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.

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…Cabozantinib also inhibits the c‐Met receptor pathways and may therefore delay the development of resistance, as this pathway is upregulated by VEGFR inhibition. Currently there is a phase II trial ongoing, with promising preliminary results …”

“…Currently there is a phase II trial ongoing, with promising preliminary results. 144 Another phase II trial is aiming to evaluate the response rate of lenvatinib in a group of 25 patients with metastatic PGL/PCC. Lenvatinib, like pazopanib, also inhibits FGFR.…”

‘Peptide receptor radionuclide therapy in the management of advanced pheochromocytoma and paraganglioma: A systematic review and meta‐analysis’

“…Malignant disease is defined by the presence of metastases in nonchromaffin tissue . Patients with such metastatic disease have poorer prognosis and shorter overall survival than those with nonmetastatic disease . Treatment options for metastatic PPGLs and inoperable disease are currently limited to radiolabelled meta‐iodo‐benzyl‐guanidine (MIBG) and systemic chemotherapy .…”

“…Patients with such metastatic disease have poorer prognosis and shorter overall survival than those with nonmetastatic disease . Treatment options for metastatic PPGLs and inoperable disease are currently limited to radiolabelled meta‐iodo‐benzyl‐guanidine (MIBG) and systemic chemotherapy . While these modalities have shown favourable albeit modest response with respect to tumour volume, data on survival benefit are scarce .…”

“…Treatment options for metastatic PPGLs and inoperable disease are currently limited to radiolabelled meta‐iodo‐benzyl‐guanidine (MIBG) and systemic chemotherapy . While these modalities have shown favourable albeit modest response with respect to tumour volume, data on survival benefit are scarce . Further, chemotherapy and I‐131 MIBG (I‐ 131 MIBG) are also associated with significant toxicity .…”