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The Efficacy of Imatinib in Unresectable/Metastatic Gastrointestinal Stromal Tumors

US Oncological Review, 2009;5(1):61-4 DOI: http://doi.org/10.17925/OHR.2009.05.1.61

Abstract:

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancy in the gastrointestinal tract. Their pathogenesis is largely based on gain-of-function mutations in the c-kit proto-oncogene, resulting in constitutive activation of the KIT receptor tyrosine kinase. Historically, there were limited options for the medical management of GIST, with tumor recurrence frequently observed following complete surgical resection of primary localized GIST and a grim prognosis for patients with unresectable or metastatic disease. However, the introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate has had a major impact on treatment outcomes for these patients with GIST. Imatinib is currently approved for the treatment of patients with KIT/CD117-positive unresectable and/or metastatic malignant GISTs. Initial therapy with the conventional 400mg/day dose is highly recommended in these patients, while a higher dose (800mg/day) has shown promise in patients who have KIT exon 9-mutant GIST and those who experience disease progression on the conventional dose. Neoadjuvant therapy has also been shown to be safe and beneficial as a palliative treatment.
Keywords: Unresectable, metastatic, gastrointestinal stromal tumor, GIST, imatinib mesylate, dose optimization, neoadjuvant
Disclosure: Shreyaskumar R Patel, MD, is on the speaker’s bureau of and receives honoraria from Novartis.
Received: March 24, 2009 Accepted: June 16, 2009
Correspondence: Shreyaskumar R Patel, MD, University of Texas MD Anderson Cancer Center, 1400 Holcomb Blvd, Unit 450/FC 11. 3022, Houston, TX 77030. E: spatel@mdanderson.org

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancy in the gastrointestinal tract. These sarcomas often originate in the stomach or small intestine, but have also been found to affect extraintestinal sites such as the mesentery and omentum. Since discovering that these tumors express the cell surface growth factor receptor KIT,1 greater understanding of GIST pathophysiology has revolutionized the therapeutic approach to treating these tumors. The ability to diagnose these tumors has been greatly improved because approximately 85% of GISTs stain positive for the CD117 antigen, an epitope for the KIT receptor tyrosine kinase.1,2 A smaller percentage of patients have mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene (5–7%) or have no detectable kinase mutations (10%).1,2

Gain-of-function mutations in the c-kit proto-oncogene result in constitutive activation of the KIT receptor tyrosine kinase, and are largely responsible for the pathogenesis of GISTs. Historically, the medical management of these tumors had limited efficacy. Surgery was the mainstay of therapy due to the high resistance of the tumors to chemotherapy and radiation. Tumor recurrence was frequently observed following complete surgical resection of primary localized GIST, with five-year survival rates of 50%.3 Prognosis was grim for the estimated one-third of patients who presented with unresectable or metastatic disease at diagnosis; with surgical intervention alone, median survival for those patients with metastatic or recurrent GISTs ranged between six and 18 months.3,4

The introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate has had a major impact on the treatment and outlook for patients with GISTs. As a competitive antagonist of the adenosine triphosphate (ATP) binding site, imatinib effectively inhibits the KIT and PDGFRA kinases by interrupting the downstream signaling cascade that leads to cell proliferation.5 Up to 85% of patients with advanced disease who are treated with imatinib have long-term disease stabilization and partial responses, with < 10% achieving complete responses. Notably, the twoyear survival of patients with advanced disease has risen to 75–80% following imatinib treatment.6–8 Imatinib is currently the standard of care for patients with advanced GIST, a disease previously thought of as untreatable. Based on newly available long-term data with imatinib, the US Food and Drug Administration (FDA) recently converted its prior accelerated approval of imatinib to full (regular) approval for the treatment of patients with KIT/CD117-positive unresectable and/or metastatic malignant GISTs.

Improved Outcomes for Patients with Advanced Disease
Early studies with imatinib in advanced GIST provided promising data. A phase II study by Demetri et al. randomized 147 patients with unresectable or metastatic GIST to receive 400 or 600mg/day of imatinib. Patients who progressed on 400mg/day had their dose increased to 600mg/day.6After a median follow-up of 21 months, partial response and stable disease were achieved in 66 and 17% of the total patient population, respectively.9Progressive disease led to death in 14% of patients. Although median survival was not reached, researchers estimated 85% to be alive at 19 months. One-third of patients who progressed on the lower dose sustained a partial response upon cross-over. Similar results were reported by a phase II study testing the efficacy of imatinib at the dose of 400mg twice daily in 27 patients with histologically proven advanced and/or metastatic GIST characterized by KIT expression.10 Of these patients, 89% experienced some degree of symptomatic improvement: 4% had complete remission, 67% partial remission, and 18% stable disease, while 11% had progressive disease. Clinical trials have reported a median time to objective response ranging from 13 to 16 weeks for patients with advanced GIST treated with imatinib,6,9 although some patients have shown dramatic symptomatic improvement within days, along with evidence of reduced metabolic activity on positron emission tomography (PET) scans. Biopsy specimens from a patient with metastatic GIST have also shown a marked decrease in tumor cells, myxoid degeneration, and scarring within one month.11 These tumor cells did not stain for the proliferation marker Ki-67, suggesting an absence of active cell division.
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Keywords: Unresectable, metastatic, gastrointestinal stromal tumor, GIST, imatinib mesylate, dose optimization, neoadjuvant