The Use of Tyrosine Kinase Inhibitors for Gastrointestinal Stromal Tumors (GIST)

Scott H. Okuno, MD | March 15, 2011
Gastrointestinal Stromal Tumors (GIST)Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with an annual incidence of 12 to 14 per million persons.1 The tumors are found in the stomach (52%), small intestine (25%), colon (11%), esophagus (5%), and rectum (2%), as well as in the omentum, mesentery, and peritoneum.2 The cellular origin of GISTs is thought to be the interstitial cells of Cajal (ICC), the intestinal pacemaker.3 GISTs appear histologically similar to leiomyosarcomas of the GI tract but are positive for the immunohistochemical marker for the KIT protein (CD117).4 The tumors occur in three histologic variants: spindle cell type (70%), epithelial type (20%), and combined spindle cell-epithelial type (10%).

The characteristic pathologic feature of GISTs is the activating mutations of KIT, which occur in roughly 85% of cases.5 Approximately 5% to 8% of GISTs have mutations of the platelet-derived growth factor receptor alfa (PDGFRα) gene6 and wild-type GIST accounts for the remainder of GIST mutations. The most common KIT mutation is on exon 11 (64%), followed by exon 9 (15%), exon 13 (<2%), and exon 17 (1%).7 The most common PDGFRα mutation is the D842V substitution on exon 18.8 The majority of exon 9 mutations occur in the small bowel and most PDGFRα mutations occur in the stomach. The exon 11 mutations are distributed throughout the GI tract.

The presenting signs and symptoms of GIST vary from abdominal pain, bloating, or bleeding, to incidental findings on imaging or at the time of surgery. Surgery is the mainstay of treatment for localized GIST. Clinical prognostic variables used to predict recurrence include tumor size, mitotic activity, and location of the tumor within the GI tract; high-risk factors include size >5 cm, >5 mitoses per 50 high-power fields, and location in the small bowel.9,10 The use of exon mutational analyses as an independent risk factor is under investigation.

TKIs for Metastatic GIST

Imatinib

Patients with metastatic or surgically nonresectable disease do not respond to the standard cytotoxic therapy used for sarcomas, and have poor outcomes. With the introduction of imatinib (Gleevec), an oral tyrosine kinase inhibitor (TKI) that selectively targets KIT, ABL, BCR-ABL, and PDGFR, up to 80% of patients experience clinical benefit, with stable or responding disease lasting a median of approximately 20 months.11-14 Common side effects of imatinib include fluid retention, rash, arthralgias, myalgias, nausea, and fatigue.

Two large phase III trials compared once-daily imatinib 400 mg to a twice-daily 400 mg regimen in patients with metastatic GIST. These two studies—conducted in the United States and Canada by the Southwest Oncology Group (SWOG)12 and in Europe and Australia (EU-AUS) by the European Organization for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group14—used the same selection criteria for study entry, treatment, and follow-up, the purpose being to later combine data. A total of 743 patients were enrolled in the SWOG trial and were followed for a median of 54 months. The median progression-free survival (PFS) was 18 months on once-daily imatinib and 20 months on the twice-daily imatinib, with median overall survival (OS) of 55 months and 51 months, respectively. There was no statistically significant difference in response rates, PFS, or OS between the two dosages. The EU-AUS enrolled 946 patients and their initial report, with a median follow up of slightly over 25 months, demonstrated a PFS advantage for the twice-daily dosing but no OS advantage. Subsequently, with longer follow up of 40 months, the EU-AUS investigators reported that once-daily and twice-daily dosing resulted in similar PFS and OS.15

Combining the SWOG and EU-AUS data with those from a median follow-up of 45 months, a meta-analysis of 1640 patients showed a small but significant PFS-related difference in patients on the twice-daily regimen as compared to those treated with the standard single dose (estimated hazard ratio [HR], 0.89; 95% CI, 0.79-1.00 but significant [P = .04, Wald test]). The benefit of the higher dose of imatinib was seen mainly in patients with the KIT exon 9 mutation.16 The OS was identical in both arms.

What then should be the initial dose of imatinib for patients with metastatic GIST? Should patients with the exon 9 mutation be started at a higher dose? Because overall survival is similar with both dosages and because higher doses of imatinib are associated with increased toxicity, it is reasonable to start all patients with metastatic GIST on 400 mg per day. If a tumor has an established exon 9 mutation, and response to therapy is important, an initial higher dose of imatinib should be used.


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