Rationale and Evidence for Sunitinib in the Treatment of Malignant Paraganglioma/Pheochromocytoma

Context: Paragangliomas are tumors that develop from extraadrenal chromaffin cells. Approximately 20% of paragangliomas are malignant, and surgical resection is considered the primary treatment when possible. The optimal systemic treatment for advanced disease is undefined, due in part to lack of effective agents. Here we report our experience suggesting that sunitinib is an effective agent in this malignancy. Setting and Patients: Three patients with metastatic paraganglioma were treated with sunitinib at the Princess Margaret Hospital. Limited analyses of tumor tissue and germline DNA were available. Intervention: Sunitinib at a standard dose (50 mg daily, 4 wk on, 2 wk off) was titrated to patient tolerance. Results: One patient has achieved a near complete response, and two patients demonstrated partial responses. Two patients demonstrated germline defects suggesting a pseudo-hypoxic drive to the tumor whereas the third demonstrated immunohistochemical evidence of this phenomenon. Conclusions: Sunitinib appears to be an active agent in this malignancy based on this limited cohort, with an understandable mechanism of action similar to that described in other hypoxia-driven tumors. A single arm phase 2 trial is underway. (J Clin Endocrinol Metab 94: 5-9, 2009)