Malignant Neoplasms of the Small Intestine 

Updated: Sep 26, 2019
Author: Ponnandai S Somasundar, MD, MPH, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS 

Overview

Practice Essentials

Malignant neoplasms of the small bowel are among the rarest types of cancer, accounting for 1-2% of all GI cancers.[1] 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. Around 98% of small-bowel tumors are made up of adenocarcinomas, carcinoid tumors, lymphomas, sarcoma (most commonly leiomyosarcoma and more rarely angiosarcoma or liposarcoma) and gastrointestinal stromal tumors (GISTs).[1]   Each of these tumor subtypes has its own distinct clinical behavior and, therefore, dictates a different treatment approach.

Unfortunately, malignant lesions of the small bowel are often discovered when they have metastasized to distant sites or at surgery indicated for another diagnosis or intestinal obstruction. Thus, these patients often have in a poor prognosis. The 5-year survival rates of small intestine cancers by stage are as follows[2] :

  • Stage I - 70%
  • Stage II - 55%
  • Stage III - 30%
  • Stage IV - 5-10%

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. For further information on carcinoid tumors, refer to Intestinal Carcinoid Tumors; for further information on GISTS, refer to Gastrointestinal Stromal Tumors (GISTs).

For patient education information, see What Is Small Intestine Cancer?

 

Pathophysiology

Approximately 64% of all small-bowel tumors are malignant, and approximately 40% of these tumors are adenocarcinomas. Epidemiologically, small-bowel adenocarcinomas bear 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 (SBAs) 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 the first large-scale genomic comparison of SBA (n = 317) with colorectal cancer (n = 6353) and gastric carcinoma (n = 889), the frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% vs 75.9%, P <  0.001; and CDKN2A: 14.5%  vs 2.6%, P <  0.001) or gastric carcinoma (KRAS: 53.6% vs 14.2%, P <  0.001; APC: 26.8% vs 7.8%, P <  0.001; and SMAD4: 17.4% vs 5.2%, P <  0.001).  BRAF was mutated in 7.6% of colorectal cancer and 9.1% of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% of BRAF-mutated cases. The ERBB2/HER2 point mutations, microsatellite instability, and high tumor mutational burden were all enriched in SBA.[3]  

 

 

Etiology

Genetic risk factors

Patients with familial adenomatous polyposis develop multiple adenomas throughout the small bowel and colon that may lead to adenocarcinomas.[4]  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.[5]  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.[6]

Aside from colorectal carcinoma, patients with hereditary nonpolyposis colorectal cancer 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 entail 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

A 1977 study by Lowenfels and Sonni found animal fat intake to be correlated with small-bowel cancer.[7]  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.[8]

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.[9, 10]

Predisposing medical conditions

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.

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.[11]

Hemminki has reported an approximately 18-fold increase in the incidence of gastrointestinal cancers in patients with Peutz-Jeghers syndrome compared with that in the general population.[12]

Epidemiology

The American Cancer Society estimates 10,590 new cases and 1590 deaths from small intestine cancer in the United States in 2019.[13]

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 that while adenocarcinomas constitute the majority of small-bowel cancers in developed countries, lymphomas predominate in less-developed countries.

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).[14]

Males represent a slight preponderance of new cases (52%) compared with females (48%).[13] 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.

Prognosis

Adenocarcinomas

The overall 5-year survival rate for resectable adenocarcinoma is 20%.[1]

A study comparing outcomes for 2123 patients with small-bowel adenocarcinoma and 248,862 patients with colon cancer found the prognosis for small-bowel adenocarcinoma is worse than that for colon cancer, and only surgery improves survival. In contrast to colon cancer, chemotherapy did not improve overall or cancer-specific survival regardless of stage. Predictors of poor survival included advanced age, black race, advanced stage, poor tumor differentiation, high comorbidity index, and distal location.[15]

Sarcomas

The 5-year survival rate for resectable leiomyosarcoma, the most common primary sarcoma of the small intestine, is approximately 50%.[1]  Negative surgical margins after surgery improve prognosis. Intestinal bleeding is common with small-bowel sarcomas and may necessitate transfusion support and surgical intervention.

 

Presentation

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. Gastrointestinal stromal tumors (GISTs) present more commonly as acute GI bleeding.

Physical Examination

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.

 

DDx

 

Workup

Laboratory Studies

The complete blood cell count (CBC) 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 follow-through 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.

Cross-sectional imaging can, in many cases, detect small-bowel malignancies that are usually inaccessible to conventional endoscopy. Modern multidetector computed tomographies permit accurate diagnosis, complete pretreatment staging, and follow-up of these lesions.[17]

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.

Video capsule endoscopy (VCE) should be the third diagnostic test performed after upper and lower endoscopic evaluation of suspected small bowel bleeding.[18] A capsule about the size of a large vitamin is swallowed. It contains a small video camera, batteries that last about 8 hours, and a radiofrequency transmitter. The camera takes about 50,000 pictures as it passes the GI system. The pictures are captured in a device like a cassette player, which is strapped to the waist.  In comparison to radiographic imaging techniques,

VCE is highly sensitive in the detection of occult arterial and venous bleeding, especially if done during bleeding episodes. Its sensitivity is higher than CT angiography or magnetic resonance enteroclysis.[19]  VCE is useful as a screening tool in patients with suspected small bowel bleeding, but has a false-negative rate of up to 19% for neoplasms. Double-balloon enteroscopy (DBE) should still be performed in patients with a high clinical suspicion of small intestine lesion, following a negative VCE result.[18]

DBE allows deeper intubation of the small intestine compared with tradtional endoscopes. To perform DBE, the enteroscope and overtube are introduced into the small bowel, typically past the ampulla, and the balloon on the overtube is inflated. The enteroscope is then further advanced into the small bowel. The balloon on the DBE enteroscope is then inflated. The overtube is subsequently advanced over the enteroscope. Now both overtube and enteroscope are drawn back (with both balloons inflated on DBE), which allows the small bowel to plicate over the enteroscope. By repeating this series of steps, a longer distance can be traversed than with conventional endoscopy. Owing to deeper intubation of the small bowel and a higher success rate with the oral approach, this is the preferred route for lesions suspected to lie within the proximal 75% of the small bowel, whereas the rectal route is used for more distal lesions.[18]

Histologic Findings

Adenocarcinoma are often moderately well differentiate and mucin producing with scattered endocrine cells. Mucin staining varies based on site of the lesion[20] :

  • Duodenum: positive for MUC1; negative for CK20
  • Jujunum and ileum: positive for CK20; negative for MUC1

Staging

Small-bowel cancer is staged according to the American Joint Committee on Cancer tumor-node-metastasis (TNM) system.[2]

Primary tumor (T) is classified as follows:

  • 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) are classified as follows:

  • NX: Regional lymph nodes cannot be assessed.
  • N0: No regional lymph node metastasis is present.
  • N1: Regional lymph node metastasis has occurred.

Distant metastasis (M) is classified as follows:

  • MX: Presence of distant metastasis cannot be assessed.
  • M0: No distant metastasis is present.
  • M1: Distant metastasis has occurred.

Stage grouping is as follows:

  • Stage 0 - Tis, N0, M0
  • Stage I - T1-2, N0, M0
  • Stage IIA - T3, N0, M0
  • Stage IIB - T4, N0, M0
  • Stage IIIA - Any T, N1, M0
  • Stage IIIB - Any T, N2, M0
  • Stage IV - Any T, any N, M1

The staging for the duodenal polyps found in familial adenomatous polyposis is that of Spigelman.[21]

 

Treatment

Approach Considerations

The mainstay of treatment for adenocarcinoma and leiomyosarcoma is radical surgical resection. If the lesion is unresectable, surgical bypass of obstruction and palliative radiation therapy are treatment options.[1]  A Japanese study by Nakanoko et al reported that patients with unresectable stage IV who received chemotherapy achieved survival durations of over 11 months. In contrast, overall survival without chemotherapy was 3.3 months.[22]  

However, no standard effective chemotherapy exists for patients with recurrent metastatic adenocarcinoma or leiomyosarcoma of the small intestine. These patients should be considered candidates for clinical trials evaluating the use of new anticancer drugs or biologicals in phase I and phase II trials. For locally recurrent disease, options include surgery, palliative radiation therapy, palliative chemotherapy and clinical trials evaluating ways of improving local control, such as the use of radiation therapy with radiosensitizers with or without systemic chemotherapy.[1]

Medical Care

Chemotherapy

Although surgical resection remains the primary component of treatment, distant recurrence is frequent after surgical resection, and this suggests a role for adjuvant systemic therapy. Chemotherapy is associated with improved long‐term survival and increasing retrospective evidence supports the use of adjuvant chemotherapy, particularly in patients with regional lymph node involvement.[23]

Chemotherapy drugs that may be used in the treatment of SBA include:

  • Capecitabine
  • 5-fluorouracil (5-FU) [24, 25, 26]
  • Oxaliplatin
  • Irinotecan

Drug combinations that have been used in advanced small intestine cancer include:

  • Capecitabine and oxaliplatin (called CAPOX) [27]
  • CAPOX and bevacizumab [28]
  • 5-FU and leucovorin with oxaliplatin (FOLFOX) [29]
  • 5-FU and leucovorin with irinotecan (FOLFIRI) [27]

Radiation Therapy

Although no survival benefit is achieved with adjuvant radiotherapy after surgery for small-bowel adenocarcinoma or sarcoma,[30] radiotherapy is used 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.

Surgical Care

Surgical resection provides the only hope of cure for patients with small-bowel adenocarcinomas and sarcomas. This is possible in approximately two thirds of patients with adenocarcinoma. The remaining have unresectable disease as a result of extensive local disease or metastases to regional lymph nodes, the liver, or the peritoneum.

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.

Tumors in the distal duodenum, jejunum, or ileum should be resected with wide margins; tumors close to the ileocecal valve may require a right hemicolectomy.  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.

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.

Consultations

 A gastroenterologist may assist in diagnosis through upper GI endoscopy and colonoscopy.

 

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).

Long-Term Monitoring

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.

 

Guidelines

Guidelines Summary

Guidelines on small bowel adenocarcinoma (SBA) from the National Comprehensive Cancer Network are summarized below.[31]                                                              

Workup

Patients with SBA require a complete staging workup, including the following:

  • Biopsy (if appropriate)
  • Pathologic tissue review
  • Imaging studies
  • Complete blood count
  • Chemistry profile
  • Carbohydrate antigen 19-9
  • Carcinoembryonic antigen
  • Studies for celiac disease or inflammatory bowel disease (depending on tumor location and patient history)
  • DNA mismatch repair (MMR) or microsatellite instability (MSI) testing

Imaging studies may include the following:

  • Esophagogastroduodenoscopy with endoscopic ultrasound is recommended when a duodenal malignancy is suspected.
  • Double balloon endoscopy may be of particular benefit for patients with small bowel strictures.
  • CT or MRI may be used to evaluate the extent of local tumor invasion and to assess for distant metastases; CT or MR enterography or enteroclysis may be used when conventional CT or MRI with contrast have failed to show a tumor.
  • PET/CT is not routinely indicated, but may be considered when CT or MR results are equivocal.

Treatment of Stage I–III Small Bowel Adenocarcinoma

Primary treatment for local (stage I–III) SBA consists of surgical resection with en bloc removal of at least 8 regional lymph nodes.

The type of resection used to treat localized SBA depends on the location of the primary tumor, as follows:

  • Segmental resection of the small bowel is often the mainstay of treatment.
  • Duodenal tumors may require either pancreaticoduodenectomy (Whipple procedure) or segmental duodenal resection.  Experienced surgeons may consider minimally invasive procedures (eg, laparoscopic surgery) for pancreaticoduodenectomy.
  • For tumors of the jejunum or ileum, segmentectomy is the preferred method of resection.

Participation in a clinical trial is preferred for all patients with SBA who are considering adjuvant therapy, as the optimal approach is unknown.

Observation is recommended after surgical treatment of all stage I SBA tumors and stage II tumors that have high MSI (MSI-H) or deficient MMR (dMMR).

Observation or 6 months of adjuvant treatment with fluorouracil/leucovorin (5-FU/LV) or capecitabine is recommended for T3, N0, M0 (stage IIA) tumors that are microsatellite stable (MSS) or MMR proficient (pMMR) and have no high-risk features.

Observation or 6 months of adjuvant treatment with 5-FU/LV/oxaliplatin (FOLFOX), capecitabine plus oxaliplatin (CAPEOX), 5-FU/LV, or capecitabine is recommended for stage II tumors that are MSS or pMMR and have high-risk features (eg, T4 stage, close or positive surgical margins, few lymph nodes examined)

Six months of adjuvant treatment with FOLFOX, CAPEOX, 5-FU/LV, or capecitabine is recommended for any locally advanced SBA with positive lymph nodes (stage III).

Chemoradiation with capecitabine or infusional 5-FU is another option for stage III duodenal cancer that is margin-positive after resection.

Patients with locally unresectable or medically inoperable SBA may undergo neoadjuvant therapy, with routine monitoring for conversion to resectable disease. I in cases where conversion to resectable disease is not feasible, palliative chemotherapy may be considered.

Treatment of Distant Metastatic (Stage IV) Small Bowel Adenocarcinoma

Recommended first-line chemotherapy regimens are FOLFOX, CAPEOX, or FOLFOXIRI (infusional 5-FU, LV, oxaliplatin, irinotecan), any of which may be combined with bevacizumab. Patients who are not appropriate candidates for intensive therapy may receive these regimens with the more toxic components excluded (ie, 5-FU/LV or capecitabine with or without bevacizumab).

Second-line therapy for tumors that are dMMR or MSI-H is checkpoint inhibitor therapy with programmed death 1 (PD-1) inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor.

FOLFIRI or taxane-based chemotherapies are second-line options for tumors that are pMMR/MSS or are refractory to checkpoint inhibitor therapies.

Larotrectinib is an option in subsequent lines of therapy for metastatic SBA with neurotrophic tyrosine receptor kinase (NTRK) gene fusion and no satisfactory alternative treatments.

Treatment with trifluridine-tipiracil or regorafenib is not recommended.

Certain patients with SBA and limited metastasis to visceral organs may be candidates for metastasectomy.

For resectable peritoneal carcinomatosis, surgical cytoreduction may be considered. With unresectable peritoneal metastases, treatment is palliative and primarily consists of systemic therapy

Posttreatment Surveillance

Due to the lack of data regarding optimal surveillance following curative-intent treatment of SBA, an approach similar to that for colorectal cancer is recommended. This includes regular history and physical examination; carcinoembryonic antigen and/or carbohydrate antigen 19-9 measurement; and CT of the chest, abdomen, and pelvis.

Patients with Crohn disease or familial syndromes (eg, Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome) may require more intensive surveillance (eg, with endoscopy/enteroscopy).

 

Medication

Medication Summary

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

Class Summary

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.

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.

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.

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.

Tyrosine kinase inhibitors

Class Summary

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.

Multikinase inhibitors

Class Summary

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.