Predicting Trends in Esophageal Adenocarcinoma Incidence and Mortality

While esophageal squamous cell carcinoma (SCC) incidence has been declining in the US and other parts of the western world, esophageal adenocarcinoma (EAC) incidence has experienced an alarming five-fold increase over the past four decades. There is no consensus regarding the causes of this increase in EAC incidence, although an increasing prevalence of gastroesophageal reflux disease (GERD) related to increases in abdominal obesity and wider eradication of Helicobacter pylori infection have been suggested, among others. A 2014 joint analysis (Kong et al., 2014) used three independent mathematical models to analyze the EAC incidence and mortality rates among men and women aged 20-84 years in the US during 1975-2010. We then projected the EAC incidence and mortality rates to the year 2030. Despite the differences in mathematical formalisms among the three models, our projections suggest that the EAC incidence rate will continue to increase. Thus, improving screening and surveillance protocols for EAC continues to be a critical public health concern that needs to be addressed.

Evaluating the Impact of Endoscopic Ablation for Barrett’s Esophagus on Esophageal Adenocarcinoma Incidence and Mortality

Until recently, most societal guidelines recommended regular surveillance in order to achieve early
detection of EAC after diagnosis of Barrett’s Esophagus (BE). New techniques for endoscopic ablation of BE such as radiofrequency ablation (RFA) have become more widely utilized with the aim of preventing the progression to EAC. Currently the American Gastroenterological Association (AGA) guidelines recommend endoscopic ablative therapy only for patients with at least high-grade dysplasia (HGD), since the incremental benefit for this therapy on low-grade dysplasia (LGD) and particularly non-dysplastic BE patients remains uncertain and under debate. Although a growing body of investigation has focused on the efficacy and durability of RFA treatment, the impact of its widespread utilization on population-level cancer control has not been analyzed.

In this base case analysis, we applied the three CISNET models to estimate the impact of endoscopic ablative treatment on EAC mortality. We evaluated multiple management strategies, testing various factors which could impact RFA effectiveness, such as point of intervention (as determined by initial dysplasia status) and individual patient risk characteristics such as age and gender.

Strategy	NDBE Patients	LGD Patients	HGD Patients
National History (NH)	No intervention	No intervention	No intervention
Surveillance (S)	3 yearly surveillance	6 months, Annual surveillance	3 monthly surveillance
BE surveillance and HGD treatment (HGD)	3 yearly surveillance	Yearly surveillance	Endoscopic ablative therapy
BE surveillance and Dysplasia treatment (LGD)	3 yearly surveillance	Endoscopic ablative	Endoscopic ablative
BE treatment (BE)	Endoscopic ablative therapy	Endoscopic ablative therapy	Endoscopic ablative therapy
Characteristics of simulated interventions on Barretts esophagus patient cohort. BE: Barretts esophagus, ND: No dysplasia, LGD: low-grade dysplasia, HGD: high-grade dysplasia

The results of our comparative simulation analyses indicated that endoscopic ablative therapy for BE can be effective for cancer control. The resources needed to achieve these results are high, especially for RFA treatment of lower grade and non-dysplastic BE where diminished efficiency limits intervention.

Analyzing current EAC targeted screening, surveillance and treatment strategy

In response to the rapid rise in EAC incidence in the US and much of the western world, the primary
cancer control measure has been to screen patients with chronic gastroesophageal reflux disease (GERD). Those identified as having BE undergo endoscopic surveillance with biopsies at regular intervals, with the goal of detecting dysplasia or early mucosally limited cancer (intramucosal carcinoma, T1a). The assumption was that this strategy would diminish EAC-associated mortality. However, the benefit of this strategy has not been demonstrated by any clinical trial. Perhaps more telling is that although this targeted screening/surveillance practice has been widely utilized for many years, there has not been an appreciable improvement in EAC incidence or survival.

We will perform a comparative modeling exercise where each of the three CISNET models will analyze the effectiveness of the current EAC control strategy, which is depicted in the figure below including management corresponding to biologic/clinical health states.

In the first phase of the modeling, we will simulate and analyze a single birth cohort. The initial birth cohort will consist of individuals born in calendar year 1930, who were 45 years old when SEER data became accurately available (1975) and were 81 years old in 2011. In the second phase, we will perform analyses from a US population perspective, as this perspective is most relevant to inform cancer control interventions and policy. All US birth cohorts from 1890-1970 will be simulated and the results aggregated to produce population results. Additionally, we will extend the analyses for the entire US population into the future (2020 and 2030) to make projections regarding the impact of these regimens on future EAC incidence and mortality. We will assess current endoscopic screening, surveillance and treatment practices to determine their projected impact in the future.

Esophageal Cancer Other Achievements: Highlights

• Do trends in obesity and other lifestyle-associated risk factors match trends in Esophageal Adenocarcinoma (EAC) in three western countries?
• How do the rate-limiting steps involved in tumor initiation, malignant transformation, and progression influence the shape of the cancer incidence curve?

Do trends in obesity and other lifestyle-associated risk factors match trends in Esophageal Adenocarcinoma (EAC) in three western countries?

As obesity is a well-established factor in EAC risk, the obesity epidemic is believed to be an important driver of the rise of EAC in western countries. We aimed to test this hypothesis by comparing changes in lifestyle-associated factors with changes in EAC incidence over time between the US, Spain, and the Netherlands.

We used population-based data bases from the three countries to extract cancer incidence (US Surveillance, Epidemiology, and End Results (SEER) data base; Spain 13 cancer registries; the Netherlands Eindhoven Cancer Registry). Obesity, smoking rates, and alcohol use were gathered from national US and European health surveys or the World Health Organization (WHO) data repository).

We found that the US, Spain, and the Netherlands showed large differences in both absolute rates and time trends in EAC incidence. Time trends for obesity, smoking, and alcohol in these countries do not correlate with EAC incidence trends. Therefore, other important drivers of this increase in EAC incidence in these countries must be present. While reversing the trend in obesity is important for overall population health, reduction in EAC must rely on the identification of other causative factors. (Kroep S et al., 2014)

How do the rate-limiting steps involved in tumor initiation, malignant transformation, and progression influence the shape of the cancer incidence curve?

Cancer incidence curves harbor information about hidden processes of tumor initiation, premalignant clonal expansion, malignant transformation, and even some limited information on tumor growth before clinical detection. Our analyses of the incidences of four digestive tract cancers show that the age-specific incidence curvesupon adjustments for secular trends and, in the case of esophageal adenocarcinoma (EAC), inclusion of an event describing the conversion of normal squamous to metaplastic Barrett's epitheliumare well approximated by a model that explicitly incorporates the stochastic growth kinetics of premalignant clones, the sporadic appearance of malignant cells within these clones, and a constant time delay corresponding to the mean sojourn time of a malignant clone. While this sojourn seems very short for pancreatic cancer (3 years), intermediate for colorectal cancer (5-7 years), it is much longer for gastric cancer and esophageal adenocarcinoma (10-12 years). Furthermore, with the exception of pancreatic cancer, our results are consistent with the assumption of a high (>95%) probability of tumor stem cell extinction or terminal differentiation. We conclude that malignant clone extinction and tumor sojourn times play important roles in reducing and delaying cancer incidence and influencing the shape of incidence curves for colorectal, gastric, pancreatic, and esophageal cancers. (Luebeck EG et al., 2013)