S388 Risk of Esophageal Cancer in Achalasia: A Matched Cohort Study Utilizing the Veterans Affairs Achalasia Cohort (VA-AC)

Abstract

Introduction: Achalasia is a postulated risk factor for esophageal cancer (EC) – both squamous cell carcinoma (SCC) and adenocarcinoma (AC). Evaluation of EC-associated risk factors and outcomes in achalasia are limited due to a lack of large, validated cohorts available for study. Our aim was to evaluate the risk of EC among individuals with compared to without achalasia utilizing a large, validated achalasia cohort: the Veterans Affairs Achalasia Cohort (VA-AC). Methods: We conducted a matched cohort study among US Veterans aged ≥18 years between 1999-2020. Individuals with achalasia from the VA-AC were matched to individuals without achalasia at a ratio of 1:4 on index achalasia encounter date, and by sex, year of birth, and first VA visit date +/- 180 days. Follow-up was censored at the outcome (EC), death from a non-EC related cause, or end of the study period. EC cases were ascertained from cancer registry and cause-specific mortality, with all cancer cases reviewed for verification. Descriptive statistics were performed for baseline characteristics. EC hazard functions were assessed using Cox regression models. Results: 1,866 Veterans with achalasia were matched to 7,464 Veterans without achalasia. Median age was 55 years (IQR 48-63), and 92% were male (Table). There were 17 EC cases among Veterans with achalasia (3 AC, 12 SCC, 2 unknown type) compared to 15 EC cases among Veterans without achalasia (11 AC, 1 SCC, 3 unknown). Median time from achalasia diagnosis to EC development was 3.0 years (IQR 1.3-9.1). Patients with achalasia had a 5.4-fold higher risk of EC (HR 5.4, 95% CI 2.8,10.5) compared to patients without achalasia. Higher cumulative incidence of EC (p< 0.0001, based on log-rank test; Figure) in those with vs without achalasia at 5-, 10- and 15-years follow-up was observed. In post hoc analysis, several individuals with EC also had candida esophagitis preceding their cancer diagnosis (12.5%) by median time 1.3 years (IQR 0.2-2.7). Based on univariate cox regression model, patients with vs without candida esophagitis had a 18.3-fold higher risk of EC (95% CI 6.2, 53.7). Conclusion: Using a national cohort of US Veterans, we found achalasia was associated with 5-fold increased EC risk compared to those without achalasia. Candida esophagitis exposure may also predict higher EC risk. Additional studies are needed to understand if this increased risk of EC warrants routine endoscopic surveillance in individuals with achalasia.Figure 1.: Cumulative Incidence of Esophageal Cancer Kaplan Meier curve demonstrating cumulative incidence at 5-, 10- and 15-year time points. Incidence at each time point was significantly higher for individuals with achalasia compared to individuals without achalasia. Table 1. - Achalasia ^ N = 1866 No AchalasiaN = 7464 Age, median (IQR) 55.0 (48.0 – 63.0) 55.0 (48.0 – 63.0) Males, n (%) 1725 (92.4) 6900 (92.4) Race/Ethnicity, n (%) Asian/Pacific Islander 23 (1.2) 113 (1.5) Black 378 (20.3) 1164 (15.6) Hispanic 125 (6.7) 326 (4.4) Multiracial/Other 25 (1.3) 157 (2.1) White 1208 (64.7) 4755 (63.7) Unknown 107 (10.1) 949 (12.7) BMI, median (IQR) 28.6 (25.1 – 32.9) 28.6 (25.4 – 32.6) Diabetes, n (%) 528 (28.3) 1686 (22.6) Smoking Status, n (%) Current 532 (28.5) 1592 (21.3) Former 386 (20.7) 1293 (17.3) Never 556 (29.8) 2398 (32.1) Unknown 392 (21.0) 2181 (29.2) Aspirin Exposure, n (%) 683 (36.6) 1699 (22.8) Barrett’s Esophagus, n (%) 125 (6.7) 189 (2.5) Candida Esophagitis, n (%) 64 (3.4) 7 (0.1) Esophageal Cancer, n (%) 17 (0.9) 15 (0.2) Squamous Cell Carcinoma 12 1 Adenocarcinoma 3 11 Unknown 2 3 *All variables are significant with p-value <.0001, except Age (Matched), Gender (Matched), and BMI which were not statistically significant at alpha=0.05.^Achalasia subjects were previously validated using an algorithm consisting of 3 or more ICD9 or ICD10 codes in a subject's lifetime plus a CPT code for esophageal manometry; the positive predictive value (PPV) for this algorithm to diagnose true achalasia subjects was 94% (95% confidence lower bound of 88.5%) BMI = body mass index; IQR = interquartile range.