Can capecitabine (Xeloda) cause esophageal damage, especially in patients with pre-existing gastrointestinal conditions or a history of radiation therapy to the chest area?

Capecitabine and Esophageal Damage

Capecitabine does not specifically cause direct esophageal damage as a characteristic toxicity, but it can cause gastrointestinal mucosal injury throughout the GI tract, including rare esophageal ulceration, particularly when combined with radiation therapy to the chest. 1

Primary Gastrointestinal Toxicities

The hallmark toxicities of capecitabine affect the lower GI tract rather than the esophagus:

• Diarrhea occurs in 39-83% of patients depending on combination therapy, with grade 3-4 severity in 7.6-24% of cases 2
• Hand-foot syndrome is the most characteristic toxicity, occurring in 50-73% of patients, with grade 3 events in 11% requiring dose modification 2
• The FDA label documents that capecitabine causes direct injury to GI tissues through its conversion to 5-FU, leading to metabolic derangement and nutritional depletion 3

Rare Esophageal Involvement

While not a primary site of toxicity, esophageal damage can occur:

• The FDA label reports esophageal ulcer as a rare adverse event (0.39% incidence) in patients receiving capecitabine plus docetaxel combination therapy 1
• Dysphagia is documented as a clinically relevant adverse event in <5% of patients in the overall safety database 1
• The British Society of Gastroenterology (2025) describes capecitabine as causing a GVHD-like pattern of mucosal injury throughout the GI tract, characterized by crypt disarray, atrophy, and increased apoptosis 3, 4

High-Risk Scenarios for Esophageal Toxicity

Concurrent Radiation Therapy

The combination of capecitabine with chest radiation significantly increases esophageal toxicity risk:

• When capecitabine is combined with pelvic or chest radiotherapy, the risk of chemotherapy-induced GI toxicity is substantially higher and more severe 3
• A study of 32 patients receiving concurrent capecitabine and radiation (including 2 with esophageal squamous carcinoma) demonstrated good tolerability, though this was primarily for lower GI malignancies 5
• The median capecitabine dose with concurrent radiation was 1600 mg/m²/day for 5 days per week during radiation therapy 5

DPD Deficiency

Patients with dihydropyrimidine dehydrogenase (DPD) deficiency face life-threatening toxicity:

• 3-5% of the population has partial or complete DPD deficiency, leading to potentially fatal bone marrow suppression and severe mucositis 3, 2
• These patients present with hair loss and mucositis (including potential esophageal involvement), which are usually uncommon outside this syndrome 3
• If heterozygous DPD mutation is present, 50% dose reductions are recommended for the first cycle; homozygous mutations require reconsideration of whether any capecitabine can be safely administered 3

Clinical Management Algorithm

Immediate Evaluation Required

Stop capecitabine immediately if the following develop 2:

• Diarrhea with fever/sepsis
• Grade 2,3, or 4 diarrhea with neutropenia
• Reduced oral intake >12 hours
• Nausea/vomiting with confusion or weakness

Diagnostic Workup for Suspected GI Injury

If esophageal symptoms develop during capecitabine therapy:

• Consider esophagogastroduodenoscopy (OGD) with small intestinal aspirate and duodenal biopsies to assess for GVHD-like mucosal injury pattern 3
• Obtain CT abdomen and pelvis to evaluate for enterocolitis 3
• Request gastroenterology review for persistent symptoms 3

Dose Modifications

For patients ≥65 years:

• Starting dose must be reduced to 1,000 mg/m² twice daily without escalation, as this population has a 34% rate of grade 3 or higher toxicity 2

For patients with prior chest radiation:

• Exercise heightened vigilance for esophageal symptoms, as radiation recall syndrome can occur (0.2% incidence) 1

Common Pitfalls to Avoid

• Never continue full-dose capecitabine in elderly patients (≥65 years) without dose reduction 2
• Do not underestimate the severity of mucositis in patients with DPD deficiency—this can be life-threatening 3
• Avoid dismissing dysphagia or odynophagia as unrelated to capecitabine, particularly in patients receiving concurrent radiation or with prior chest radiation 1
• Remember that smoking and low BMI (<18.5 kg/m²) increase the risk of radiation-related toxicity when capecitabine is combined with radiotherapy 3

Bottom Line

While esophageal damage is not a characteristic toxicity of capecitabine monotherapy, it can occur rarely as part of the drug's broader GI mucosal injury pattern, and risk increases substantially when combined with chest radiation or in patients with DPD deficiency. The primary GI toxicities remain diarrhea and lower GI tract injury rather than esophageal involvement.