Treatment for Patients With Malignant Pheochromocytomas and Paragangliomas: A Perspective From the Hallmarks of Cancer

Abstract

Malignant pheochromocytomas and paragangliomas affect a very small percentage of the general population. A substantial number of these patients have a hereditary predisposition for the disease and consequently, bear the risk of developing these tumors throughout their entire lives. It is, however, unclear why some patients with no hereditary predisposition develop these tumors, which frequently share a similar molecular phenotype with their hereditary counterparts. Both hereditary and sporadic tumors usually appear at an early age, and affected people often die before reaching their expected lifespans. Unfortunately, there is currently no systemic therapy approved for patients with this orphan disease. Therefore, pheochromocytomas and paragangliomas are very challenging malignancies. The recognition of genetic and molecular abnormalities responsible for the development of these tumors as well as the identification of effective therapies for other malignancies that share a similar pathogenesis is leading to the development of exciting clinical trials. Tyrosine kinase inhibitors, radiopharmaceutical agents, and immunotherapy are currently under evaluation in prospective clinical trials. A phase 2 clinical trial of the highly specific metaiodobenzylguanidine, iobenguane ¹³¹I, has provided impressive results; this radiopharmaceutical agent may become the first approved systemic therapy for patients with malignant pheochromocytoma and paraganglioma by the United States Food and Drug Administration. Nevertheless, systemic therapies are still not able to cure the disease. This review will discuss the development of systemic therapeutic approaches using the hallmarks of cancer as a framework. This approach will help the reader to understand where research efforts currently stand and what the future for this difficult field may be.

Keywords: immunotherapy; paraganglioma; pheochromocytoma; radionuclides; tyrosine kinase inhibitors.

Figure 1

The 10 hallmarks of cancer and metastatic pheochromocytomas and paragangliomas (MPPGs). This figure describes the 10 hallmarks of cancer and several mechanisms identified to date in patients with MPPG that contribute to their tumor development.

Figure 2

Potential therapies for patients with metastatic pheochromocytomas and paraganglioma (MPPG). This figure describes potential therapies for patients with MPPG. Some of these therapies are currently evaluated in clinical trials: ¹axitinib, cabozantinib, lenvatinib, pazopanib, and sunitinib; ²iobenguane ¹³¹I, ¹⁷⁷Lu-DOTATATE; ³PT2977; ⁴axitinib, cabozantinib, lenvatinib, pazopanib, and sunitinib; ⁵cabozantinib; and ⁶pembrolizumab.