Association for Academic SurgeryRole of operative therapy in treatment of metastatic gastrointestinal stromal tumors☆
Introduction
The role of operative resection in patients with metastatic gastrointestinal stromal tumors (GISTs) remains investigational [1], [2], [3]. Historically, tumor metastases or recurrence have conferred a high likelihood for tumor progression and poor prognosis even after complete resection [4], [5]. Since the development of tyrosine kinase inhibitors (TKIs) in the early 2000s, the focus of treatment of patients with advanced disease has shifted to medical therapy.
GISTs arise along the gastrointestinal tract as a result of activating mutations in one of the protein tyrosine kinase receptors: KIT (CD117) or platelet-derived growth factor receptor-α (PDGFRA). Imatinib mesylate and sunitinib malate, approved by the Food and Drug Administration in February 2002 and January 2006, respectively, actively block the KIT and PDGFRA receptors and inhibit tumor growth [2], [6]. Subsequent level 1 data have supported the use of imatinib to improve recurrence-free survival after resection of primary GIST and to achieve significantly longer progression-free survival (PFS) among patients with advanced unresectable or metastatic GIST [7], [8]. However, not all GISTs respond to TKI therapy, and approximately 20% of patients do not tolerate specific TKI agents [2], [9], [10]. In addition, different exon mutations, wild-type status, and the development of tumor mutations during therapy can result in treatment resistance to TKIs [2], [11], [12].
Resection remains an option for patients with metastatic GIST. Previous, single-institution reports have demonstrated a benefit from resection for patients with stable disease or limited progression during TKI therapy and suggested a lack of benefit for patients with disease progression during imatinib therapy [6], [13]. Our aim was to examine our experience with operative therapy in patients with metastatic GIST, focusing on the effect of the preresection tumor response to TKI on PFS and overall survival (OS) in patients treated with operative metastasectomy.
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Patients and measures
The Mayo Clinic institutional review board reviewed and approved the present study protocol. All consecutive patients treated at the Mayo Clinic (Rochester, MN) for metastatic and/or recurrent GIST from January 2002 to June 2011 were included in this retrospective study. All patients had immunohistochemically confirmed GIST according to the histologic examination and CD117, CD34, or PDGFRA positivity.
The clinically relevant demographic and clinical covariates included age, sex, primary tumor
Demographic and clinical covariates of patients with metastatic or recurrent GIST
A total of 438 patients were treated for GIST during the study period. Of these patients, 87 (20%), with a median age of 61 y (IQR 50–71; 55% male) had metastatic GIST (84% metastatic, 3% recurrent only, and 13% metastatic and recurrent). One half of these patients (n = 43) had metastatic disease at the time of original diagnosis. The median interval to the development of metastases in the other 44 patients was 29 mo (IQR 13–61). Of the 87 patients, 54 (62%) underwent operative exploration.
Discussion
Currently, the standard treatment of metastatic GIST is medical therapy with TKI [1], [2], [3]. Published evidence from phase II and III multicenter trials supports the use of TKI as an adjuvant treatment in patients with a moderate to high risk of recurrence [2], [7], [18]. In addition, the recently published phase II Radiation Therapy Oncology Group 0132 trial, which, in part, assessed tumor progression among patients with metastatic and/or recurrent GIST demonstrated increased tumor
Conclusions
Operative metastasectomy can be performed safely in patients with metastatic GIST. The preoperative response to TKI therapy and margin-negative resection are strongly associated with improved PFS and OS. A better understanding of molecular genetics and targeted TKI therapy, along with ongoing drug development, should lead to an improved selection process for patients who will benefit from operative metastasectomy.
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Presented at the Association for Academic Surgeons Program of the 7th Annual Academic Surgical Congress, Las Vegas, Nevada, February 14–16, 2012.