Exploring the Natural History of Esophageal Adenocarcinoma and Possibilities for Early Detection and Intervention

objectives: The incidence of esophageal adenocarcinoma (EAC) has been rising in the Western world for the past few decades. The prognosis for diagnosed EAC patients is poor and although new treatment methods are emerging, only 15% of the diagnosed EAC patients survive after 5 years. The aim of this study was to systematically review the current knowledge on the possibilities for early detection of EAC and the benefits of early detection with regard to the burden of EAC in the population. methods: We performed a systematic literature search for articles published between 2002 and 2013 (Medline, PubMed). We summarized evidence on possibilities of early detection of EAC based on predictive signs, symptoms and risk factors; decreasing doctor/ patient delay; screening and surveillance for EAC and its precursor lesion Barrett’s esophagus (BE); risk factors for progression to EAC in BE patients under surveillance, and whether early detection of EAC led to improved prognosis. results: We included 49 papers in our study. Risk factors for (precursors of) EAC were male gender, waist-to hip ratio, gastro-esophageal reflux symptoms and genetic factors. However, early detection on the basis of (a combination of) these risk factors in the general population did not lead to earlier detection of EAC. Scarce evidence indicates that patientand doctor delay did not negatively impact survival of EAC. Observational studies show that patients diagnosed in a surveillance program for BE had a better survival than those diagnosed outside such a program. However, whether surveillance for BE will lead to health benefits, in terms of mortality reduction, was not investigated. Modeling studies suggest that surveillance for BE can be effective in patients with dysplasia, while cost-effectiveness improves by stratification of patients based on risk factors for carcinogenesis. Esophagitis, nodularity, BE segment length, dysplasia, and detecting aneuploidy/ tetraploidy or methylation in biopsies from BE are predictors for malignant progression. conclusion: Early detection of EAC on a population level by means of screening is not yet shown to be successful as signs, symptoms and risk factors identified for EAC in the general population are also associated with other diseases and not exclusively predictive for EAC. There is no definite evidence, but only strong suggestions that early detection of EAC in a high-risk population, such as BE patients is effective by means of surveillance. In order to improve cost-effectiveness, surveillance should be optimized by improving risk stratification in this population. New diagnostic modalities are emerging including geneticand epigenetic markers that might provide higher predictive values for progressive BE, providing new opportunities for early detection on both population level and high-risk populations. Ea rl y d et ec tio n fo r E so p ha ge al a d en o ca rc in o m a C ha p te r 5 8 5 INtroDuctIoN Esophagus cancer can be divided into two subgroups: esophageal adenocarcinoma (EAC) and squamous cell carcinoma (SCC). In countries where incidence rates of EAC have been examined, there has been a sharp increase in cancer incidence over the past few decades, whereas rates of SCC have remained relatively stable. In many Western countries the incidence of EAC has increased more rapidly than any other malignancy. Although new techniques for treatment of EAC are emerging, survival of patients diagnosed with EAC has remained poor because most cases are diagnosed at an advanced stage of malignancy, resulting in a 5-year survival rate of less than 15%. The main precursor of EAC is Barrett’s esophagus (BE), which can only be diagnosed by endoscopy and biopsy taking for histologic confirmation. Currently ~92% of diagnosed EAC is found at first endoscopy, that is, without an earlier confirmed BE diagnosis. Furthermore, only a small percentage of BE diagnosed patients (6-11%) eventually develops EAC. In order to decrease the burden of this disease in the population, it is essential to know if early detection of EAC is possible, and how large the potential health gain is of diagnosing this disease in an earlier phase of malignancy. There are different aspects of early detection, which are included in the conceptual framework of potential health gains (figure 1). The first aspect pertains to the question whether early detection is possible by earlier recognition of specific signs, symptoms and risk factors. For this, we will investigate which of these factors are associated with BE and EAC development. The second aspect concerns the question whether doctorand/or patient delay occur. Problems with swallowing are among the first indications of EAC. A delayed diagnosis can be caused by patient’s unawareness of signs, symptoms and high risk factors, delaying the time between symptoms and visiting a doctor. Furthermore, it can be speculated that if patients and doctors would have a higher awareness of determinants and associated factors of EAC, EAC might be earlier detected because indications for EAC have been timely identified. The time between a doctor’s visit and reference towards specific medical care can also cause a delay in diagnosis. A third aspect to consider is screening and surveillance. Screening involves the detection of a cancer or it’s precursor in order to treat the patient in an early phase and prevent the silent development towards a malignant cancer or progression into an advanced/late tumor stage. Examples of currently used population-wide screening include breast, cervix an colorectal cancer. With surveillance a population known to be at higher than average risk is regularly being examined. Currently, early detection of EAC is possible by diagnosing the precursor BE with upper endoscopy after which regular surveillance or treatment according to dysplastic grade is generally advised. An emerging question is whether determinants for malignant high-grade dysplasia (HGD) Ea rl y d et ec tio n fo r E so p ha ge al a d en o ca rc in o m a C ha p te r 5 8 6 and EAC in BE can be identified to optimize surveillance for patients with high risk. The potential health gains from screening and surveillance for EAC in terms of mortality reduction are required to provide evidence for valid decision making considering both costs and benefits for screening and surveillance methods. In this study we aimed at summarizing the current evidence on whether early detection of EAC and its precursors is possible based on i. signs, symptoms and risk factors, ii. decreasing doctorand/or patient diagnostic delay, iii. screening for and surveillance of BE and iv. risk stratification within BE patients.