because there are typically no symptoms in the early stages of ESCC, the vast majority of cases are clinically diagnosed at an advanced stage. The overall five-year survival is about 20% in China, and is even lower in less developed countries. However, if the disease is found at an early stage, the five-year survival may be 80% or greater. This profound improvement in survival indicates there is clearly a need for effective early detection strategies to enable earlier diagnosis and curative treatment. Esophageal squamous dysplasia (ESD) is considered to be the premalignant precursor lesion for ESCC, and harbors a high risk for progression into invasive cancer. ESD as well as early-stage malignant lesions (carcinoma in situ, CIS) are therefore screening targets for ESCC. Various screening methods have been tested, and endoscopy with iodine staining is the gold standard technique for the diagnosis of ESCC and its precursor lesions. Endoscopic screening has therefore been widely accepted as an optimal strategy in the secondary prevention of ESCC. However, taking the high cost and invasive nature of endoscopy into consideration, the efficacy and cost-effectiveness of such screening, must be evaluated prior to introduction of a population-wide screening program. Evidence regarding the efficacy of endoscopic screening for ESCC has been based predominantly on observational studies in high risk regions. There has been only one non-randomized controlled trial which reported that endoscopy plays a positive role in reducing mortality. No randomized controlled trials (RCTs) evaluating endoscopic screening have been reported to date. Observational studies and trials which are not randomized are limited in determining the true benefits of screening on reducing mortality due to potential lead-time bias, length-time bias and confounding bias. Hence, one-step large-scale population-based RCT are needed to determine the efficacy of endoscopic screening for ESCC.

In January 2012, we initiated the ESECC (Endoscopic Screening for Esophageal Cancer in China) trial in rural Hua County of Henan Province, which is a high-risk region in northern central China. This is the first population-based RCT aiming to evaluate the efficacy and cost-effectiveness of endoscopic screening for ESCC worldwide.

STUDY DESIGN Setting and participants This ESECC trial was undertaken in rural Hua County, which is an agricultural region in the northern part of Henan Province, Peoples Republic of China with a rural population of 1.1 million. The mortality for ESCC in this area is among the highest in the world.

Participants were eligible for the study if they meet the following criteria: 1) permanent residency in a target village; 2) age 45-69 (>5 years of life expectancy), and no history of endoscopic examination within 5 years prior to the initial interview; 3) no history of cancer or mental disorder; 4) negative for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV); 5) voluntary participation and agreement to complete all phases of the examination.

Randomization This ESECC trial was designed as a cluster RCT. There are a total of 968 villages in rural Hua County, and 668 target villages were randomly selected from the 846 villages with population sizes ranging from 500 to 3,000 in Hua County. These 668 target villages were randomly allocated into the screening arm of the study or the control arm at a ratio of 1:1 (334 villages in each arm), using a blocked randomization procedure based on the total population size of each village for balancing the sample sizes between the two study arms.

Sample size According to the New Rural Cooperative Medical Scheme (NCMS) registration system of Hua County, the combined incidence rate of advanced esophageal cancer and cancer of the gastric cardia in the targeted population (age 45-69) was estimated to be 184.07/100,000 in 2011. Calculation of required sample size was based on the following assumptions: the average period of progression from severe dysplasia to EC is 5 years, and the accrual time is 5 years; the study period was set at 10 years, and 5% of the participants would be lost to follow-up per year; 5% of the participants in the control arm would seek endoscopic examination independently during the study period. Finally, with a total of 32,337 participants enrolled (1:1 between arms, ~20% of all eligible residents in target villages), statistical power of 86% at a one-sided 0.025 significance level can be achieved, even if only 30% of advanced EC cases were protected by screening. The number of participants enrolled in each target village was determined by the weight of the population size of the very village in the total population of the whole arm.

Intervention An informed consent was obtained from each study participant. Basic information including name, gender, date of birth, address and phone number was then collected and managed using a custom-designed database system. All participants received a physical examination which included measurement of height, weight and blood pressure. Blood samples were collected to screen for HBV, HCV and HIV, and participants with any of these infections were excluded. A computer aided one-on-one questionnaire investigation was conducted for all participants by trained interviewers to collect data on potential risk factors for esophageal cancer. EQ-5D-3L, a standardized generic instrument, was used in this ESECC trial to assess health related quality of life (HRQOL).Standardized explanations regarding the items in the questionnaire were provided if the participant was unable to understand the questions or respond appropriately.

In the screening arm, standard upper gastrointestinal endoscopy (UGE) with iodine staining was performed by physicians experienced in endoscopic examination. The entire esophagus and stomach were visually examined and biopsies were taken from all focal lesions. Standard sites in the esophagus (28 and 33 centimeters distal to the incisors in the 6 o'clock position) were biopsied if no visually identifiable abnormalities were found elsewhere. Biopsy specimens were fixed in 10% formaldehyde, embedded in paraffin, sectioned at 5μm, and stained with hematoxylin and eosin. The biopsy slides were reviewed by pathologists at Anyang Cancer Hospital without knowledge of the endoscopic findings. Diagnoses of ESD (mild, moderate and severe), CIS and squamous cell carcinoma were independently confirmed by two pathologists and discrepancies in their histologic diagnoses were adjudicated by consultation. To reflect the situation in real population-level screening as much as possible, participants who were diagnosed with severe squamous dysplasia, CIS or squamous cell carcinoma in the esophagus or malignant lesions in other sites were only informed of the diagnosis and provided with appropriate medical advice, rather than arranging directly for their further clinical treatment.

In the control arm, no endoscopic screening was performed and an abdominal ultrasound scan which had no association with the diagnosis of esophageal cancer was used.

Follow-up and outcomes The primary endpoint of the trial was EC-specific mortality, and the secondary endpoints included mortality from all causes, incidence of advanced EC and cost per quality-adjusted-life-year (QALY) gained. Two sources of follow-up data were used to identify outcome events in this study, namely door-to-door interviews, and electronic registry data. A record of vital events, including the experience of UGE, onset of cancer and death, will continue to be collected through annual door-to-door interviews with all cohort members. Data regarding cancer occurrence and death were also collected from the New Rural Cooperative Medical Scheme (NCMS) of Hua County, which is a government-run health insurance program in rural China with a nearly 100% participation rate which has been proved to be an ideal data source regarding cancer occurrence, diagnosis and treatment, and from the Death Registry of National Centers for Disease Control and Prevention (DR-CCDC) respectively.

Ethics statement This trial was approved by the Institutional Review Board of the Peking University School of Oncology, China. Informed consent was obtained from each participants.

Participants were eligible for the study if they meet the following criteria: 1) permanent residency in a target village; 2) age 45-69 (>5 years of life expectancy), and no history of endoscopic examination within 5 years prior to the initial interview; 3) no history of cancer or mental disorder; 4) negative for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV); 5) voluntary participation and agreement to complete all phases of the examination.