Elsevier

Advances in Surgery

Volume 48, Issue 1, September 2014, Pages 165-183
Advances in Surgery

Gastrointestinal Stromal Tumors: Who Should Get Imatinib and for How Long?

https://doi.org/10.1016/j.yasu.2014.05.014Get rights and content

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Key points

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    Imatinib is the first-line therapy for patients with unresectable, recurrent, or metastatic gastrointestinal stromal tumor (GIST), except those with PDGFRA D842V mutations, which do not respond to imatinib.

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    When there is imatinib resistance or intolerance in advanced disease, imatinib dose escalation, sunitinib, regorafenib, or clinical trials are indicated.

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    Cytoreductive surgery may be considered for imatinib-sensitive or imatinib-stable advanced disease, although clinical trials are lacking.

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Oncogenic kinase mutations and imatinib

It is now evident that 70% to 80% of GISTs harbor mutations in the KIT proto-oncogene and induce constitutive kinase activation, activate downstream signaling pathways that inhibit apoptosis, and stimulate cell proliferation. Mutations most commonly occur in the juxtamembrane domain in exon 11 that normally inhibits the kinase activation loop in the absence of ligand binding (Table 1). Deletions are the most common variant, with insertions and substitutions also seen (see Table 1).

Is imatinib effective in metastatic GIST?

Although a randomized controlled trial comparing imatinib with standard chemotherapy has never been performed, the efficacy of imatinib in metastatic GIST is clear.

Following initial efficacy in smaller phase I and II trials [12], [13], the United States–Finnish B2222 randomized phase II trial examined 2 different imatinib dosing regimens in a cohort of 147 metastatic GIST patients [14]. In this study, 81.6% of all treated patients demonstrated disease regression or stabilization, with the

Who is at greatest risk for recurrence following resection?

Current data demonstrate that tumor size, site, and mitotic index are the most important prognostic indicators [36], [37], [38]. Each has been shown on multivariate analysis to independently predict recurrence-free survival (RFS) after resection of primary, localized GIST [38]. Tumor rupture has also been shown to increase the risk of peritoneal recurrence [4]. Multiple stratification schemas have been developed, incorporating these risk factors to predict the risk of recurrence and hence

Summary

The application of imatinib for the treatment of GIST remains a remarkable illustration of the ability and promise of targeted molecular therapy. It is gradually becoming evident that the benefit of imatinib depends on the complex interplay between mutational variations that govern tumor sensitivity to the drug, and biological variables that drive clinical outcome. Evidence is mounting that only a select fraction of patients in the adjuvant setting may benefit from imatinib. Unfortunately, most

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    Funding: National Institutes of Health, United States. National Cancer Institute R01 CA102613.

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