Advanced and metastatic small bowel adenocarcinoma

Metastatic small bowel adenocarcinoma has been treated for two decades with regimens borrowed from colorectal cancer, guided by phase 2 trials rather than randomised evidence. Capecitabine with oxaliplatin (CAPOX) produced responses in about half of patients in a phase 2 trial at MD Anderson (Journal of Clinical Oncology 2009) and, with FOLFOX, became the first-line standard; FOLFIRI is used in second line, and a randomised Japanese phase 2 and a French cohort supported these choices. Bevacizumab is added by analogy with colon cancer, while anti-EGFR antibodies are not used because the tumours behave more like gastric than colorectal cancer in that respect and are usually KRAS mutant or otherwise unresponsive. In the BALLAD era, the NCCN guideline lists taxane-based regimens as a further option, reflecting the tumour's kinship with gastric adenocarcinoma.

The molecular exceptions matter more than in colon cancer. Mismatch repair deficiency, found in a larger proportion of small bowel than colorectal adenocarcinomas, predicts benefit from pembrolizumab, approved for all mismatch-repair-deficient solid tumours in 2017 and recommended in first line for these patients; the ZEBRA phase 2 trial of pembrolizumab in unselected small bowel adenocarcinoma found responses concentrated in the mismatch-repair-deficient minority. HER2 amplification or mutation occurs in a subset and responds to trastuzumab-based therapy or trastuzumab deruxtecan in tumour-agnostic trials, and comprehensive genomic profiling is recommended for every patient with advanced disease. Resection of limited liver or peritoneal metastases and cytoreductive surgery with HIPEC are considered in selected patients, and circulating tumour DNA is being explored for monitoring. Survival remains shorter than in colorectal cancer, in part because the tumours respond less and in part because they are diagnosed late.