Esophageal Squamous Cell Carcinoma Clinical Trial
Official title:
Effcacy of Endoscopic Screening for Esophageal Cancer in China (ESECC): a Population-based Randomized Controlled Trial
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.
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