Lay Summary: Chemotherapy for small bowel adenocarcinoma and sarcoma is reviewed.
Small bowel adenocarcinoma (SBA) is a very rare entity accounting for one-fourth of the small intestine neoplasms. Usually accompanied by nonspecific symptoms occurring late in the course of the disease, they are associated with a dismal prognosis. It appears that SBA shares several genetic characteristics with large bowel tumors, but also has unique features. The similarity to large bowel cancers has led to application of colon cancer protocols to small bowel cancer.
Because of its low prevalence, few clinical trials have been performed to assess the efficacy of chemotherapy for treating small-bowel cancer.
The largest published study was in 1984 by Jigyasu et al and involved 14 subjects with metastatic small-bowel adenocarcinoma who were treated with 21 chemotherapy regimens, most containing 5-fluorouracil (5-FU). Two minor responses and one partial response occurred, with a median survival of 9 months.
In their 1984 review of 65 patients with small-bowel adenocarcinoma, Ouriel and Adams reported a mean survival of 10.7 months in 6 patients with metastatic disease treated with 5-FU–based regimens, compared with a mean survival of 4 months in 6 patients with metastatic disease who received no chemotherapy. An additional 6 patients with recurrent disease were also treated with chemotherapy and had a mean survival of 11.5 months, compared with 21 patients with recurrent disease who received no chemotherapy and survived a mean of 7.9 months.
More recently, a 1998 British study by Crawley et al reported 8 patients with advanced small-bowel adenocarcinoma treated with infusional 5-FU–based regimens and found a response rate of 37.5% and a median survival of 13 months.
Newer agents found to be effective for colorectal carcinoma also may be active for small-bowel adenocarcinoma.
As reported by Polyzos and colleagues in 2003, 3 subjects with 5-FU–refractory small-bowel adenocarcinoma were treated with salvage irinotecan therapy. Two patients achieved a minor response and had improvement of their symptoms.
Also in 2003, Bettini and colleagues found that the FOLFOX 4 regimen (ie, combination infusional 5-FU, oxaliplatin, and leucovorin) was safely administered as adjuvant chemotherapy in 3 subjects with resected small-bowel adenocarcinoma associated with celiac disease.
Because these are uncontrolled studies with few patients, drawing conclusions regarding the benefit of chemotherapy for small-bowel adenocarcinoma, either in the metastatic or adjuvant setting, is difficult. In patients with a good performance status, any attempts using the regimens mentioned seem reasonable.
Similarly, few studies have assessed the efficacy of cytotoxic chemotherapy for small-bowel sarcomas. An analysis by Fernandez-Trigo and Sugerbaker from 1993 reported on 7 randomized prospective studies of subjects with nonextremity sarcomas and found no survival benefit with the addition of adjuvant chemotherapy after surgery.
Studies of chemotherapy in patients with metastatic GI soft tissue sarcomas have also yielded disappointing results.
For example, the Southwest Oncology Group, as reported by Zalupski et al in 1991, found that only 3 (7%) of 43 subjects with GI sarcomas responded to a combination of doxorubicin and dacarbazine, whereas 21% of subjects with leiomyosarcomas of other sites responded to the same combination.
A trial reported by Blair et al in 1994 found that a combination of ifosfamide and etoposide produced no responses among 10 patients with GI sarcomas. In 2006, Fishman reviewed 114 patients for natural history.
Forty-four patients received palliative chemotherapy with an overall response rate (ORR) of 36% during a first or second line regimen (9% complete responses and 27% partial responses). Newer chemotherapy regimens including gemcitabine and irinotecan combinations appeared to have higher ORR, than older fluorouracil-based regimens. Some patients responded to more than one line of chemotherapy. Palliative chemotherapy predicted for overall survival (OS) in a multivariate analysis (HR 0.47, P = 0.035).
She concluded: “Chemotherapy appears to have activity in adenocarcinoma of the small bowel. Prospective trials evaluating patient benefit are required to confirm this activity using newer systemic therapies, until such time retrospective reviews such as this will continue to guide treatment decisions.” A 2010 review staes that retrospective studies have indicated that chemotherapy prolongs OS in patients with advanced SBA, but there is no agreed frontline regimen owing to a lack of randomized trials.
Evidence indicates that in general, small-bowel sarcomas and GISTs are more resistant to chemotherapy than sarcomas in other sites. A 2000 Dutch study by Plaat et al found greater expression of multidrug-resistance proteins in GISTs compared with non-GI leiomyosarcomas. The use of imatinib for GIST is outside the scope of this brief review.
There is a generally accepted belief that you can treat distal small bowel adenocarcinoma as colon cancer and proximal as gastric cancer, but it is not experimentally confirmed and certainly should not extend into later line treatment.
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