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The Role of Tyrosine Kinase Inhibitors in the Treatment of Gastrointestinal Stromal Tumors

Authors: Margaret von Mehren, MD; Neeta Somaiah, MDFaculty and Disclosures



Gastrointestinal (GI) mesenchymal tumors are rare tumors of the GI tract, comprising less than 1% of all GI tumors.[1] Gastrointestinal stromal tumors (GISTs) are the most common GI mesenchymal tumors. This article will review the epidemiology, molecular markers, clinical and prognostic features, and treatment of GIST, focusing on how targeted therapy has successfully exploited the oncologic drivers of this disease. Before their molecular characterization, GISTs were frequently misdiagnosed as leiomyosarcomas, leiomyomas, or leiomyoblastomas,[2] and the only therapy for GIST was surgery. Treatment paradigms changed when it was discovered that GIST cells express KIT, a tyrosine kinase growth factor receptor, which is mutated in 85% of cases. This discovery has led to the development of effective therapies that use small molecules to block the receptor tyrosine kinases. These therapies include the small molecule inhibitors imatinib and sunitinib. These agents are inhibitors of KIT and PDGFR. Though treatment with these therapies has proven effective in the metastatic disease setting, resistance does occur. Studies have demonstrated the efficacy and safety of imatinib in the adjuvant setting, with reports demonstrating the safety of both agents in the neoadjuvant setting. Alternative tyrosine kinase inhibitors (TKIs), as well as novel therapeutic strategies, are being explored in patients with GIST refractory to standard therapy.



The incidence of GIST is being clarified as pathologists, surgeons, and medical oncologists correctly identify the disease. A population-based study from Iceland of GIST, diagnosed between 1990 and 2003, estimated the annual incidence to be 1.1 per 100,000 persons.[3] A population-based study of western Sweden identified 288 primary GISTs between 1983 and 2000, with an annual incidence of 14.5 per million and an estimated overall prevalence of 129 per million.[4] The Surveillance, Epidemiology, and End Results Registry (SEER) database identified cases diagnosed between 1992 and 2000 and determined the age-adjusted yearly incidence rate was 0.68 per 100,000.[5] The median age at diagnosis in these cohorts was 65.8 and 63 years, respectively, with some studies suggesting an increased incidence among men. The SEER database analysis also suggested a higher incidence in black patients.


The most common site of primary tumors is the stomach (39% to 70%); followed by the small intestine (31% to 45%); colon, rectum, and anus (10% to 16%); and mesentery and peritoneum (8%); with rare cases arising in the esophagus.[1,6,7] Case reports in the literature also describe primary tumors of the duodenal ampulla,[8] appendix,[9] gallbladder,[10] and urinary bladder.[11] Metastatic disease is most often found in the liver, peritoneum, and omentum.[1] Less common metastatic sites include lung and bone, with a case report describing a brain metastasis.[12]