January 17, 2007

Malignant Neoplasms of the Small Intestine

Synonyms and related keywords: small bowel cancer, small-bowel cancer, small bowel neoplasm, small-bowel neoplasm, small bowel malignancy, small-bowel malignancy, small bowel tumor, small-bowel tumor, small bowel mass, small-bowel mass, small intestine malignancy, small intestine tumor, small intestine cancer, gastrointestinal malignancy, gastrointestinal tumor, gastrointestinal cancer, GI cancer, GI malignancy, GI tumor, gastrointestinal mass, GI mass, gastrointestinal neoplasm, GI neoplasm, small bowel adenocarcinoma, small-bowel adenocarcinoma, adenocarcinoma, GI adenocarcinoma, small intestine adenocarcinoma, GI adenocarcinoma, familial adenomatous polyposis, FAP, gastrointestinal stromal tumor, GIST


Background: Although the small bowel contains 90% of the mucosal surface area and 75% of the length of the alimentary tract and is located between 2 organs with high cancer prevalence (ie, stomach, colon), malignant neoplasms of the small bowel are among the rarest types of cancer, accounting for only 2% of all GI cancers. Many theories have been proposed to explain this low prevalence. For example, the small intestine secretes large volumes of alkaline fluid, enzymes, and immunoglobulin A, which may dilute and detoxify potential carcinogens and prevent prolonged contact with the mucosa. Also, the limited numbers of bacteria in the small bowel are less capable of transforming potential procarcinogens to their active breakdown products.

Elucidating the precise reasons for the low prevalence of small-bowel cancers may lead to strategies for preventing cancers of the stomach, colon, and other sites. However, research into the natural history and prognosis of patients with small-bowel cancer has been limited by the small number of cases and the heterogeneity of tumor types, including adenocarcinomas, carcinoids, sarcomas, and lymphomas. Each of these tumor subtypes has its own distinct clinical behavior and, therefore, dictates a different treatment approach. This review focuses on adenocarcinoma because adenocarcinoma is the most common histologic type of small-bowel malignancy in the United States. Sarcomas are also briefly discussed. Carcinoid tumors and lymphomas are described in other articles of this journal (eg, see Carcinoid Tumor, Intestinal).

Pathophysiology: Approximately 64% of all small-bowel tumors are malignant, and approximately 40% of these tumors are adenocarcinomas. Epidemiologically, small-bowel adenocarcinomas have a striking resemblance to large-bowel adenocarcinomas. For example, although small-bowel adenocarcinomas are only one fiftieth as common as large-bowel adenocarcinomas, they share a similar geographic distribution, with predominance in Western countries. In addition, they tend to co-occur in the same individuals, with an increased risk of small-bowel adenocarcinoma in survivors of colorectal cancer and vice versa.

Furthermore, similar to adenocarcinomas in the colon, those in the small bowel arise from premalignant adenomas. This occurs both sporadically and in the context of familial adenomatous polyposis. Through a stepwise accumulation of genetic mutations, these adenomas become dysplastic and progress to carcinomas in situ and then to invasive adenocarcinomas. They then metastasize via the lymphatics or portal circulation to the liver, lung, bone, brain, and other distant sites.

Despite these similarities with colon cancer, small-bowel adenocarcinomas tend to cluster away from the colon, toward the gastric end of the small intestine. Approximately 50% arise in the duodenum, 30% in the jejunum, and 20% in the ileum. The duodenum is the first portion of the small bowel to be exposed to ingested chemicals and pancreaticobiliary secretions. This fact, combined with the higher prevalence of cancer in the duodenum, may indicate that the substances (ie, ingested chemicals, pancreaticobiliary secretions) may have carcinogenic properties. Animal studies have demonstrated that diverting bile decreases the prevalence of experimentally induced small-bowel cancers, which suggests that bile may be carcinogenic.

In addition, genetic analyses of sporadic small-bowel adenocarcinomas suggest similarities and differences from the pathogenesis from colorectal carcinomas. Although K-ras mutation and p53 overexpression appear to be as common in small-bowel adenocarcinoma as in colorectal carcinoma, mutation of the APC tumor suppressor gene, which is characteristic of colorectal carcinoma, does not commonly occur in small-bowel adenocarcinoma (Arai, 1997; Wheeler, 2002). The SMAD4/DPC4 gene, which is often mutated in pancreatic and colorectal carcinomas, also appears to be inactivated in small-bowel adenocarcinomas (Svrcek, 2003; Blaker, 2002).

Sarcomas account for approximately 15% of small-bowel malignancies in the United States. While some may exhibit clear histologic features of smooth muscle origin, many tumors display only partial differentiation with incomplete expression of muscle-associated antigens. Because they are mesenchymal neoplasms believed to be derived from the interstitial cells of Cajal in the GI tract, they have recently been named with the more general term GI stromal tumors (GISTs). Recent studies have demonstrated that nearly all GISTs, unlike true sarcomas, express a growth-factor receptor with tyrosine kinase activity encoded by the proto-oncogene c-kit. As reported by Miettinen et al in 1999, mutations in c-kit that cause constitutive tyrosine kinase activity and result in uncontrolled cell proliferation have been detected in approximately 60% of GISTs and appear to play a central role in tumorigenesis.

While most GISTs are located in the stomach, 30% of GISTs are found in the small bowel. These tumors are distributed more evenly throughout the small bowel compared with adenocarcinomas, and they tend to grow extraluminally. Because they are highly vascular lesions that commonly ulcerate, intestinal bleeding is a frequent symptom. Compared with gastric GISTs, small-bowel GISTs tend to be more aggressive and have a worse prognosis. Metastases develop primarily via the hematogenous route, commonly involving the liver and lungs. GISTs also may invade adjacent organs directly or spread via peritoneal seeding. Lymphatic metastases are rare but are believed to be a marker for more widespread metastatic disease.


  • In the US: The incidence of small-bowel cancers is estimated to be approximately 5400 cases per year.
  • Internationally: In general, small-bowel cancer prevalence is lower in Asia and in less industrialized countries than in Western countries. In addition, several hospital-based series indicate a predominance of lymphomas in less developed countries.

Mortality/Morbidity: In the United States, approximately 1100 patients die of small-bowel cancer each year. Based on recent series, the 5-year overall survival rate for patients with adenocarcinoma is 30-35%. The 5-year survival rate for patients with small-bowel sarcomas is approximately 25%.

Race: Population-based studies in the United States have suggested somewhat higher prevalence rates of small-bowel cancer for blacks than for whites. In 1993, the age-adjusted prevalence rate was 2.4 cases per 100,000 population for black males versus 1.6 cases per 100,000 population for white males and 2 cases per 100,000 population for black females versus 1.1 cases per 100,000 population for white females.

Sex: Males have a somewhat higher prevalence of small-bowel cancer compared with females, with a male-to-female ratio of 1.4:1.

Age: The prevalence of small-bowel cancer tends to increase with age, with a mean age at diagnosis of approximately 60 years. Adenocarcinomas, more than the other histologic subtypes, tend to be diagnosed in somewhat older patients.


History: Small-bowel cancer typically is asymptomatic in its early stages, but more than 90% of patients eventually develop symptoms as the disease progresses.

Physical: Patients with small-bowel malignancies may present with fairly unremarkable physical examination findings.



Ampullary Carcinoma
Benign Neoplasm of the Small Intestine
Bile Duct Tumors
Colon Cancer, Adenocarcinoma
Crohn Disease
Duodenal Ulcers
Gastric Cancer
Gastritis, Chronic
Intestinal Leiomyosarcoma
Intestinal Polypoid Adenomas
Intestinal Pseudo-obstruction: Surgical Perspective
Irritable Bowel Syndrome
Pancreatic Cancer

Other Problems to be Considered:

Intestinal leiomyoma


Lab Studies:

Imaging Studies:


Histologic Findings:

Staging: This is according to the American Joint Committee on Cancer staging system.


Medical Care:

Surgical Care:



No standard regimen demonstrates benefit in an adjuvant or metastatic setting for small-bowel adenocarcinoma. Because of the similarity to colorectal adenocarcinoma, a regimen containing 5-FU with leucovorin (ie, Roswell Park, Mayo Clinic) may be used. Newer agents active in colorectal carcinoma, such as irinotecan and oxaliplatin, may also be considered, in combination with 5-FU. Small-bowel sarcomas, most of which are c-kit–positive GISTs, are resistant to cytotoxic chemotherapy. However, patients with advanced disease may be treated with imatinib.

Drug Category: Chemotherapeutic agents -- Chemical substances or drugs that treat neoplastic diseases by interfering with DNA synthesis.
Drug Name
Fluorouracil (Adrucil) -- Fluorinated pyrimidine analog. Metabolite, FdUMP, inhibits thymidylate synthase that is essential in folate metabolism. 5-FU metabolites FUTP and FdUTP inhibit RNA and DNA synthesis by incorporating into RNA and DNA, respectively.
Adult DoseSingle-agent adjuvant regimens
Roswell Park: 500 mg/m2 IV qwk for 6 wk, repeat cycle q8wk for total of 4-6 cycles
Mayo Clinic: 425 mg/m2 IV on days 1-5, repeat cycle q4wk for total of 4-6 cycles
Combination regimens
IFL (combined with irinotecan): 500 mg/m2 IV bolus qwk for 4 wk; repeat cycle q6wk
FOLFOX 4 (combined with oxaliplatin): 400 mg/m2 IV bolus, followed by 600 mg/m2 IV infusion over 22 h on days 1 and 2; repeat cycle q2wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; bone marrow suppression; serious infection; poor nutritional status; active ischemic heart disease; MI within 6 mo
InteractionsMethotrexate and trimetrexate administered prior to 5-FU increases formation of FUTP and enhances cell killing and toxicity; increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents
Pregnancy D - Unsafe in pregnancy
PrecautionsNausea, oral and GI ulcers, depression of immune system, hemopoiesis failure (bone marrow suppression), hand-foot syndrome, neurologic toxicity, and cardiac ischemia may occur; adjust dosage in renal impairment
Drug Name
Leucovorin (Wellcovorin) -- Racemic mixture of 5-formyltetrahydrofolate. Metabolized to reduced folate 5,10-methylenetetrahydrofolate, which forms ternary complex with FdUMP and thymidylate synthase, enhancing inhibition of the latter.
Adult DoseRoswell Park: 500 mg/m2 IV over 2 h qwk for 6 wk, administered before 5-FU; repeat cycle q8wk for total of 4-6 cycles
Mayo Clinic: 20 mg/m2 IV on days 1-5, administered before 5-FU; repeat cycle q4wk for total of 4-6 cycles
IFL: 20 mg/m2 IV bolus, after irinotecan and before 5-FU, qwk for 4 wk; repeat cycle q6wk
FOLFOX 4: 200 mg/m2 IV over 2 h on days 1 and 2, prior to bolus 5-FU; repeat cycle q2wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; pernicious anemia; vitamin-deficient megaloblastic anemias
InteractionsMay decrease serum levels and efficacy of phenobarbital, phenytoin, and primidone; rescues against toxic effects of methotrexate
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsAllergic reactions, nausea, and vomiting may occur with administration; do not administer intrathecally or intraventricularly; use in pernicious anemia or vitamin B-12 deficiency megaloblastic anemias may cause hematologic remission, but allow neurologic manifestations to progress
Drug Name
Irinotecan (Camptosar) -- Camptothecin derivative that inhibits topoisomerase I, resulting in double-stranded DNA damage. Approved as first-line therapy in combination with 5-FU and leucovorin or as second-line, single-agent therapy after 5-FU for advanced colorectal cancer.
Adult DoseSingle-agent: 125 mg/m2 IV over 90 min qwk for 4 wk, repeat cycle every 6 wk; alternatively, 350 mg/m2 IV over 90 min q3wk
IFL combination: 125 mg/m2 IV over 90 min before leucovorin and 5-FU, qwk for 4 wk; repeat cycle q6wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; ongoing severe diarrhea or neutropenic fever from prior treatment with irinotecan; significant liver function abnormalities including any degree of jaundice
InteractionsBecause can cause diarrhea and dehydration, use of laxatives and diuretics may need to be reduced or omitted during treatment; patients who received prior abdominal or pelvic radiation therapy are at increased risk for severe myelosuppression; concurrent use with radiation not recommended
Pregnancy D - Unsafe in pregnancy
PrecautionsCan induce early and late diarrhea; early diarrhea may be accompanied by cholinergic symptoms (eg, rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing); atropine (0.25-1 mg IV/SC) may be given to prevent or treat these symptoms; late diarrhea occurs more than 24 h after irinotecan and can be severe and life-threatening; late diarrhea should be treated promptly with loperamide, and fluids and antibiotics should be given if dehydration and fever occur; if diarrhea grade 2 or higher occurs, subsequent doses should be reduced
Severe neutropenia is another toxicity, which has resulted in deaths from sepsis; patients with neutropenic fever or ANC less than 1000 should have subsequent doses reduced
In clinical trials, patient with baseline performance status of 2 had higher rates of hospitalization, early death, and other complications; therefore, treatment in these patients should be closely monitored
Drug Name
Oxaliplatin (Eloxatin) -- Organoplatinum complex that acts as an alkylating agent. Metabolites cross-link with DNA, inhibiting DNA synthesis and function. Combination with 5-FU and leucovorin (FOLFOX 4 regimen) is approved for treatment of advanced colorectal cancer.
Adult DoseFOLFOX 4: 85 mg/m2 IV over 2 h (with leucovorin, before 5-FU) on day 1; repeat q2wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity (also other platinum compounds); should be given cautiously in patients with preexisting neuropathy
InteractionsBecause of renally excretion, coadministration of nephrotoxic drugs may potentially affect clearance
Pregnancy D - Unsafe in pregnancy
PrecautionsMay cause acute, reversible, peripheral, sensory neuropathy precipitated by cold exposure; may also cause a persistent peripheral sensory neuropathy characterized by paresthesias; other common adverse events of FOLFOX 4 include neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and rare cases of pulmonary fibrosis
Drug Category: Tyrosine kinase inhibitors -- Inhibit tyrosine kinase activity of c-kit, bcr-abl, and PDGFR oncogenes.
Drug Name
Imatinib mesylate (Gleevec) -- Small molecule that selectively inhibits tyrosine kinase activity of c-kit, bcr-abl, and PDGFR. Available in 100-mg caps.
Adult Dose400 mg/d or 600 mg/d PO for adult patients with unresectable or metastatic GIST
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsBecause of metabolism by hepatic cytochrome P-450 3A4 enzyme, plasma levels may be affected by other drugs that alter activity of this enzyme (eg, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, phenytoin, simvastatin)
Pregnancy D - Unsafe in pregnancy
PrecautionsMost common toxicities include fluid retention and edema, nausea, diarrhea, abdominal discomfort, muscle cramps, fatigue, and skin rash; most events are mild to moderate in severity; adverse events may be more common at 600 mg/d versus 400 mg/d
Drug Category: Multikinase inhibitors -- Elicit actions via multiple tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression.
Drug Name
Sunitinib (Sutent) -- Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).
Indicated for persons with gastrointestinal stromal tumors (GISTs) whose disease has progressed or who are unable to tolerate treatment with imatinib (Gleevec). Delays median time to tumor progression.
Adult DoseStandard dose: 50 mg PO qd on a schedule of 4 wk on treatment followed by 2 wk off treatment, then repeat cycle
Dose modification: Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability
Coadministration with potent CYP4503A4 inhibitors: Minimum dose of 37.5 mg PO qd during treatment phase of cycle
Coadministration with CYP4503A4 inducers: Maximum dose of 87.5 mg PO qd during treatment phase of cycle
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; concurrent administration with St John's wort
InteractionsPotent CYP4503A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations; CYP4503A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease plasma concentrations; St John's wort induces metabolism and decreases plasma concentrations unpredictably (do not take concurrently)
Pregnancy D - Unsafe in pregnancy
PrecautionsCommon adverse effects include diarrhea, skin discoloration, mouth irritation, weakness, and altered taste; may cause fatigue, hypertension, bleeding, swelling, and hypothyroidism; in clinical trials, decreased left ventricular ejection fraction to below lower limits of normal in 15% of patients (monitor for CHF and discontinue if clinical manifestations of CHF develop); may cause hemorrhagic events that may include epistaxis or rectal, gingival, GI, genital, or wound bleeding


Further Inpatient Care:

Further Outpatient Care:

  • Patients who have undergone surgical resection for localized disease should have a follow-up visit in the outpatient setting every 3 months to assess for symptoms or signs suggestive of recurrent disease.
  • CBC count and liver function test results may be checked periodically to identify anemia related to blood loss or abnormal liver enzymes related to hepatic metastases or biliary obstruction, respectively.
  • Abdominal CT scan images should be obtained every 6 months to identify subclinical recurrent disease early, which may be amenable to repeat surgical resection.
  • Patients with small-bowel adenocarcinoma should also undergo colorectal cancer screening (ie, colonoscopy) because of the high risk of secondary malignancies.
  • Patients with advanced metastatic disease may be treated with chemotherapy in an outpatient setting. They should also be observed for hematologic and other toxicity related to chemotherapy.



Patient Education:


Medical/Legal Pitfalls:

No comments: