Introduction

Optimal management after radical endoscopic resection (R0 ER) of high-risk (HR) T1 esophageal adenocarcinoma (EAC) is still a matter of debate due to conflicting reports on the risk of lymph node metastasis (LNM). In case of submucosal (sm) invasion, a/o poor differentiation, a/o lympho-vascular invasion (LVI), additional treatment is often still recommended. In this prospective international multicenter cohort study (PREFER, NCT03222635), we aim to evaluate the safety of a strict endoscopic follow-up (FU) strategy following R0 ER for T1b and HR-T1a EAC.

Aims & Methods

Patients treated with R0 ER of T1b EAC were included from July 2017 - July 2023, in 19 hospitals in Europe and Australia. Patients were defined as HR-T1b EAC in case of sm invasion ≥ 500um, a/o poor differentiation, a/o LVI. From July 2020 we also included HR-T1a EAC, with HR defined as presence of poor differentiation a/o LVI, as part of an ongoing prospective registry. To allow for appropriate FU we assessed outcomes for patients included up to July 2023, at which time inclusion for the prospective PREFER study was complete.
After R0 ER, patients underwent re-staging with endoscopic ultrasound (EUS) and CT/PET. If there were no signs of metastasis (cN0M0), patients were consented for strict endoscopic FU, with gastroscopy and EUS 3-monthly the first 2 years, 6-monthly during years 3 and 4, and at year 5. CT/PET was repeated after 1 year. Primary outcomes were 5-year disease-specific and overall survival; secondary outcomes were rates of distant metastasis, LNM, and local recurrence ineligible for endoscopic treatment.

Results

Per July 2023, 200 patients (166 male, median age 70 (IQR 63 - 76) years) were included, 157 T1b patients (n = 54 low-risk (LR) T1b and n = 103 HR-T1b) and 43 HR-T1a patients.
For the T1b group, median FU was 21 (IQR 12-38) months. Thus far, 11/157 patients (7%) have successfully completed the 5-year FU without signs of metastatic disease or intra-luminal tumor recurrence ineligible for endoscopic re-treatment. Distant metastases were diagnosed in 3/157 (2%, 95%CI 0 - 4) patients, all without signs of local recurrence or LNM: 1/3 underwent resection of a lung metastasis, with no signs of recurrence after 9 months; 1/3 had liver metastasis and started palliative systemic therapy 4 months ago; 1/3 had liver metastasis, declined further treatment and died. Locoregional LNM were diagnosed in 9/157 (6%, 95% CI 2 - 9). All were detected at a curable stage, but 1/9 declined further treatment and died from EAC; the other patients received appropriate treatment and are disease-free after median 26 (IQR 12 - 27) months post additional treatment. In total, 8/157 patients (5%, 95%CI 2 - 9) developed intra-luminal tumor recurrence ineligible for endoscopic re-treatment, 3/8 declined additional treatment and eventually died from EAC. Furthermore, 10/157 patients (6%) died during FU due to unrelated causes.
In the HR-T1a group, no recurrent disease was diagnosed after a median FU of 16 (IQR 12 - 23) months.

Conclusion

The preliminary findings of this first prospective study on HR-T1 EAC support a strict endoscopic FU strategy in select patients who underwent R0 ER with no signs of metastatic disease (cN0M0) at baseline.

Introduction

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus. Inflammation in EoE has been associated with potential risk of esophageal cancer (EC), with controversial results by the most recent studies [1] [2] [3].

Aims & Methods

The aim of this study was to estimate the true risk burden of EC in EoE, further investigating the confounding role of overlapping gastroesophageal reflux disease (GERD) or Barrett Esophagus (BE) on EC occurrence. We conducted a retrospective multicenter cohort study on aggregated data of EoE patients accessing the global federated health research network “TriNetX”, with access to electronic medical records from approximately a hundred million patients across large healthcare organizations (HCOs), based on the ICD-10 code (K20.0), from January 1^st 2000 until March 31^st 2025. We inferred the risk of EC, by comparing two different EoE cohorts: cohort A including EoE diagnosis (excluding eosinophilic gastrointestinal disorders [EGIDS]), not applying any other restrictive criteria; cohort B with only pure EoE diagnosis excluding any instance of GERD (K21.0) and Barrett esophagus (BE) (K22.7) or other EGIDS. The control cohort comprised patients encountered in outpatient clinic for undefined issues (Z00), without diagnosis of EoE/BE or pre-cancerous lesions. We used propensity score nearest neighbor greedy matching, adjusting for PPI use, family history of GI cancer, age, sex, other esophageal diseases (K22.0) and GERD status. Kaplan-Meyer (KM) curves with censoring were built for time-to-event analysis. Log Rank test was used to compare KM curves. Hazard Ratios (HRs) and Risk Ratio (RR) estimation for EC risk were calculated and compared. Sub-analyses for squamous-cell cancer (SCC) vs adenocarcinoma, and for EC location in the esophagus (distal, medium and proximal) were implemented.

Results

After 1:1 propensity score matching, 92,447 patients with EoE (with or without GERD) (cohort A) (mean age 38.9±20.7 years, M 59.7%, previous history of malignant GI neoplasm 2.7%, GERD 40.4%, other esophageal diseases 14.9%, PPI use 40.4%; all p>0.05 with control group) and 32,270 patients pure EoE (without GERD/BE) (cohort B) (mean age 33.9±19.3 years, M 64.7%, previous history of malignant GI neoplasm 1.2%, GERD 0%, other esophageal diseases 8.3%, PPI use 23.2%; all p>0.05 with control group), were compared with controls subjects. Mean follow-up of cohort A was 1298.6 days compared to 1046.5 days in cohort B. The total number of EC occurrences in cohort A were 44 in EA group compared to 31 in the control group, resulting in a HR of 1.676 (1.058-2.657, 95%CI), while a non-significant RR of 1.419 (0.896, 2.247, 95%CI). The KM survival analysis resulted significant (log-rank test p=0.026). Interestingly, when comparing cohort B (pure EoE without GERD or BE) with the control group, only 10 instances of EC in both groups where encountered during the follow-up, with a non-significant HR of 0.893 (0.290-2.754 95%CI) with no difference in the KM survival analysis (p= 0.844). No differences in sub-analysis for squamous cell or adenocarcinoma cancer, neither for EC occurrence in different esophageal localizations were detected.

Conclusion

The results from this global retrospective study on more than 90,000 EoE patients, confirmed the irrelevant risk of EC in pure EoE. The mild association reported in other studies may be likely due to EoE overlap with GERD/BE. No specific surveillance for EC seems needed in EoE when GERD and BE are not present.

References

1. Albaneze N, Cotton CC, Anderson C, Katzka DA, Dellon ES. No Association Between Eosinophilic Oesophagitis and Oesophageal Cancer in US Adults: A Case-Control Study. Aliment Pharmacol Ther. 2025 Jan;61(2):363-368. doi: 10.1111/apt.18431. Epub 2024 Dec 4. PMID: 39629856; PMCID: PMC11680457.
2. Zhou MJ, Hsing AW, Clarke JO. Prevalence and predictors of Barrett's esophagus and esophageal cancer in patients with eosinophilic esophagitis. Dis Esophagus. 2025 Jan 7;38(1):doae120. doi: 10.1093/dote/doae120. PMID: 39775829.
3. Uchida AM, Schuman SS, Pyne A, Peterson K, Carlson M, Garber JJ, Roelstraete B, Ludvigsson JF. Risk of Cancer Diagnosis in Patients With Eosinophilic Esophagitis Using a Nationwide Swedish Population Cohort. United European Gastroenterol J. 2024 Dec;12(10):1378-1387. doi: 10.1002/ueg2.12713. Epub 2024 Nov 20. PMID: 39565026; PMCID: PMC11652337.

Disclosure

E.V. received speaker and/or consulting fees from Sanofi/Regeneron, Falk Pharma, Apollo Therapeutics, and Aurora Biofarma. EVS received consulting fees from Dr Falk Pharma and Reckitt Benckiser; research support from Medtronic and Diversatek Healthcare. DAC.: Medtronic(Speaking, Consulting, License); Diversatek (Consulting); Braintree(Consulting); Medpace (Consulting); Phathom Pharmaceuticals(Speaking); Regeneron/Sanofi(Speaking). AJB received research funding from BMS, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Uniquity, Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Uniquity, Reckitt, AlfaSigma and AstraZeneca. All other authors did not have any disclosures.