Chapter 1
Epidemiology of esophageal carcinoma

Mohammad H. Shakhatreh & Hashem B El-Serag

Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Houston VA HSR&D Center of Excellence, Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, USA

1.1 The incidence and mortality related to esophageal cancer

Esophageal cancer is the sixth most common cancer among men and the ninth among women, affecting more than 450,000 people globally each year. Approximately 90% of cases of esophageal cancer are squamous cell carcinoma (ESCC) [1], and the rest are adenocarcinoma (EA). The highest reported incidence and mortality rates for ESCC occur in Jiashan, China, with an age-adjusted incidence rate of 14.6 cases per 100,000 (Figure 1.1). The highest age-adjusted incidence rates of EA occur in Scotland (6.6 per 100,000) and in other parts of the United Kingdom [2]. In the United States, the age-adjusted rate of esophageal cancer in 2009 was 4.1 per 100,000; EA alone had 2.7 cancers per 100,000, a sharp increase from the 1973 rate of 0.4 cancers per 100,000 [3] (Figure 1.2)

Figure 1.1 Age-adjusted incidence rates of EA (a) and ESCC (b) in 1998-2002 using world standard population (2000). EA: Esophageal adenocarcinoma. ESCC: Esophageal squamous cell carcinoma. CI5-IX: Cancer Incidence in Five Continents, volume 9. IARC: International Agency for Research on Cancer. SEER: Surveillance, epidemiology and end results. NECSN: North East Cancer Surveillance Network.

Data from CI5-IX (2007), IARC.

Figure 1.2 Trends in incidence and five-year relative survival of EA, ESCC, GEJ-CA. Data from SEER 9 Regs research data, Nov 2011 sub, vintage 2009 pops (1973-2009) <Katrina/Rita Population adjustment> - linked to county attributes - Total US, 1969-2010 counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2012, based on the November 2011 submission. SEER: Surveillance, epidemiology, and end results. EA: Esophageal adenocarcinoma. ESCC: Esophageal squamous cell carcinoma. GEJ CA: Gastro-esophageal junction carcinoma.

Although EA is the fastest-rising malignancy among white men in the United States, its increase may be slowing [4]. The US average annual percentage change in incidence was 8.4 (95% CI 7.7-9.1) before 1997, but it decreased to 1.6 (95% CI 0.0-3.3) from 1998 to 2009 [5]. In Scandinavia, the average annual percentage change has continued to increase [6].

In addition to geographic differences in the distribution of EA, there are remarkable variations in the demographics of persons affected by this cancer. The incidence of EA increases with age and peaks in the eighth decade of life. Independent of age, however, people born in more recent years have a higher incidence of EA [7]. EA incidence is five-fold higher among non-Hispanic whites than among blacks, while ESCC incidence rates among black men are four times higher than for white men [8]. Finally, most esophageal cancer cases (77.7%) affect men [6].

The incidence of EA is 7-10 times higher in men, while the incidence of ESCC is only 2-3 times higher in men than in women, according to numerous cancer registries around the world [9, 10]. This sex discrepancy varies among different races; for example, in the 50-59 age group, the highest male-to-female ratio was 20.5 in Hispanics, followed by 10.8 in whites and then 7.0 in blacks. With EA, male predominance is evident globally (Figure 1.1). Whether the difference in incidence rates among men and women or between whites and blacks is due to less gastroesophageal reflux disease (GERD) and/or Barrett's Esophagus (BE) prevalence, or to a less progressive form of these diseases, is unknown. Despite an equal distribution of GERD between men and women [11, 12], men seem to have a more severe form of the disease, with a higher complication rate [13].

With ESCC, some areas (e.g. South Karachi, Pakistan; West Midlands, UK; Oman; Penang, Malaysia; South Australia; Kuwait) have a higher age-adjusted incidence rate among women than among men [2] (Figure 1.1). The reason behind this is unknown. The main risk factors for ESCC, which show broad regional variation, include heavy alcohol consumption, tobacco smoking and human papilloma virus infection, as well as few rare disorders, such as achalasia of the cardia, and tylosis. These will not be discussed further in this review.

1.2 Mortality

Esophageal cancer is a highly fatal disease. The overall five-year relative survival for patients diagnosed with esophageal cancer in the United States was approximately 17.3% between 2003 and 2009 (Figure 1.2). The disease stage at time of diagnosis impacts survival greatly, as the age-adjusted five-year relative survival of 38.6% in localized disease declines to 3.5% in disease associated with distant spread. However, the overall survival over the past two decades has slightly, but significantly, improved. Despite the use of screening endoscopy in high-risk groups, about 35% of EA cases between 2004 and 2010 were diagnosed at an advanced stage [14]. A higher mortality rate for nonwhite Hispanics and blacks mostly has been attributed to the decreased receipt of cancer-directed surgery, indicating possible ethnic disparities in treatment application or availability [15].

1.2.1 Progression of BE to EA

A summary of published annual EA-risk data of nondysplastic BE ranges from 0.12-0.50% to 0.33-0.70% in population-based studies and meta-analyses, respectively [16]. Recent studies have indicated that the risk of progression from BE to EA is lower than previously reported [17]. The risk in a Dutch study of 42,207 patients was 0.4% [18]; in an Irish study of 8,522 patients, it was 0.22% per year (95% CI 0.19-0.26%) [19]; and in a Danish study of 11,028 patients, it was 0.12% (95% CI 0.09-0.15) [20].

1.3 Risk factors for EA

Risk factors for esophageal adenocarcinoma are outlined in Table 1.1.

Table 1.1 Summary of risk factors for the development of esophageal adenocarcinoma

GERD: Gastroesophageal reflux disease. EA: Esophageal adenocarcinoma. H. pylori: Helicobacter pylori. NSAIDs: Non-steroidal anti-inflammatory drugs. PPI: Proton pump inhibitor.

1.3.1 GERD

Several population-based case control studies have established a strong association, including a dose-response relationship between GERD symptoms and EA (and adenocarcinoma of the gastric cardia), but not ESCC [21, 22]. In a meta-analysis of five population-based studies, the presence of at least weekly GERD symptoms was associated with an odds ratio (OR) for developing EA of 4.92 (95% CI 3.90-6.22), which increased to 7.4 (95% CI 4.94-11.10) when the symptoms occurred on a daily basis, compared with asymptomatic controls or those with less frequent symptoms [23]. However, up to 40% of the patients with EA may not report bothersome GERD symptoms.

1.3.2 Tobacco smoking

A pooled analysis of individual data from ten case-control and two cohort studies from Australia, Canada, Ireland, the United Kingdom and the United States, including 1242 EA cases, 1263 gastroesopheageal junction cancer (GEJ-CA) cases, 954 ESCC cases and 7053 controls without cancer [24], reported an increased risk of both types of esophageal cancer with history of tobacco smoking. The calculated OR of EA increased from 1.66 (95% CI 1.1-2.4) with 1-29 pack-years of smoking to 2.77 (95% CI 1.4-5.6) with >60 pack-years smoking history, with a statistically significant trend (p < 0.01). The same study concluded that, for equal pack-years of smoking, more cigarettes per day for shorter duration was less deleterious than fewer cigarettes per day for longer duration. For example:

Previous smokers have in EA, when comparing those with equal pack-years of smoking, patients who smoked 10-19 cigarettes/day had an increased risk compared with those who smoked more than 40 cigarettes/day (p for trend = 0.40). Previous smokers have a lower risk of developing EA or ESCC than current smokers, but slightly higher than those who have never smoked [25]. Tobacco smoking does not seem to play a major role in developing BE [26]; however, in patients with established BE, the risk of EA increases with the magnitude and duration of smoking history [27]. Some studies indicate that the effect...