Abstract and Introduction
Abstract
Context: Metastatic pheochromocytomas and paragangliomas (mPPGL) are rare vascular neuroendocrine tumors that highly express vascular growth factors. Systemic treatment options in cases of unresectable multisite disease are limited. Multikinase inhibitors that inhibit angiogenesis, such as lenvatinib, have proven effective in several other malignancies, and may be a viable option for mPPGL.
Objective: We aimed to evaluate the efficacy of lenvatinib as salvage therapy in mPPGLs.
Methods: This was a retrospective analysis of mPPGL patients ≥ 18 years of age who received lenvatinib from 2015 to 2020 at a tertiary referral center. Patients were started on lenvatinib 20 mg daily and dose was adjusted according to tolerance or disease progression.
Results: Eleven patients were included. Median treatment duration was 14.7 months (95% CI, 2.3-NE). Treatment was discontinued due to disease progression, adverse events, or death. Overall survival at 12 months was 80.8% (95% CI, 42.3–94.9%) but its median was not reached. Median progression-free survival was 14.7 months (95% CI, 1.7-NE). Among the 8 patients with measurable disease, overall response rate was 63%, as 5/8 experienced a partial response and 3/8 had stable disease. Worsening hypertension and anemia were the most common adverse events.
Conclusion: Lenvatinib may be a viable treatment option for mPPGL, although at the potential risk of worsening hypertension. Larger, multicenter studies are needed to better characterize treatment efficacy.
Introduction
Pheochromocytomas and paragangliomas (PPGL) are chromaffin cell tumors that arise from the adrenal medulla and from parasympathetic and sympathetic ganglia, respectively.[1] Because both tumors arise from chromaffin cells, they share many common characteristics and treatment strategies. Although these tumors are usually nonmetastatic, 15% to 17% are metastatic.[2] Patients harboring succinate dehydrogenase (SDH) subunit B mutation are more likely to develop metastatic disease.[3,4] In general, the 5-year mortality rate for metastatic PPGL (mPPGL) is 37% (95% CI, 24%-51%).[5]
First-line treatment is surgical resection of the primary lesion(s) and/or isolated metastatic lesion(s). Systemic management for multisite disease burden includes metaiodobenzylguanidine labeled with iodine 131 (131I-MIBG), DOTATATE labeled with lutetium 177 (177Lu-DOTATATE), kinase inhibitors, or chemotherapy for multisite disease burden,[6] with MIBG being the only approved systemic option.[7] Cytotoxic chemotherapy, traditionally cyclophosphamide, vincristine, and dacarbazine (CVD), has long been utilized for mPPGL, where partial or complete response rates varied from 44% to 100%.[8–10] However, this wide disparity can be explained by differences in patient population and protocols/duration of treatment employed.
In general, mPPGL are very vascular tumors due to high growth factor expression promoting angiogenesis. The most common of these angiogenic growth factors is vascular endothelium growth factor (VEGF);[11] however other angiogenic factors also exist. Certain hereditary conditions, especially those with the SDHB mutations or other SDH mutations involving subunits A, C, D, and co-factor SDHAF2 (SDHx) may further promote tumor vascularity.[12] These mutations inactivate the SDH enzyme, leading to an accumulation of succinate and consequently inducing a pseudohypoxic state; this, in turn, increases the expression of VEGF and other angiogenic factors.[13–17] Other hereditary conditions linked to PPGL, especially von Hippel-Lindau (VHL) syndrome, have a similar molecular background.[18,19]
Multitargeted kinase inhibitors (MKI), specifically those inhibiting angiogenesis, have appropriately been investigated for therapy in mPPGL. Sunitinib and pazopanib, for example, have been studied for this indication with some success.[20–22] Lenvatinib is a broad coverage MKI that is currently approved and highly effective in the treatment of advanced thyroid, renal, hepatic, and endometrial carcinoma. It has already been trialed in a single patient with SDHB(+) mPPGL and was noted to have significant reduction in tumor burden.[23] We hypothesized that lenvatinib may also be effective as a therapeutic option in mPPGL. Herein we describe a prospective phase 2 study and a retrospective mPPGL case cohort treated with lenvatinib.
J Endo Soc. 2022;6(5) © 2022 Endocrine Society
