Neoadjuvant Therapy for Gastrointestinal Stromal Tumor (GIST): Racing Against Resistance

Abstract

The advent of imatinib mesylate (Gleevec; Novartis Pharmaceuticals, Basel Switzerland) has generated much interest and investigation in gastrointestinal stromal tumor (GIST), a rare and, until recently, poorly understood malignancy. The dramatic responses achieved in a solid tumor with a targeted agent have made GIST a paradigm for the use of new molecular agents. GIST is the most common mesenchymal tumor of the gastrointestinal tract and immunohistochemical reactivity for KIT (CD117) expression is a hallmark of GIST, and is found in nearly all cases. Mutations in KIT, or less commonly, platelet-derived growth factor alpha (PDGFRA) can be identified in over 90% of GISTs. These mutations cause constitutive activation of signaling through the associated tyrosine kinase receptors and are thought to be central to the oncogenesis of GIST. Imatinib is a small molecular inhibitor of KIT and PDGFRA. In the February 2007 issue of the Annals of Surgical Oncology, Haller et al. report their experience with a patient having a large gastric GIST that was markedly reduced in size by neoadjuvant imatinib treatment. This case report highlights several pertinent issues related to imatinib therapy, particularly related to its combined use with surgical resection. While complete response of GIST is rare, partial response occurs in 50% to perhaps as high as 67% of GIST patients treated with imatinib. Prolonged treatment, however, is associated with resistance, which can often be attributed to the development of secondary KIT mutations. In fact, half of patients will become resistant to imatinib by approximately 2 years on treatment. The benefits and limitations of both surgical resection and tyrosine kinase inhibitor therapy for the treatment of GIST make it attractive to explore the combination of these modalities. There are several settings in which this might be advantageous ranging from adjuvant treatment after complete surgical resection of primary localized tumors (up to half of patients might otherwise recur) to surgical resection of residual metastatic disease after initial treatment with a tyrosine kinase inhibitor. The authors specifically address the use of neoadjuvant imatinib treatment prior to surgical resection of a primary GIST. The rationale for neoadjuvant treatment of GIST is similar to that for many other tumors. Most GISTs will respond to imatinib. Resection of responsive tumors may be accomplished with less morbidity and sacrifice of adjacent organs. Some tumors that are deemed unresectable may become resectable. Manipulation of smaller, treated tumors may result in less intraoperative dislodgement of viable tumor cells. Early treatment of distant micrometastatic disease may improve oncologic outcome. Furthermore, progression, particularly distant progression, of patients on neoadjuvant treatment may indicate the futility of surgery in these patients. Several authors have reported their experience with neoadjuvant treatment of GIST prior to surgical Received September 24, 2006; accepted September 27, 2006; published online: January 30, 2007. Address correspondence and reprint requests to: Ronald P. DeMatteo, MD; E-mail: dematter@mskcc.org