Raghav, K. & Overman, M. J. Nat. Rev. Clin. Oncol. 10, 534–544 (2013) R3 조영학 / prof. 맹치훈 Small bowel adenocarcinomas - existing evidence and evolving paradigms -

Introduction Small bowel caners Carcinoids, adenocarcinomas, lymphomas, sarcomas Rare : 3% of all gastrointestinal malignancies 8,810 new cases diagnosed in the USA in 2013 CML, testicular cancer, Hodgkin lymphoma and anal cancer Small bowel adenocarcinomas one-third of all small bowel cancers

Carcinoid : 44%, ileum Adenocarcinoma : 30%, duodenum

Small bowel adenocarcinomas Epidemiology second most common small bowel cancer annual incidence of about 7.3 cases per million worldwide higher rates in North America and Western Europe lower rates in Asian countries more than half (56%) in the duodenum Male > female black individuals

Small bowel and colorectal adenocarcinoma Small bowel adenocarcinomas have a poorer stage-stratified cancer-specific survival than colon cancer

Small bowel adenocarcinomas arise from a similar phenotypic adenoma to carcinoma transformation as seen in CRC risk of progression to a carcinoma size (8.3% for 1cm) histology (14.3% for tubular, 23.1% for tubulovillous and 36% for villous)

Small bowel and colorectal adenocarcinoma 50-fold lower incidence of small bowel adenocarcinomas small intestine encompasses 80% of the anatomical length and 99% of the absorptive surface of the gastrointestinal tract markedly lower rate of mutations in the APC gene unique microenvironment of the small intestine that protects against carcinogenic stimuli. low bacterial load, dilute liquid contents, relatively rapid transit time  decreases the amount and duration of exposure to carcinogens higher levels of lymphoid aggregates and IgA levels

Aetiology aetiology of most small bowel adenocarcinomas remains unclear Risk factor Crohn’s disease, Celiac disease Obesity Lynch syndrome, familial adenomatous polyposis (FAP), Peutz– Jeghers syndrome (PJS) No relationships alcohol, tobacco use, dietary habits

Molecular biology Accumulation of genetic alterations has a key role in the adenoma–dysplasia– carcinoma sequence in the development of small bowel adenocarcinomas

Clinical presentation and diagnosis Varied and nonspecific presentation Median age of presentation : 55 to 65 years Most cases diagnosed : seventh or eighth decade Predisposing conditions and familial cancer syndromes : Age of onset tends to be lower Older people (age ≥60 years) : higher frequency of duodenal tumours Diagnosed with advanced-stage disease (32% stage IV, 27% stage III, 30% stage II and 10% stage I) Symptom : abdominal pain (45–76%), nausea and vomiting (16–52%), weight loss (28%), fatigue and anaemia (15–30%), gastrointestinal bleeding (7–23%) Laboratory testing : iron deficiency anaemia Tumour markers : CEA (30%), CA 19 ‑ 9 (40%)

Clinical presentation and diagnosis Immunophenotyping homeobox protein CDX-2 : 70% cytokeratin (CK)20, CK7 : 57%, 31% Imaging Conventional abdominal radiography : obstruction Upper gastrointestinal series (conventional, enteroclysis : 33%, 90% ) CT enterography : sensitivity 93%, specificity 94% CT enteroclysis : sensitivity 94%, specificity 100% PET–CT : metastatic disease

Clinical presentation and diagnosis Endoscopy upper endoscopy – duodenum push enteroscopy - proximal jejunum, double-balloon enteroscopy - entire small-bowel time consuming, technically challenging, limited in availability Wireless video capsule endoscopy (VCE) entire small bowel lumen low false-positive rate (2%), lowest false-negative rate (19%) standard first choice endoscopic approach potential for capsule retention due to stenotic malignant, Crohn’s lesions

Prognosis Prognostic factor Tumour stage poor differentiation, positive margins, duodenal location, male gender, black ethnicity, older age High lymph-node ratio (>50–75%), low number of assessed lymph nodes

Treatment strategy Surgery for locoregional disease 5 ‑ year survival : resected, unresected (54%, 0%) Duodenal adenocarcinomas first and second portion : pancreaticoduodenectomy third and fourth portion : wide local excision with regional lymphadenectomy Jejunum or ileal adenocarcinomas : wide local excision and regional lymph-node dissection Adjuvant therapy recurrence pattern : predominantly at distant sites absence of prospective randomized trial high-risk disease (such as positive lymph nodes)  adjuvant fluoropyrimidine-based chemotherapy

Treatment strategy Metastatic disease Systemic chemotherapy multiple retrospective comparisons have demonstrated the survival advantage of palliative chemotherapy

no randomized trials have compared the efficacy of different chemotherapy regimens fluoropyrimidine and oxaliplatin as the backbone chemotherapy similar activity with response rates of 39–52% and median PFS of 7.8 to 11.3 months Standard frontline therapy CAPOX (capecitabine and oxaliplatin) or FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) Second-line therapy FOLFIRI (5-fluorouracil, leucovorin and irinotecan) Role of targeted agents has not been established in small bowel adenocarcinomas

Treatment strategy Metastatic disease Surgery Obstruction (nausea, vomiting and poor nutrition) and bleeding palliative surgery (segmental resection or bypass) radiation therapy (especially for duodenal primaries) self-expandable metal stents (duodenal adenocarcinoma) Oligometastatic liver disease metastatectomy

Treatment strategy