Neoadjuvant imatinib therapy can be used for patients with large tumors or difficult-to-access small GIST that are considered marginally resectable. In addition, patients with primary localized GIST deemed unresectable are often treated with imatinib.[4,11]
Before the advent of molecularly targeted therapy with TKI, efforts to treat GIST with conventional cytotoxic chemotherapy were essentially futile. The extreme resistance of GIST to chemotherapy may be caused, in part, by the increased expression of P-glycoprotein, the product of the MDR-1 (multidrug resistance-1) gene, and MRP1 (multidrug resistance protein-1), which are cellular efflux pumps that may prevent chemotherapeutic agents from reaching therapeutic intracellular concentrations in GIST cells.[1,12] There is universal agreement that standard chemotherapy has no role in the primary therapy of GIST.[4,5,6]
Tyrosine Kinase Inhibitor Therapy
TKIs have revolutionized the management of GIST. The TKI imatinib mesylate is used as the first-line treatment for unresectable, metastatic, or recurrent GIST. Although complete responses are rare, a large majority of patients with metastatic or inoperable GIST have either a partial response or disease stabilization after starting imatinib. Median survival rates have gone from less than 2 years to more than 5 years since the advent of imatinib therapy.
Therapy with neoadjuvant imatinib to reduce the tumor volume may be used for patients with very large primary GIST that cannot be removed without the risk of unacceptable morbidity. Additional therapy with adjuvant imatinib is being studied to determine whether imatinib reduces recurrence, which is common after resection of primary GIST.
Because disease progression has been reported to follow the cessation of imatinib therapy, patients with unresectable or metastatic disease are often treated with a TKI indefinitely, as long as the disease does not progress and patient tolerance permits.[1,14] In a multicenter trial in which 58 patients with advanced GIST who had disease stability after at least 1 year of imatinib therapy were randomly assigned to continue (N = 26) or to discontinue (N = 32) imatinib (with reinstitution for progression), 8 and 26 patients progressed at a median of 18 and 6.1 months, respectively (P < .0001). However, 24 of the 26 patients in the latter group responded again to reinstitution of imatinib.[Level of evidence: 1iiDiii] There were no differences in overall survival (OS), development of imatinib resistance, or quality of life between the two groups.[Level of evidence: 1iiA and 1iiC]
Drug dose and schedule
A patient with unresectable or metastatic GIST may be treated with an initial dose of 400 mg imatinib mesylate daily, with therapeutic effects monitored by 18 fluoro-deoxyglucose-positron emission tomography (18 FDG-PET) or computed tomography; dose escalation to 400 mg twice a day may be appropriate for patients with progressive disease, although it is unlikely to help patients who progress within 2 months of initiation of imatinib therapy.[4,15,16,17] An initial dose of 800 mg daily may be appropriate for patients with GIST harboring KIT exon 9 mutations. Resistance to imatinib may be primary with rapid progression of disease despite an increase in the imatinib dose, although this appears to occur in fewer than 20% of patients; some investigators have speculated that GIST with primary resistance to imatinib have mutations in other oncogenic signaling pathways that do not involve KIT.[1,19,20]