Small Bowel Cancer

Epidemiology & Impact

Small bowel cancers are rare (approximately 12,070 cases annually, less than 3% of GI malignancies) despite the small intestine being 75% of GI tract length. Four types: adenocarcinoma (30-40%), NETs (40-45%), lymphoma (15-20%), GIST (10-15%). Risk factors include Crohn's disease, celiac disease, FAP, and Lynch syndrome.

Risk factors for small bowel adenocarcinoma include Crohn's disease (particularly ileal involvement, conferring 20-30 fold increased risk), celiac disease, familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (Lynch syndrome), and Peutz-Jeghers syndrome. Diagnosis is often delayed due to nonspecific symptoms, with a median time from symptom onset to diagnosis of 6-8 months. Capsule endoscopy and CT/MR enterography have improved diagnostic yield. The duodenum is the most common site (55-60%), followed by jejunum (20-25%) and ileum (15-20%). Prognosis is stage-dependent, with 5-year survival rates of 55-65% for localized disease dropping to 30-40% for regional and under 10% for distant disease.

Molecular Biology & Biomarkers

Small bowel adenocarcinomas have KRAS (50%), TP53 (40-50%), and APC (15-25%) mutations. Importantly, MSI-high/dMMR occurs in 15-20% — significantly higher than colorectal cancer — making immunotherapy particularly relevant. HER2 amplification occurs in approximately 10% of duodenal adenocarcinomas.

Small bowel adenocarcinoma exhibits molecular heterogeneity depending on anatomical location. Duodenal cancers share features with colorectal cancer (APC mutations, WNT pathway activation), while jejunal and ileal cancers may more closely resemble gastric cancer. Key molecular alterations include TP53 mutation (40-60%), KRAS mutation (15-45%), SMAD4 loss (15-25%), and PIK3CA mutation (5-10%). Microsatellite instability-high (MSI-H) status is found in approximately 5-15% of cases and represents a critical biomarker for immunotherapy eligibility. HER2 amplification occurs in roughly 5% of cases. Celiac disease-associated small bowel cancers have distinct molecular profiles with more frequent KRAS alterations and microsatellite instability.

Evolving Treatment Landscape

Treatment extrapolates from colorectal cancer. FOLFOX is standard first-line for advanced disease. Pembrolizumab has significant activity in the high proportion of MSI-high cases. For GISTs, imatinib is standard; for NETs, somatostatin analogs and PRRT based on grade.

Surgical resection with adequate lymphadenectomy is the cornerstone of curative treatment for localized disease. Adjuvant chemotherapy with fluoropyrimidine-based regimens is commonly used for node-positive disease, though prospective evidence is limited. For advanced or metastatic disease, FOLFOX (oxaliplatin, 5-FU, leucovorin) has become the standard first-line regimen based on the AGEO-NADEGE prospective cohort. Pembrolizumab is approved for MSI-H tumors via the tumor-agnostic indication, making MSI testing mandatory. Second-line options include FOLFIRI and gemcitabine-based regimens. The BALLAD trial (Biomarker Adaptive trial in Locally Advanced and metastatic Duodenal cancer) represents a key ongoing prospective effort.

Note: There are no tumor-specific FDA-approved therapies for small bowel adenocarcinoma. Treatment borrows from colorectal cancer protocols (FOLFOX, FOLFIRI, FOLFOXIRI). Pembrolizumab is available via the MSI-H/dMMR tumor-agnostic indication for eligible patients, which is particularly relevant as a subset of small bowel cancers are MSI-H.

EMA-Approved Therapies for Small Bowel Cancer

The European Medicines Agency (EMA) regulates drug approvals across the European Union. Below are key therapies with comparative information to FDA approvals.

For complete European drug information, visit ema.europa.eu ↗