Review

The case presented by Kale and colleagues¹ describes a 61-year-old woman with a locally advanced gastrointestinal stromal tumor (GIST) and highlights some of the critical issues regarding the management of this complex and rare disease. The patient was symptomatic, as are typically 69% of patients.² Imaging confirmed the presence of a 21-cm mass arising ostensibly from the stomach, and esophagogastroduodenoscopy confirmed the presence of a mass eroding into the gastric mucosa with extrinsic compression on the stomach.

The first issue raised in the case report is whether there is a need for a tissue diagnosis prior to definitive treatment. The differential diagnosis of the tumor shown in Figure 2 includes GIST, retroperitoneal sarcoma (RPS), gastric adenocarcinoma, and lymphoma, with the first two types of tumors as the most likely. Although a tissue diagnosis will help confirm the histology of the malignancy, it is not absolutely necessary in this case unless preoperative therapy is under consideration. For instance, if this were a RPS, preoperative radiation therapy could be entertained, whereas a diagnosis of GIST (as in the case presented by Kale and associates) would allow preoperative therapy with imatinib mesylate (Gleevec, Novartis). However, this tumor was symptomatic with early satiety and gastrointestinal bleeding, and thus surgery is recommended even in the absence of a preoperative diagnosis.

The second issue is the approach to obtaining a tissue diagnosis. In the case presented by Kale and coworkers, endoscopic biopsies were nondiagnostic, which is not surprising. Endoscopic ultrasound–guided fine-needle aspiration may provide adequate tissue to exclude other malignancies and, combined with immunohistochemistry and reverse-transcriptase polymerase chain reaction analysis for KIT mutations, would generally confirm the diagnosis of GIST.³

The patient underwent exploratory laparotomy but was found to be unresectable due to involvement of adjacent structures. In general, primary GISTs do not invade surrounding organs despite such an appearance on imaging.⁴ The tumor may abut other structures but can usually be separated from them. However, when vascular structures are involved, or the resection may potentially result in significant morbidity, a primary lesion may be considered locally advanced. Patients with locally advanced disease are treated with imatinib mesylate. These individuals should be closely followed, as the tumor may respond dramatically to imatinib and become resectable. The use of imatinib mesylate as a neoadjuvant agent remains investigational and was the subject of the Radiation Therapy Oncology Group 0312 trial. This trial enrolled individuals with potentially resectable primary GIST of at least 5 cm or recurrent GIST of at least 2 cm and treated them with 600 mg of imatinib mesylate daily for 8–10 weeks preoperatively and 24 months postoperatively. The results are pending.

The patient treated by Kale and colleagues did not undergo pretreatment positron emission tomography (PET) scan. The authors correctly report that PET scans provide highly sensitive results for both initial diagnosis and serial monitoring. However, there is no role for routine PET imaging, even if such scans were to become less costly and more widely available. In unequivocal cases of primary GIST or in routine surveillance, contrast-enhanced computed tomography (CT) usually suffices. In fact, at the Center for Sarcoma and Bone Oncology at the Dana-Farber/Brigham and Women's Cancer Center, PET scans (specifically, in the form of PET/CTs) are only obtained in patients with ambiguous findings on CT or magnetic resonance imaging or in patients with advanced GIST on protocol therapy on which PET is required. The routine use of PET is not recommended.⁵

Had this tumor proven to be resectable, this patient would still have been at risk for recurrent disease. According to Miettinen and Lasota,⁶ the tumor site of origin is a prognostic factor for recurrence, in addition to tumor size and mitotic count. Based upon their updated findings, the patient presented by Kale and associates, with a GIST of gastric origin and size of more than 10 cm, has a moderate-to-high risk of developing recurrent disease (depending on mitotic count, which was not reported). The American College of Surgeons Oncology Group Z9001 phase III randomized trial established that adjuvant imatinib mesylate decreased the risk of recurrent disease.⁷ Therefore, adjuvant imatinib mesylate following complete macroscopic resection would be indicated were this tumor resectable.

Another issue raised by the authors is the surgical management of advanced GIST following treatment with tyrosine kinase inhibitors (TKIs). Several institutions have reported long-term recurrence-free survival (RFS) and overall survival after surgical resection of metastatic GIST following preoperative imatinib mesylate (and in some cases, the second-line TKI sunitinib malate [Sutent, Pfizer]).^8–13 Although these studies have validated the role of surgery in certain cases of advanced GIST, there is still no evidence that RFS/progression-free survival or overall survival rates improve in patients undergoing surgery (with resumption of postoperative imatinib mesylate) compared to those patients who are simply maintained on imatinib mesylate without undergoing surgery.

Finally, there is the issue of treatment after the identification of imatinib mesylate resistance. The current standard of care is to initiate patients on sunitinib malate. Mutation analysis is not required in patients who develop imatinib mesylate resistance. The first step in management for a patient resistant to the standard dose of imatinib mesylate (400 mg daily) is dose escalation to 600 mg or 800 mg per day (usually dosed as 300 mg or 400 mg twice daily, respectively). If disease progression continues on higher-dose imatinib mesylate, or if this higher dosing is poorly tolerated, then sunitinib malate is started. Sunitinib dosing is generally either 50 mg daily (4 weeks of therapy followed by 2 weeks off-drug) or 37.5 mg daily administered continuously. There is no indication for routine mutation analysis at this time, though as testing becomes more readily available, it may become the standard of care.