Approach to the patient with metastatic pheochromocytoma and paraganglioma: advances in systemic therapy

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of the adrenal and extra-adrenal chromaffin cells. Although most PPGLs remain localized, approximately 25% develop metastatic disease (MPPGL), leading to substantial morbidity due to tumor burden and catecholamine excess. These tumors have a heterogeneous biologic activity, with some having an aggressive course requiring intensive treatment, and others behaving indolently, not requiring treatment over many years. Because there are no sufficiently accurate predictors of future behavior, all PPGLs are considered to have the potential for metastatic disease. Over the past decade, the treatment landscape for MPPGL has evolved dramatically. In addition to cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine, several targeted radiopharmaceuticals have shown activity against MPPGL. Furthermore, multi-target tyrosine kinase inhibitors, including sunitinib and cabozantinib, have demonstrated substantial disease control in prospective clinical trials. Most notably, belzutifan, a hypoxia-inducible factor-2α inhibitor, recently became the first oral therapy approved by the US Food and Drug Administration for MPPGL, demonstrating durable responses, improvement in hypertension, and preservation of quality of life. In this review, we highlight an illustrative case of MPPGL and provide a contemporary framework of the treatment landscape. We also present an algorithm that integrates clinical phenotype and tumor genotype to advise which systemic therapies may benefit individual patients with MPPGL. As therapeutic options continue to expand, we emphasize the role of multidisciplinary management as essential in the treatment of these rare and biologically complex malignancies.