The Role of Imatinib Following Complete Resection of Primary Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumor (GIST) is the most prevalent mesenchymal tumor of the gastrointestinal tract, primarily arising in the stomach and small intestine.^1,2 It can be a life-threatening disease, with an expected incidence of approximately 5,000 new cases each year in the US.^3,4 Surgery is the standard of care for primary GISTs and the goal of resection is to completely remove the tumor with clear margins.^5,6 As GISTs are soft and fragile, surgical resection needs to be performed carefully to avoid tumor rupture or hemorrhage, with a resultant increased risk for tumor dissemination.^5,7,8 Surgery may not always be indicated, especially in instances of metastatic or locally advanced GIST.

Prior to the approval of the targeted agent imatinib, there were no other effective therapies for metastatic GIST as both radiotherapy and conventional chemotherapy were generally ineffective.^5,9–14 Imatinib mesylate (Gleevec®, Novartis) is a potent inhibitor of several receptor protein tyrosine kinases including KIT, platelet-derived growth factor, and BCR/ABL.^15–19 Its use in GIST is based on the fact that most GISTs express KIT, and up to 90% of patients have a c-kit or PDGFRalpha gene mutation.^16,20,21 GISTs frequently result from gain-of-function mutations in the c-kit gene, which encodes the transmembrane tyrosine kinase KIT.^16,20–23 Once this mutated gene is expressed, KIT signaling is constitutively activated, resulting in uncontrolled cell proliferation and resistance to apoptosis.^20–22 In GIST, imatinib primarily acts by inhibiting this pathophysiological pathway, thereby inhibiting tumor growth. While surgery remains the standard of care for GIST, imatinib therapy has altered the treatment paradigm. Imatinib has been shown to induce partial response or stable disease in 80% of patients with metastatic GIST.^24,25 In both unresectable and/or metastatic GIST patients, imatinib therapy has demonstrated durable response rates and favorable progression-free survival (PFS) and overall survival (OS).^24–27

The US Food and Drug Administration (FDA) has approved imatinib for the treatment of patients with KIT-positive unresectable and/or metastatic malignant GIST. The recommended dose of imatinib is 400mg/day. The US-specific prescribing notes state that a dose increase to 800mg/daily (given as 400mg twice daily) may be considered depending on the impact of the lower dose (400mg/day) on disease progression.

Around 46% of GIST patients are candidates for surgery, and the tumor can be completely resected in most of these patients;^28–31 however, 40–90% of these patients have a documented recurrence within two years of surgery with median disease-free survival (DFS) as low as three years.^28–31 Furthermore, the five-year OS rate after complete surgical resection is only about 48–65%.^29,32–34 This has led to the search for an adjuvant therapy option to prevent or delay recurrence and, hopefully, to improve OS rates. Imatinib is currently being evaluated in the adjuvant setting for primary GIST treatment, and the published data from the adjuvant trials will be discussed in this article. The rationale for imatinib in the adjuvant setting is based on its demonstrated efficacy and tolerability in patients with unresectable and/or metastatic GIST, and its potential benefit in an earlier and minimal residual status, particularly in patients at higher risk of relapse.