Small bowel adenocarcinomas--existing evidence and evolving paradigms

Abstract

Small bowel cancers account for 3% of all gastrointestinal malignancies and small bowel adenocarcinomas represent a third of all small bowel cancers. Rarity of small bowel adenocarcinomas restricts molecular understanding and presents unique diagnostic and therapeutic challenges. Better cross-sectional imaging techniques and development of enteroscopy and capsule endoscopy have facilitated earlier and more-accurate diagnosis. Surgical resection remains the mainstay of therapy for locoregional disease. In the metastatic setting, fluoropyrimidine and oxaliplatin-based chemotherapy has shown clinical benefit in prospective non-randomized trials. Although frequently grouped under the same therapeutic umbrella as large bowel adenocarcinomas, small bowel adenocarcinomas are distinct clinical and molecular entities. Recent progress in molecular characterization has aided our understanding of the pathogenesis of these tumours and holds potential for prospective development of novel targeted therapies. Multi-institutional collaborative efforts directed towards cogent understanding of tumour biology and designing sensible clinical trials are essential for developing improved therapeutic strategies. In this Review, we endeavour to outline an evidence-based approach to present-day management of small bowel adenocarcinoma, describe contemporary challenges and uncover evolving paradigms in the management of these rare 'orphan' neoplasias.

Figure 1 |

Epidemiology of small bowel tumours from the National Cancer Data Base (NCDB) (1985–2005) and U.S. Surveillance, Epidemiology and End Results (SEER) (1973–2005) cohorts and Connecticut Tumor Registry 1980–2000.^,, a | Majority of adenocarcinomas and carcinoids are seen in the duodenum and the ileum, respectively. b | Incidence of small bowel tumours, especially carcinoids, adenocarcinomas and lymphomas has increased in the past few years. c | The proportion of histological tumour subtypes found in the small bowel varies depending on the anatomic location of the small bowel.

Figure 2 |

The adenoma–carcinoma sequence in small bowel adenocarcinomas. a | A number of molecular alterations are implicated in small bowel carcinogenesis. c | Risk of progression of adenoma to malignancy depends on the tumour size and histology.

Figure 3|

Schematic management of patients with small bowel adenocarcinomas. Treatment strategy depends on disease stage and involves en-bloc resection for locoregional disease and systemic chemotherapy for metastatic disease. All current recommendations are based on case series, retrospective reviews or non-randomized prospective trials because of an absence of any randomized data. Abbreviations: PS, performance status; 5-FU, 5-fluorouracil; FOLFOX, 5-FU, leucovorin and oxaliplatin; CAPOX, capecitabine plus oxaliplatin; FOLFIRI, 5-FU, leucovorin and irinotecan; KRAS-WT, KRAS wild-type; XRT, radiation therapy.

Figure 4 |

Role of chemotherapy in metastatic small bowel adenocarcinoma. a | Median overall survival is significantly more in patients receiving palliative chemotherapy (13.7 months) as compared to best-supportive care (4.0 months) alone. b | Response rate to palliative chemotherapy show moderate correlation with median overall survival in metastatic small bowel adenocarcinomas. c | Median progression-free survival on palliative chemotherapy correlates strongly with median survival in metastatic small bowel adenocarcinomas.