Malignant pheochromocytomas and paragangliomas are rare endocrine malignancies, for which there are no FDA-approved therapies for patients with these tumors. Until recently, patients with malignant pheochromocytomas and paragangliomas were primarily treated with surgery and chemotherapy. Surgical resection of the primary tumor is, indeed, associated with a higher survival rate and improved quality of life. Although chemotherapy is more palliative than curative, and toxicity limits its longer-term use, chemotherapy may decrease tumor burden, stabilize the disease, and improve blood pressure. Approximately, 37% of patients respond to chemotherapy.
During this century, several molecular aspects that determine the origin and development of pheochromocytomas and paragangliomas have been recognized. These aspects correlate with several of the 10 hallmarks of cancer: replicative immortality, angiogenesis, genome instability and mutations, tumor promoting inflammation, invasion and metastases, cell death resistance, sustained proliferative signaling, deregulation of energy, evasion of growth suppressors, and avoidance of immune destruction.
Several tyrosine kinase inhibitors (axitinib, cabozantinib, pazopanib, and sunitinib), two radiopharmaceutical agents (ultratrace iobenguane I131, Lu177-dotate) and immune therapy (pembrolizumab) are under evaluation in prospective clinical trials. These trials are exploring how these novel interventions may impact the hallmarks of cancer. We will review the rationale and mechanisms of action of these medications; analyze the results of several phase 2 clinical trials (achievement of primary and secondary endpoints and safety); and describe how these results enhance the understanding of the pathogenesis of malignant pheochromocytomas and paragangliomas.