Long term follow-up from the Barrett's esophagus screening trial 3 (BEST3) demonstrates high negative predictive value of capsule-sponge-Trefoil-factor-3 (TFF3) test for esophageal adenocarcinoma.

WORKUP (NCCN ESOPH-1): H&P; EGD with biopsy; chest/abdomen CT with oral and IV contrast; pelvis CT with contrast ONLY as clinically indicated; FDG-PET/CT (skull base to mid-thigh) if no evidence of M1 disease; CBC and comprehensive chemistry; EUS if no evidence of M1 or unresectable disease; endoscopic resection (ER) is recommended for accurate staging of early-stage cancers (Tis, T1a, or T1b) and may also be therapeutic; bronchoscopy if the tumor is at or above the carina with no evidence of M1; biopsy of metastatic disease as clinically indicated; assign Siewert category; nutritional assessment and counseling; smoking-cessation counseling; screen for family history. BIOMARKERS: universal MSI (PCR/NGS) or MMR (IHC) testing AND universal PD-L1 testing in ALL newly diagnosed patients; HER2 and CLDN18.2 testing if advanced/metastatic adenocarcinoma is documented or suspected; NGS should be considered. Multidisciplinary evaluation is recommended for stage I-IVA (locoregional) disease (ESOPH-E). ENDOSCOPIC THERAPY (ESOPH-A): the goal of endoscopic therapy (EMR, ESD, and/or ablation) is complete removal or eradication of early-stage disease, pTis, pT1a, and SELECTED superficial pT1b without LVI, plus the pre-neoplastic Barrett's segment. Tis/HGD must first be fully characterized for nodularity, lateral spread and multifocality, with EUS to rule out nodal metastases in select higher-risk cases. Areas of nodularity or ulceration must be RESECTED, not ablated. Completely flat lesions ≤2 cm (squamous HGD/Tis, and BE with flat HGD) should be treated by ER because it gives more accurate histologic assessment; flat lesions >2 cm can be treated by ER but with greater complication risk, and may be treated by ablation alone (data for ablation-alone in squamous HGD are very limited). Lesions pathologically limited to lamina propria/muscularis mucosae (pT1a) or superficial submucosa (pT1b), in the absence of nodal metastases, LVI, or poor differentiation, can be treated with full ER, HOWEVER a thorough patient-and-surgeon discussion of esophagectomy versus the risk of concurrent nodal disease should be undertaken, especially for larger tumors or deeper invasion. Ablation of residual Barrett's should follow ER; complete BE eradication may also be achieved by widefield EMR or ESD at the initial intervention when needed to resect superficial tumor or nodularity ≤2 cm. For SCC, the level of evidence for ablation after ER is LOW; additional ablation may be needed only for multifocal HGD/CIS elsewhere, and may not be needed for completely excised lesions. Endoscopic therapy is 'PREFERRED' for limited early-stage disease: Tis and T1a, ≤2 cm, well or moderately differentiated. Esophagectomy is indicated for extensive carcinoma in situ (pTis/HGD), pT1a, or superficial pT1b, especially nodular disease not adequately controlled endoscopically. PRIMARY TREATMENT, MEDICALLY FIT PATIENTS, ADENOCARCINOMA (ESOPH-13): cT1b-cT2, N0 LOW-RISK (<3 cm, well differentiated) → esophagectomy. cT2 N0 HIGH-RISK (LVI, ≥3 cm, or poorly differentiated), cT1b-cT2 N+, or cT3-cT4a any N → perioperative systemic therapy is PREFERRED (FLOT: 5-FU 2600 mg/m2 IV over 24 h day 1, leucovorin 200 mg/m2, oxaliplatin 85 mg/m2, docetaxel 50 mg/m2, every 14 days, 4 cycles pre- and 4 cycles postoperatively; or FLOT + durvalumab 1500 mg for PD-L1 CPS ≥1 or TAP ≥1%, category 1 for EGJ, category 2A for esophageal adenocarcinoma; note MATTERHORN showed no EFS advantage for durvalumab in diffuse-type disease), QUALIFIER: perioperative therapy is preferred for patients medically fit and with access to frequent toxicity evaluation; preoperative chemoradiation for planned esophagectomy remains an option and may be considered for borderline-resectable patients or patients who are not FLOT candidates (perioperative FOLFOX/CAPOX is another alternative). Consider neoadjuvant or perioperative immune checkpoint inhibitor if the tumor is MSI-H/dMMR (in multidisciplinary consultation; the role of surgery after complete response is unclear). Definitive chemoradiation for patients who are medically unfit/inoperable for surgery or who decline surgery. cT4b → definitive chemoradiation, or chemotherapy alone with invasion of trachea, great vessels, vertebral body, or heart. SQUAMOUS CELL CARCINOMA (ESOPH-2): cT1b-cT2, N0 LOW-RISK (<3 cm, well differentiated) → esophagectomy (non-cervical esophagus). cT2 N0 high-risk (LVI, ≥3 cm, poorly differentiated), cT1b-cT2 N+, or cT3-cT4a any N → PREOPERATIVE CHEMORADIATION is preferred (or definitive chemoradiation). cT4b → definitive chemoradiation, or chemotherapy alone for trachea/great-vessel/vertebral/cardiac invasion. NCCN states explicitly: 'Preoperative chemoradiation is preferred for esophageal SCC.' Preoperative RT dose 41.4-50.4 Gy at 1.8-2.0 Gy/day (23-28 fractions); preferred concurrent regimens include weekly paclitaxel 50 mg/m2 + carboplatin AUC 2 (CROSS, category 1) and fluorouracil + oxaliplatin (category 1). POSTOPERATIVE (ESOPH-F): nivolumab is the preferred postoperative regimen ONLY after PREOPERATIVE CHEMORADIATION with R0 resection and residual pathologic disease (category 1), 240 mg IV every 14 days for 16 weeks, then 480 mg IV every 28 days, maximum treatment duration 1 year. PALLIATION (ESOPH-A/H): esophageal dilation with balloons or bougies for temporary relief of malignant or treatment-related obstruction (avoid overdilation, perforation risk); long-term dysphagia palliation by endoscopic tumor ablation (Nd:YAG laser, PDT, cryoablation) or expandable metal/plastic stents; feeding gastrostomy or jejunostomy for anorexia/dysphagia/malnutrition, but placement of a GASTROSTOMY preoperatively may compromise the gastric vasculature and interfere with gastric-conduit reconstruction and SHOULD BE AVOIDED (feeding jejunostomy is generally preferred for postoperative nutritional support; multidisciplinary expertise is recommended before percutaneous gastrostomy).