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Gastrointestinal Oncology Systemic Treatment for Gastrointestinal Stromal Tumor—A State of Art Xiaolan Feng, MD, PhD, FRCPC 1 and Don Morris, MD, PhD, FRCPC 2 1. Medical Oncology Fellow; 2. Associate Professor, Tom Baker Cancer Center, Cancer Control, Alberta Health Services, Calgary, Alberta, Canada Abstract The availability of the tyrosine kinase inhibitor (TKI) small molecule imatinib has revolutionized the systemic treatment for gastrointestinal stromal tumor (GIST), historically one of the most chemoresistant solid malignancies. Prior to imatinib availability approximately 14 years ago, surgery was the only effective treatment modality. Imatinib is now accepted as the first-line systemic treatment for advanced GIST and subsequently has become the standard systemic treatment for GIST in the neoadjuvant and adjuvant settings. Sunitinib and regorafenib have been approved for second- and third-line treatments, respectively, for patients with advanced GIST progressing on imatinib. The dramatic and continuing efficacy of TKIs targeting oncogenic driver pathways such as KIT, platelet-derived growth factor receptor alpha (PDGFRα), and vascular epithelial growth factor receptors (VEGFs), in advanced GIST supports the utility of targeted therapy in oncogene addicted solid malignancies. Molecular mutational diagnostics has further defined subpopulations of responders. Although significant gains have been made in the treatment of GIST patients, future research is still warranted to help further improve clinical outcomes of patients with GIST. Keywords Gastrointestinal stromal tumor (GIST), KIT, platelet-derived growth factor receptor alpha (PDGFRα), complete response (CR), partial response (PR), stable disease (SD), disease-free survival (DFS), overall survival (OS), neoadjuvant, adjuvant, metastatic/advanced Disclosure: Xiaolan Feng, MD, PhD, FRCPC and Don Morris, MD, PhD, FRCPC, have no conflicts of interest to declare. No funding was received in the publication of this article. Received: July 8, 2014 Accepted: September 18, 2014 Citation: Oncology & Hematology Review, 2014;10(2):110–22 Correspondence: Xiaolan Feng, MD, PhD, FRCPC, Tom Baker Cancer Center, Cancer Control, Alberta Health Services, 1331 29th ST NW, T2N 4N1, Canada. E: fxiaolan@ucalgary.ca Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract. They are thought to be derived from the interstitial cells of Cajal, the so-called pacemaker cells that regulate gastrointestinal peristaltic function. The annual incidence of GIST is approximately 10–15 per million population with some regional variation, 1 making them the most common subtype of sarcoma. More than a decade ago, systemic chemotherapy for GIST was very disappointing with response rates typically reported of 5–7 %. Surgery was and perhaps is still the only curative modality. The report of the KIT oncogene as the major driver mutation of GIST in 1998 2 coupled with the first case report 3 of a chemotherapy refractory GIST patient (with liver and peritoneal metastasis) that demonstrated a dramatic radiographic response to imatinib demonstrated one of the first successful examples of utilizing targeted therapy for oncogene addicted solid malignancies. In this review, we will summarize and highlight the historical and recent advancements in the systemic treatment of GIST in the metastatic, adjuvant, and neoadjuvant settings. Inoperable/Metastatic Therapy First Line—Imatinib There are few controversies in choosing initial systemic therapy in the management of unresectable advanced or metastatic GIST based on several phase III clinical trials (see Table 1). Level 1 evidence supports the use of imatinib as first-line treatment for advanced/metastatic GIST based 110 on its high clinical benefit rate of 80 %, median progression-free survival (mPFS) approaching 24 months, and a median overall survival (mOS) of nearly 5 years based on extended follow-up of the initial pivotal B2222 phase II trial 4,5 and two large phase III (EORTC62005 6 and SWOGS0033 7 ) trials. The European (EORTC62005) 6 and North American trial (SWOGS0033) 7 compared imatinib 400 mg/day versus 800 mg/day as the initial therapy allowing for crossover at progression in nearly 1,700 patients GIST patients combined. These trials have established imatinib 400 mg/day as the initial treating dose for most patients, as there was no difference between the low- and high-dose arms in terms of response rate and PFS rate. 6,7 Post hoc tumor mutation analysis in both trials demonstrated that patients with KIT exon 9 mutant tumors had a significantly shorter PFS than patients harboring a KIT exon 11 mutation. 6,7 In addition, patients with KIT exon 9 mutant tumors appear to have a longer PFS if treated at 800  mg/day versus 400  mg/day; however, this did not translate into an OS benefit likely due to the fact that tumor control can be restored in many of these patients by using 800 mg upon disease progression or switching to a second-line therapy. 6,7 Thus it is unclear that exon 9 mutant GIST patients should be treated at a starting dose of 800 mg/day versus a standard dose of 400  mg/day followed by escalation to 800 mg/day upon progression. We do know, however, from toxicity data that tolerance is improved with escalation from 400 mg to 800 mg over several weeks. Therefore, our © Tou c h ME d ica l ME d ia 2014