Multimodality Therapy for Metastatic Gastrointestinal Stromal Tumor
Gastrointestinal stromal tumors (GISTs) represent approximately 80 % of sarcomas that arise from the gastrointestinal tract. The primary tumor most commonly arises from the stomach (40–60 %), with small intestine and colon being the next two most common s
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Introduction
Gastrointestinal stromal tumors (GISTs) represent approximately 80 % of sarcomas that arise from the gastrointestinal tract. The primary tumor most commonly arises from the stomach (40–60 %), with small intestine and colon being the next two most common sites of primary disease. GISTs primarily metastasize to the liver and peritoneum. Rarer sites of metastasis include lymph nodes (usually in pediatric-type GIST), lung, and bone. As in other cancer types, prognosis and 5-year overall survival (OS) are significantly impacted by tumor extent at the time of GIST diagnosis. In the contemporary era since widespread use of targeted tyrosine kinase inhibitor (TKI) therapies, individuals with localized GIST have a 5-year OS of 91 %. In comparison, those with locally advanced disease and metastatic disease at the time of diagnosis have 5-year OS rates of 74 % and 48 %, respectively [1]. Median OS of advanced or metastatic GIST is approximately 51–57 months [2]. This chapter will begin with an overview of the role of TKIs in the treatment of metastatic GIST. Next, the roles of systemic chemotherapy, radiation therapy, and hyperthermic intraperitoneal chemotherapy (HIPEC) will be addressed. Finally, the role of surgical management in the treatment of metastatic GIST will be explored.
D.A. Mahvi, MD • E.Z. Keung, MD • C.P. Raut, MD, MSc (*) Department of Surgery, Brigham and Women’s Hospital, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA e-mail: [email protected]
© Springer International Publishing Switzerland 2017 C.R. Scoggins et al. (eds.), Gastrointestinal Stromal Tumors, DOI 10.1007/978-3-319-42632-7_14
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Tyrosine Kinase Inhibitors Imatinib
The treatment and outcomes of metastatic GIST changed dramatically with the introduction of imatinib (Gleevec). In 1998, Hirota and colleagues [3] reported that GISTs frequently are characterized by gain-of-function mutations in the gene encoding the c-KIT receptor tyrosine kinase (RTK). Others furthered the understanding of the disease by identifying CD117 as a sensitive marker for the disease [4] and demonstrating that the interstitial cells of Cajal were likely the cells of origin [5]. This work paved way for future therapeutic options. Imatinib is a tyrosine kinase inhibitor (TKI) that was initially developed in the 1990s for the treatment of chronic myelogenous leukemia (CML) to target the fusion protein BCL–ABL. This constitutively active RTK arises as a result of a reciprocal translocation of chromosome 9 and 22 that occurs in the majority of patients with CML. Approximately 95 % of GISTs exhibit pathological overexpression of KIT (CD117) [6]. Imatinib has been found to be specific for the tyrosine kinase domain abl, c-kit, and platelet-derived growth factor receptor (PDGFR) [7]. Imatinib was first shown to have activity in vitro against a GIST cell line by Tuveson et al. [8]. These findings prompted Joensuu et al. [9] to treat a Finnish patient with the drug. Th
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