Cancer Health Center

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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]

Chemotherapy

Before the advent of molecularly targeted therapy with TKI, efforts to treat GIST with conventional cytotoxic chemotherapy were essentially futile.[1] 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.[13]

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.[11] Additional therapy with adjuvant imatinib is being studied to determine whether imatinib reduces recurrence, which is common after resection of primary GIST.[4]

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.[14][Level of evidence: 1iiDiii] There were no differences in overall survival (OS), development of imatinib resistance, or quality of life between the two groups.[14][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.[18] 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]