Improved outcome with multimodal treatment and imatinib rechallenge in advanced GIST

Dear Editor: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the digestive tract. Surgery and imatinib are the recommended treatments for advanced highrisk GIST. However, even in most patients showing an initial response, imatinib resistance is developed within a few years. After progression, current therapeutic options include the switch to other tyrosine kinase inhibitors (TKI) or surgical debulking. We here report long-term survival in a metastatic GIST patient treated with reiterated multimodal therapeutic approaches and as a fourth-line treatment, imatinib rechallenge. Molecular analysis of the tumors provided a framework for interpretation of the pattern of response observed. A 52-year-old man was referred to surgical intervention for an abdominal mass in January 2003. Surgery revealed a major (15 cm) intestinal tumor, together with other smaller peritoneal nodules, which were also resected. At pathological evaluation, the lesions displayed a spindle cell morphology, were CD117 (KIT) positive, CD34 positive, desmin negative, focally positive for smooth muscle actin and S100, and negative for cytokeratins, consistent with a diagnosis of metastatic, high-risk GIST. Six months later, the patient relapsed and underwent a II surgery with complete resection (R0) of a mass of 12 cm at the right iliac fossa, pathologically confirmed as GIST. Adjuvant imatinib (400 mg/day) was administered for 24 months, without evidence of recurrence. Eight months after imatinib discontinuation, a CT scan revealed a mass of 6 cm at the right iliac fossa and multiple peritoneal nodules without clinical symptoms. Imatinib was therefore resumed at the same dose. Radiological assessment showed an initial response, but 14 months later, disease progression was observed. Patient then underwent curative III surgery (R0) for a major mass (8 cm) proximal to the rectum and multiple peritoneal and omental nodules of smaller size. After surgery, imatinib was continued at 400 mg/day until, 8 months later, disease recurrence was documented by CT scan with a larger pararectal mass and multiple small peritoneal nodules. Patient was again subjected to tumor debulking (IV surgery) with microscopic residual disease (R=1). Patient resumed imatinib at a higher dose (800 mg/day). Due to disease progression, after 3 months, he was switched to sunitinib (50 mg/day), reducing the dosage (37.5 mg/day) after the first cycle because of poor tolerance. Treatment was continued for 15 months until pelvic progression was detected. For his third line treatment, the patient was enrolled in a clinical trial evaluating nilotinib efficacy in patients with unresectable/metastatic GIST and refractory to imatinib and/ or sunitinib. Nilotinib was given at 800 mg/day for 2 months, until CT scan showed abdominal progression. Surgical Gianmaria Miolo and Elena Torrisi contributed equally to this work.