eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Malignant Neoplasms of the Small Intestine

N Joseph Espat, MD, MS, FACS, Professor and Chief of Surgical Oncology, Vice-Chairman of Department of Surgery, Roger Williams Medical Center
Ponnandai S Somasundar, MD, FACS, Assistant Professor of Surgery, Boston University; Surgical Oncologist, Roger Williams Medical Center; Director of Oncology, Kent County Hospital; Piero Marco Fisichella, MD, Assistant Professor of Surgery, Stritch School of Medicine, Loyola University; Director, Esophageal Motility Center, Loyola University Medical Center

Updated: Apr 30, 2008

Introduction

Background

Malignant neoplasms of the small bowel are among the rarest types of cancer, accounting for only 2% of all GI cancers. 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. Unfortunately, malignant lesions are often discovered when they have metastasized to distant sites or at surgery when indicated for other diagnosis or intestinal obstruction.

This review focuses on adenocarcinoma, as it 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, Carcinoid Tumor, Intestinal). Around 98% of small bowel tumors are made up of adenocarcinomas,carcinoid tumors, lymphomas or sarcoma/gastrointestinal stromal tumors (GISTs).

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.^{[1,2 ]}The SMAD4/DPC4 gene, which is often mutated in pancreatic and colorectal carcinomas, also appears to be inactivated in small-bowel adenocarcinomas.^{[3,4 ]}

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.^{[5 ]}

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.

Frequency

United States

The incidence of small-bowel cancers in the United States in 2007 was projected to be 5640 cases, of which 2940 cases were projected to be in males and 2700 were projected to be in females. An estimated 1090 persons (males 570; females 520) were projected to die of the disease in 2007.^{[6 ]}

International

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

The 5-year overall survival rate for patients with adenocarcinoma has been estimated to be 30-35%. The 5-year survival rate for patients with small-bowel sarcomas is approximately 25%.^{[7 ]}

Race

Population-based studies in the United States have suggested somewhat higher prevalence rates of small-bowel cancer for blacks than for whites. According to one study, blacks have almost twice the incidence of carcinomas than whites do (10.6 versus 5.6 per million population).^{[8 ]}

Sex

Men have higher rates of all types of small bowel cancer than women do, with a male-to-female ratio of 1.4:1.^{[8 ]}

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.

Clinical

History

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

• Because of the nonspecific nature of symptoms, a significant delay between the onset of symptoms and diagnosis often occurs, averaging 6-8 months.
• Nausea, vomiting, and intestinal obstruction are common presenting symptoms. Half of these patients undergo emergency surgery for intestinal obstruction.
• Abdominal pain and weight loss complicate the clinical presentation.
• Bleeding is less common.
• The few published series on small bowel neoplasms that are available cannot be used as generalizations for presentation of the individual histologic subtypes. However, it does appear that adenocarcinomas are more frequently associated with pain and obstruction when compared to sarcomas and carcinoids. Sarcomas (GIST) present more commonly with acute GI bleeding.

Physical

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

• A tender and distended abdomen may be found due to obstruction.
• Peritoneal signs indicate perforation.
• Jaundice from biliary obstruction or liver metastases may occur rarely.
• Guaiac-positive stool or acute GI bleeding, suggests intestinal bleeding, although this occurs more frequently in persons with benign small-bowel tumors.

Causes

• Genetic risk factors
  • Familial adenomatous polyposis: Patients with this condition develop multiple adenomas throughout the small bowel and colon that may lead to adenocarcinomas. After the colon, the duodenum is the most common site of adenocarcinoma. A 1993 study from Johns Hopkins by Offerhaus et al found that patients with familial adenomatous polyposis have a relative risk of more than 300 for duodenal adenocarcinoma but no elevated risk for gastric or nonduodenal small-bowel cancer.^{[9 ]}Molecular genetic studies of duodenal polyps in patients with familial adenomatous polyposis performed by Kashiwagi et al in 1997 found a high frequency of p53 overexpression in dysplastic adenomas, although the frequency of TP53 and k-ras gene mutations was much lower.^{[10 ]}
  • Hereditary nonpolyposis colorectal cancer: Aside from colorectal carcinoma, patients with this genetic syndrome also develop endometrial, gastric, small bowel, upper urinary tract, and ovarian carcinomas. The lifetime risk of small-bowel adenocarcinoma in patients with hereditary nonpolyposis colorectal cancer is 1-4%, which is more than 100 times the risk in the general population. Small bowel adenocarcinomas in persons with hereditary nonpolyposis colorectal cancer are distributed fairly evenly throughout the small bowel. They occur at younger age and appear to have a better prognosis than sporadic small-bowel cancers. The most commonly mutated genes in the germline of patients with hereditary nonpolyposis colorectal cancer are HMLH1 and HMSH2, which are involved in DNA mismatch repair.
• Environmental risk factors
  • Diet: A 1977 study by Lowenfels and Sonni found animal fat intake to be correlated with small-bowel cancer.^{[11 ]}Another study, in 1993 by Chow et al, reported that consumption of red meat and salt-cured or smoked foods raised the risk of small-bowel cancer 2-3 times.^{[12 ]}
  • Tobacco and alcohol: Studies from 1994 by Chen et al found an association between smoking and small-bowel adenocarcinoma and between alcohol consumption and small-bowel adenocarcinoma, but this has not been confirmed in other studies.^{[13 ]}
• Predisposing medical conditions
  • Crohn disease: The relative risk of small-bowel adenocarcinoma is estimated to be between 15 and more than 100 in patients with Crohn disease. Unlike most small-bowel adenocarcinomas, Crohn-related tumors generally occur in the ileum, reflecting the distribution of Crohn disease. The risk of adenocarcinoma does not begin until at least 10 years after the onset of Crohn disease, and the adenocarcinoma typically occurs more than 20 years afterwards.
  • Celiac disease (nontropical sprue): Patients with celiac disease appear to be at increased risk of small-bowel lymphoma and adenocarcinoma. A 2001 survey of adult celiac disease patients in the United States performed by Green et al found a relative risk of 300 for the development of lymphoma and 67 for the development of adenocarcinoma. Small-bowel adenocarcinomas associated with celiac disease appear to have an increased incidence of defective DNA mismatch repair compared with those not associated with celiac disease and are also associated with an earlier stage at diagnosis and a better prognosis.^{[14 ]}
  • Peutz-Jeghers syndrome: Hemminki has reported an approximately 18-fold increase in the incidence compared to that in the general population.^{[15 ]}

Differential Diagnoses

Other Problems to Be Considered

Intestinal leiomyoma

Workup

Laboratory Studies

• CBC count may show mild anemia related to chronic blood loss.
• Liver function tests may reveal hyperbilirubinemia, which may be related to biliary obstruction from periampullary tumors.^{[16 ]}Elevated transaminase levels also may be found in the presence of liver metastases.
• Carcinoembryonic antigen levels may be elevated.

Imaging Studies

• Plain abdominal x-ray films may reveal partial or complete small-bowel obstruction.
• Upper GI series with small-bowel followthrough show abnormalities in 53-83% of patients with small-bowel cancer.
• Small bowel enteroclysis studies are done with double contrast barium enema, which has a sensitivity of 95%. However, it is difficult to perform as it requires a long tube to be inserted in the small bowel to instill air and contrast.
• Abdominal CT scan may elucidate the site and extent of local disease and the presence of liver metastases.

Other Tests

In those rare cases of bleeding due to a small bowel tumor, the diagnostic approach is the same for all cases of lower GI bleeding. In case of negative upper and lower endoscopy, tagged red blood cell scan and angiography can be helpful in localizing the disease process. A newer test is called the capsule endoscopy, which has a better sensitivity and specificity is being performed for occult GI bleeding.

Procedures

• Upper GI endoscopy with small-bowel enteroscopy (push enteroscopy) may identify and allow biopsy of lesions in the duodenum and jejunum. Push enteroscopy is difficult to perform. The endoscopes are long and difficult to manipulate. The procedure takes a long time to perform.
• Colonoscopy with retrograde ileoscopy may be useful in identifying ileal tumors.
• Capsule endoscopy: This test is done with a pill with dimensions of 11 × 26 mm in size and weighs 4 g. The pill has a small video camera, batteries, and a radiofrequency transmitter. The batteries last 8 hours. The pill takes about 50,000 pictures as it passes the GI system. The pictures are captured in a device like a Walkman, which is strapped to the waist. It was FDA approved for small bowel use in 2001. Cobrin et al reported that 9% of cases of occult GI bleeding were caused by small bowel tumors.^{[17 ]}

Histologic Findings

• Adenocarcinomas (40%) - Grade I (well differentiated, 0-42%), grade II (moderately differentiated, 24-45%), grade III (poorly differentiated, 34-42%)
• Sarcomas/GISTs (15%) - High-grade lesions (>5 mitoses per 10 high-power fields, infiltration of overlying mucosa by the tumor). Immunohistochemical staining is an important marker for GIST. Miettinen et al reported that GISTs arising at different anatomic sites display different percent of immunohistochemical staining. Their review of 292 patients revealed that there was equal positivity for both CD34 and smooth muscle actin. However, in cases of GISTs arising from stomach, colon, and rectum, 100% of them were positive for CD34 and none for smooth muscle actin. Only 50% of the small bowel GISTs were positive for CD34. Miettinen et al also reported that c-kit protein (CD117 or c-kit) is expressed in 85-100% of the GIST tumors.^{[5 ]} C-Kit is a transmembrane protein receptor with a tyrosine kinase domain intracellularly. Only those patients who are c-kit-positive respond to imatinib mesylate.
• Carcinoids (30%)
• Lymphomas (15%)

Staging

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

• Primary tumor (T)
  • TX: Primary tumor cannot be assessed.
  • T0: No evidence of primary tumor is present.
  • Tis: Carcinoma in situ is present.
  • T1: Tumor invades the lamina propria or submucosa.
  • T2: Tumor invades the muscularis propria.
  • T3: Tumor invades through the muscularis propria into subserosa or into nonperitonealized perimuscular tissue (mesentery or retroperitoneum), with extension of less than 2 cm.
  • T4: Tumor penetrates the visceral peritoneum or directly invades other organs or structures.
• Regional lymph nodes (N)
  • NX: Regional lymph nodes cannot be assessed.
  • N0: No regional lymph node metastasis is present.
  • N1: Regional lymph node metastasis has occurred.
• Distant metastases (M)
  • MX: Presence of distant metastasis cannot be assessed.
  • M0: No distant metastasis is present.
  • M1: Distant metastasis has occurred.
• Stage grouping
  • Stage 0 - Tis, N0, M0
  • Stage I - T1-2, N0, M0
  • Stage II - T3-4, N0, M0
  • Stage III - Any T, N1, M0
  • Stage IV - Any T, any N, M1

The staging for the duodenal polyps found in familial adenomatous polyposis is that of Spigelman.^{[18 ]}

Treatment

Medical Care

• 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.^{[19 ]}
  • 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.^{[20 ]}
  • 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.^{[21 ]}
• 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.^{[22 ]}
  • 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 patients with resected small-bowel adenocarcinoma associated with celiac disease.^{[23 ]}
• 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.^{[24 ]}
• 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.^{[25 ]}
  • 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.^{[26 ]}
• 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.^{[27 ]}
• Unlike conventional chemotherapy, the recently developed novel agent imatinib mesylate (also known as STI571 and Gleevec) has shown promising activity in GISTs. Imatinib is a small molecule that selectively inhibits the tyrosine kinase activity of bcr-abl, c-kit, and PDGFR.
  • In 2002, Demetri et al reported a multinational study of 147 subjects with advanced GISTs who were randomized to receive 400 mg or 600 mg of imatinib daily. Results demonstrated a 54% partial response rate and 28% stable disease, with a median duration of response greater than 24 weeks and no differences in response between the two doses.^{[28 ]}
  • Another study of imatinib by the European Organization for Research and Treatment of Cancer, as reported by van Oosterom et al in 2002, indicated a 54% partial response rate and 37% stable disease rate, with a duration of response greater than 10 months, among 35 subjects with GISTs.^{[29 ]}
• These studies have led to the US Food and Drug Administration approval of imatinib for advanced GISTs. However, its effect on survival and its role in the adjuvant setting remain to be defined by the results of ongoing randomized clinical trials.
• The FDA has recently approved Sunitinib (Sutent) as targeted therapy for patients in whom imatinib fails in the form of disease progression or inability to tolerate the drug.

Surgical Care

• Surgical resection provides the only hope of cure for patients with small-bowel adenocarcinomas. This is possible in approximately two thirds of patients. The remaining have unresectable disease as a result of extensive local disease or metastases to regional lymph nodes, the liver, or the peritoneum.
• Use wide local excision on lesions in the distal duodenum, jejunum, or ileum.
  • Patients with lesions in the proximal duodenum, including those in the periampullary region, should undergo pancreaticoduodenectomy, which now has an operative mortality rate of less than 5%.
  • Several studies have shown that patients who undergo resection have an improved 5-year survival rate of 40-60%.
  • Surgery is indicated for palliation in patients with symptomatic advanced disease, such as intestinal obstruction.
  • Ileal tumors are more likely to develop intestinal obstruction than jejunal tumors. Emergency surgery for these patients relieves the obstruction but precludes a complete and negative margin resection.
• Despite the efficacy of imatinib for GISTs, surgical resection remains the primary therapy for small-bowel sarcomas, although 35-50% are unresectable because of metastatic disease. Similar to proximal duodenal adenocarcinomas, small-bowel sarcomas located in this region should be resected with a pancreaticoduodenectomy.
  • Those in the distal duodenum, jejunum, or ileum should be resected with wide margins; tumors close to the ileocecal valve may require a right hemicolectomy.  DeMatteo et al reported a  series from Memorial Sloan-Kettering of 200 patients with GISTs showing median survival of patients with complete excision was 66 months, as opposed to those with incomplete resection at 22 months, justifying the removal of adjacent organs to obtain complete resection of the primary disease.^{[7 ]}
  • Lymph node metastasis is rare, and therefore an extensive lymph node dissection is not recommended.
  • Resection appears to prolong survival, but recurrence with widely metastatic disease is typical.

Consultations

• Gastroenterologist: This specialist may assist in diagnosis through upper GI endoscopy and colonoscopy.
• Radiation oncologist
  • Although no survival benefit is achieved with adjuvant radiotherapy after surgery for small-bowel adenocarcinoma or sarcoma, radiotherapy may be useful as a palliative procedure for pain relief or obstructive symptoms in patients with advanced disease. Also, radiotherapy may be of benefit for controlling chronic tumor-related blood loss.
  • While postoperative radiotherapy has been shown to improve local control for sarcomas of the extremities, its role for GIST and GI sarcomas is not clear. Adjuvant brachytherapy and intraoperative radiation are also being investigated for treatment of GI sarcomas.

Medication

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.

Chemotherapeutic agents

Chemical substances or drugs that treat neoplastic diseases by interfering with DNA synthesis.

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.

Dosing

Adult

Single-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

Not established

Interactions

Methotrexate 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

Contraindications

Documented hypersensitivity; bone marrow suppression; serious infection; poor nutritional status; active ischemic heart disease; MI within 6 mo

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Nausea, 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

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.

Dosing

Adult

Roswell 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

Not established

Interactions

May decrease serum levels and efficacy of phenobarbital, phenytoin, and primidone; rescues against toxic effects of methotrexate

Contraindications

Documented hypersensitivity; pernicious anemia; vitamin-deficient megaloblastic anemias

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Allergic 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

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.

Dosing

Adult

Single-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

Not established

Interactions

Because 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

Contraindications

Documented hypersensitivity; ongoing severe diarrhea or neutropenic fever from prior treatment with irinotecan; significant liver function abnormalities including any degree of jaundice

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Can 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 <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

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.

Dosing

Adult

FOLFOX 4: 85 mg/m² IV over 2 h (with leucovorin, before 5-FU) on day 1; repeat q2wk

Pediatric

Not established

Interactions

Because of renally excretion, coadministration of nephrotoxic drugs may potentially affect clearance

Contraindications

Documented hypersensitivity (also other platinum compounds); should be given cautiously in patients with preexisting neuropathy

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May 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

Tyrosine kinase inhibitors

Inhibit tyrosine kinase activity of c-kit, bcr-abl, and PDGFR oncogenes.

Imatinib mesylate (Gleevec)

Small molecule that selectively inhibits tyrosine kinase activity of c-kit, bcr-abl, and PDGFR. Available in 100-mg caps.

Dosing

Adult

400 mg/d or 600 mg/d PO for adult patients with unresectable or metastatic GIST

Pediatric

Not established

Interactions

Because 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)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Most 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

Multikinase inhibitors

Elicit actions via multiple tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression.

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.

Dosing

Adult

Standard 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

Not established

Interactions

Potent 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)

Contraindications

Documented hypersensitivity; concurrent administration with St John's wort

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common 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

Follow-up

Further Inpatient Care

• Patients who develop serious symptoms related to disease progression may need admission to a hospital for inpatient care (see Complications).

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.

Complications

• Partial or complete small-bowel obstruction may occur because of an obstructing intraluminal tumor. This may be treated either conservatively (ie, nasogastric tube decompression and parenteral nutrition) or with surgery (ie, small-bowel resection or bypass).
• Intestinal bleeding is common with small-bowel sarcomas and may require transfusion support and surgical intervention.
• Biliary obstruction may result from compression of the extrahepatic common bile duct by a periampullary or proximal duodenal tumor. Biliary stenting via endoscopic retrograde cholangiopancreatography or transhepatic biliary drainage may be performed if feasible.

Prognosis

• Adenocarcinomas       
  • In 1999, Howe et al reviewed 4995 patients with small-bowel adenocarcinoma from the National Cancer Data Base from 1985-1995 and found the following factors to correlate with survival: patient age, tumor site (favoring jejunum and ileum), clinical stage, and whether curative resection was performed.
  • Other smaller studies by Bakaeen et al and Ryder et al, both in 2000, also found tumor size, histologic grade, nodal metastases, and positive surgical margins to be prognostic factors.^{[30,31 ]}
• Sarcomas
  • Tumor size greater than 4.5 cm in duodenal GIST and greater than 5 cm in jejunoileal GIST that have been reported to be malignant, patient age, and stage of disease are clinical features that have prognostic value.
  • The most important histologic feature associated with survival is the mitotic count of the tumor, with those having greater than 2 mitoses in duodenal GIST and 5 or more mitoses per 50 high-power fields in jejunoileal GIST. These indicate malignant potential of the tumor.
  • Emory et al have reported a series of 1004 GISTs. Multivariate analysis revealed that GISTs localized in the small intestine were significantly associated with worse overall survival than GISTs from the colon and stomach.^{[32 ]}
  • Negative surgical margins after surgery improve prognosis.

Patient Education

For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education article Cancer of the Small Intestine.

Miscellaneous

Medicolegal Pitfalls

Because effective medical therapy is available for small-bowel GISTs and lymphomas, accurate histopathologic diagnosis (including assessment of c-kit overexpression) is essential. Failure to identify patients with these tumor types may result in inadequate treatment.

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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

Contributor Information and Disclosures

Author

N Joseph Espat, MD, MS, FACS, Professor and Chief of Surgical Oncology, Vice-Chairman of Department of Surgery, Roger Williams Medical Center
N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Hepato-Pancreato-Biliary Association, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, and Surgical Infection Society
Disclosure: Nothing to disclose.

Coauthor(s)

Ponnandai S Somasundar, MD, FACS, Assistant Professor of Surgery, Boston University; Surgical Oncologist, Roger Williams Medical Center; Director of Oncology, Kent County Hospital
Ponnandai S Somasundar, MD, FACS is a member of the following medical societies: American College of Surgeons, American Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Association of Surgeons of India, and Society of Surgical Oncology
Disclosure: Nothing to disclose.

Piero Marco Fisichella, MD, Assistant Professor of Surgery, Stritch School of Medicine, Loyola University; Director, Esophageal Motility Center, Loyola University Medical Center
Piero Marco Fisichella, MD is a member of the following medical societies: American College of Surgeons, American Medical Association, Association for Academic Surgery, Society for Surgery of the Alimentary Tract, and Society of American Gastrointestinal and Endoscopic Surgeons
Disclosure: Nothing to disclose.

Medical Editor

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, American Society for Therapeutic Radiology and Oncology, and American Society of Clinical Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Visiting Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Clinical Oncology, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting

eMedicine extends its thanks to Alfred I Neugut, MD, PhD, Head, Cancer Prevention and Control, Herbert Irving Comprehensive Cancer Center; Professor, Department of Medicine and Public Health, Columbia University College of Physicians and Surgeons and Allen C Chen, MD, MS, Assistant Professor, Department of Medicine, Division of Medical Oncology, New York University School of Medicine for previous versions of this article.

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