Esophagus/Reflux, in full.

In patients with classic GERD symptoms (heartburn, regurgitation) and no alarm symptoms, give an 8-week trial of empiric PPI ONCE DAILY before a meal (strong, moderate evidence); administer PPI 30-60 minutes before a meal rather than at bedtime (strong, moderate). Endoscopy is the FIRST test in patients presenting with dysphagia or other alarm symptoms, the guideline names weight loss and GI bleeding, and also in patients with multiple risk factors for Barrett's esophagus (strong, low). If classic symptoms respond to the 8-week trial, attempt to discontinue the PPI (conditional, low); for patients without erosive esophagitis or Barrett's whose symptoms resolved, an attempt at discontinuation should be made; patients requiring maintenance should take the lowest effective dose. If symptoms do not respond adequately to the 8-week trial, or return on discontinuation, perform diagnostic endoscopy, ideally after PPIs are stopped for 2-4 weeks (strong, low). Where GERD is suspected but unclear and endoscopy shows no objective evidence, perform reflux monitoring OFF therapy to establish the diagnosis (strong, low); conversely, do NOT perform off-therapy reflux monitoring solely as a diagnostic test in patients already known to have LA grade C or D esophagitis or long-segment Barrett's, because the diagnosis is already established (strong, low). In refractory GERD, optimize PPI therapy first (strong, moderate); then pH monitoring OFF PPIs if GERD was not previously established by pH study, long-segment Barrett's, or LA grade C/D esophagitis, versus impedance-pH ON PPIs where GERD is already established but symptoms persist on twice-daily PPI (both conditional, low). Before antireflux surgery or endoscopic therapy, HRM is recommended to rule out achalasia and absent contractility, with provocative testing (e.g., multiple rapid swallows) to identify contractile reserve in ineffective esophageal motility; on-therapy reflux monitoring is suggested before intervention in patients with prior objective GERD findings who remain symptomatic. Antireflux surgery by an experienced surgeon is an option for patients with OBJECTIVE evidence of GERD, with severe esophagitis (LA C/D), large hiatal hernia, or persistent troublesome symptoms benefiting most; TIF is suggested only for troublesome regurgitation or heartburn in patients who do not wish to undergo antireflux surgery and who are WITHOUT severe esophagitis (LA C/D) or hiatal hernia >2 cm. For extraesophageal symptoms WITHOUT typical GERD symptoms, perform reflux testing BEFORE starting PPI therapy (strong, moderate); with concomitant typical symptoms, consider twice-daily PPI for 8-12 weeks before further testing (conditional, low). Lifestyle: weight loss in overweight/obese patients (strong, moderate); avoid meals within 2-3 hours of bedtime, avoid tobacco, avoid trigger foods, and elevate the head of the bed for nighttime symptoms (all conditional, low).

ACG 2025 makes 19 GRADE-rated statements plus non-graded key concepts. DIAGNOSIS: EoE is diagnosed by symptoms of esophageal dysfunction plus at least 15 eos/hpf in at least 1 hpf on esophageal biopsy, after evaluating for non-EoE disorders that cause or potentially contribute to esophageal eosinophilia (strong recommendation, low-quality evidence). A PPI trial is NOT a diagnostic criterion and the term PPI-REE is abandoned; PPIs are positioned purely as a treatment. Obtain at least 6 esophageal biopsies from at least 2 esophageal levels (e.g., proximal/mid and distal), targeting endoscopic findings if possible (strong, low). Use a systematic endoscopic scoring system such as the EoE Endoscopic Reference Score (EREFS) at every endoscopy (strong, low). Quantify eosinophil counts, not merely report them as above threshold, on biopsies from every endoscopy performed for EoE (strong, low), since serial counts gauge anti-inflammatory effect; the guideline notes eosinophil density (~60 eos/mm2) may be preferable for cross-setting comparison but that this has not yet been adopted in practice. Key concept: perform the diagnostic endoscopy off treatment (no dietary restriction and no PPI) to maximize diagnostic sensitivity. TREATMENT, the three anti-inflammatory options do NOT carry equal recommendation strength: swallowed topical steroids are recommended (STRONG, moderate evidence); PPIs are suggested (CONDITIONAL, low); empiric food elimination diet is suggested (CONDITIONAL, low). Because the field lacks comparative efficacy trials, the guideline states the choice among them is individualized to disease characteristics and patient preference within a shared decision-making framework, and advises that a single anti-inflammatory therapy be selected initially. Either fluticasone propionate or budesonide is a reasonable initial topical steroid (conditional, low); options include the FDA-approved budesonide oral suspension, the EMA-approved budesonide orodispersible tablet, and off-label asthma preparations adapted for esophageal delivery. Administer topical steroids after meals or at bedtime with nothing to eat or drink for 30-60 minutes to maximize esophageal dwell time; in young children prefer a slurry/suspension over an inhaler device. Dosing (Table 6): high-dose PPI, adults, double the approved reflux dose per day (e.g., omeprazole 20 mg twice daily or 40 mg daily or PPI equivalent); children, 2 mg/kg/day (or 1 mg/kg twice daily). Budesonide, adults 2-4 mg/day, divisible twice daily (approved budesonide oral suspension dosing is 2 mg twice daily); children 1-2 mg/day by age/height/weight. Fluticasone, adults 1,760 mcg/day in divided doses; children 110-880 mcg/day in divided doses. Currently available allergy testing (skin prick, patch, or serum Ig panels) is NOT suggested to direct elimination diets (conditional, very low). Providers MAY consider starting with a less-restrictive empiric elimination (1FED or 2FED) as the initial diet choice, incorporating patient preference through shared decision-making, and should collaborate with a dietician or nutritionist; after an initial dietary response a structured food reintroduction process is advised, with endoscopy and biopsy after each food reintroduced, because symptoms alone must not be used to determine food triggers. BIOLOGICS: dupilumab is suggested for EoE in individuals 12 years of age or older who are nonresponsive to PPI therapy (conditional, moderate) and, as a separate statement, for pediatric patients aged 1-11 years weighing at least 15 kg who are nonresponsive to PPI therapy (conditional, low). Dosing: 15 to <30 kg, 200 mg subcutaneously every other week; 30 to <40 kg, 300 mg subcutaneously every other week; >=40 kg, 300 mg subcutaneously weekly. Key concept: use dupilumab as step-up therapy in difficult-to-treat patients, and consider it in patients with multiple atopic conditions that would independently meet requirements for its use; the guideline explicitly states its position in the treatment algorithm is still being determined. No recommendation can be made for or against cendakimab, benralizumab, lirentelimab, mepolizumab, or reslizumab. Omalizumab is suggested AGAINST (conditional, low), as are cromolyn and montelukast (conditional, very low). DILATION: endoscopic dilation is suggested as an ADJUNCT to medical therapy for esophageal strictures causing dysphagia (conditional, low). Dilation alone does not affect underlying inflammatory disease activity, so in fibrostenotic EoE it should occur in conjunction with effective medical or dietary anti-inflammatory therapy. Use a start-low-and-go-slow approach: begin with a dilator size that may underestimate esophageal caliber, relook after dilation, and work to larger sizes until a mucosal disruption ('dilation effect') or the target diameter is reached. In adults and adolescents, a goal luminal diameter that relieves dysphagia and food impaction, typically at least 16 mm, should be achieved over one or more sessions, depending on initial luminal caliber and the effect observed during dilation. Dilation technique may be chosen by stricture characteristics and endoscopist preference. MAINTENANCE: continuation of EFFECTIVE dietary or pharmacologic therapy is advised to prevent recurrence of symptoms, histologic inflammation, and endoscopic abnormalities, notably graded STRONG despite low-quality evidence, because disease activity almost universally recurs when treatment is stopped. For patients on pharmacologic treatment, providers should consider identifying the lowest effective dose for long-term use, with any dose-reduction decision individualized. MONITORING AND RESPONSE: evaluate treatment response with symptomatic AND endoscopic AND histologic outcomes (strong, low); providers are advised NOT to monitor symptoms alone, since symptoms do not strongly correlate with endoscopic or histologic disease activity. Perform endoscopy to assess response 8-12 weeks after starting a new therapy such as PPI, topical steroid, or food elimination diet; for dupilumab the assessment interval may range from 12 to 24 weeks based on clinical trial findings. Providers MAY consider using a histologic response threshold of <15 eos/hpf, with the improvement in eosinophil count interpreted in the context of other histologic features, endoscopic findings, and symptoms, the guideline frames this as a 'may consider' key concept rather than a fixed target. Follow-up should be individualized and at shorter intervals for patients with complications (food impaction, perforation, strictures requiring dilation, malnutrition); repeat endoscopy after any treatment change such as dose reduction; care gaps of 2 years or more are associated with progression to fibrostenosis. PEDIATRIC-SPECIFIC: in children with EoE and dysphagia, an esophagram is suggested to evaluate fibrostenotic disease (conditional, very low); evaluation by a feeding therapist and/or dietician is suggested as an adjunctive intervention in children with feeding dysfunction (conditional, very low); growth, development including eating skills, and nutrition are treatment goals in children in addition to symptomatic, endoscopic, and histologic goals.

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).