Managing Metastatic Small Bowel Cancer

Managing Metastatic Small Bowel Cancer

Dr. Paola Montenegro

By Paola Montenegro, MD

Article Highlights

  • The outcomes for small bowel adenocarcinomas have been shown to be worse than for colorectal cancer.
  • The recommended frontline therapy is either CAPOX or FOLFOX.
  • Pathways such as VEGF, EGFR, and MSI are highly expressed in small bowel adenocarcinomas.
  • Standard treatment for metastatic disease has not been well established.

Small bowel cancers account for 3% of all gastrointestinal malignancies, and small bowel adenocarcinomas represent a third of these—although it has 50-fold lower incidence than large-bowel adenocarcinoma, despite the fact that the small intestine encompasses 80% of the anatomical length and 99% of the absorptive surface of the gastrointestinal tract.1

The incidence rates for these cancers in the United States are rising for small bowel adenocarcinomas and declining for colorectal cancer.2,3

Treatment Therapies

The diagnosis of small bowel adenocarcinoma is frequently delayed because of the nonspecific clinical symptoms and the limitations of imaging studies. The standard therapy for curative intent for locoregional disease is surgical resection; however, distant relapses occur in 86% of patients and locoregional relapses occur in 18% of patients.4 Despite of the absence of prospective randomized data, the use of adjuvant therapy has increased from 8.1% in 1985 to 22.2% in 2005 (p < 0.0001).5

The outcomes for small bowel adenocarcinomas are worse than colorectal cancer. The 5-year stage-specific survival, even in stage I adenocarcinomas of jejunum and ileum with adequate lymph node sampling, is worse than stage I colon cancer (81.6% vs. 93.3% [p < 0.01], respectively).6

In the metastatic setting, chemotherapy with fluoropyrimidine and oxaliplatin has shown clinical benefit in prospective nonrandomized trials,7 although the use of antibodies or targeted therapy is not yet established. The median overall survival is 13 months for patients receiving systemic chemotherapy, which is 9 months longer than best supportive care (Table).8-11

Recommended frontline therapy consists of either CAPOX (capecitabine and oxaliplatin) or FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin). FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) can be used in the second line for patients who received frontline treatment with oxaliplatin regimes. The FOLFIRI regimen showed a disease control rate of approximately 50% and a median progression-free survival of 3 to 5 months.12

Common Mutations

A recent study of 7,559 patients with either small bowel (317 patients), colorectal (6,353 patients), or gastric cancers (889 patients) showed distinct differences in the genomic alterations present in small bowel cancer compared with other gastric cancers. TP53 mutations were present in nearly 40% of patients.13APC mutations were present in 26.8% of patients with small bowel adenocarcinomas, in 75.9% of patients with colorectal cancers, and in fewer than 8% of gastric cancers.14

The rate of KRAS mutations in small bowel adenocarcinomas is similar to that seen in colorectal cancer.15BRAF mutations were also present at about the same rate in both cancers, but only 10% of small bowel adenocarcinomas with BRAF mutations had V600E mutations, as compared to 73% of colorectal cancers with BRAF mutations. BRAF mutations were present in less than 2% of patients with gastric cancer.14

Other pathways such as VEGF (91%), EGFR (71%), and microsatellite instability (MSI; 21%) are highly expressed in small bowel adenocarcinomas. The MSI phenotype was mainly related to a loss of expression of MLH1 protein and was more frequently observed in duodenal and jejunal tumors.16

In a recent comparative analysis of copy number alterations between small bowel, colorectal, and gastric adenocarcinomas, duodenal adenocarcinomas were more similar to colorectal cancers than gastric cancers, and were found to have extremely low rates of HER2 amplification or overexpression (12%).17,18

Dysregulation of the Wnt/b-catenin pathway, TGFb signaling, and cell-cycle regulation is involved in the pathogenesis of these tumors, as suggested by the abnormal nuclear accumulation of catenin observed in 40% to 50% of cases.19 All of these molecular characteristics suggested that small bowel adenocarcinoma is a distinct disease.

A few cases have reported responses to anti-EGFR therapy in patients with KRAS wild-type tumors. The observed overexpression of VEGF-A, EGFR, and MSI suggests that therapies targeting these signaling pathways might display antitumor activity; at this moment there are prospective studies using anti-EGFR (e.g., panitumumab [NCT01202409], bevacizumab [NCT01208103], and pembrolizumab [NCT02949219]).

Data concerning metastasectomy in small bowel adenocarcinomas are limited. Although a study evaluating hepatic resection in patients with oligometastatic liver disease has demonstrated improved survival of 21% in 5 years, the number of patients with small bowel adenocarcinomas was low, thus it is not possible to draw conclusions from this data.20

Combining Research Efforts

Small bowel adenocarcinomas are rare malignancies. Although they are morphologically similar to colorectal cancer adenocarcinomas, they are a different disease with distinct clinical, pathologic, and molecular characteristics to gastric and colorectal cancers. Despite being more molecularly similar to colon cancer than stomach cancer, its behavior has worse prognosis, perhaps by being influenced by other factors such as the microbiota or tumor microenvironment.

Standard treatment for metastatic disease has not been well established; however, combinations of 5-fluorouracil and oxaliplatin appear to be the most effective. Knowledge about the molecular profile of small-intestine cancers offers a great opportunity for the use of new therapies in randomized studies—and worldwide, multicenter research efforts are required because of the regional and racial differences and rarity of this cancer.

About the Author: Dr. Montenegro is with the Instituto Nacional de Enfermedades Neoplásicas.