Abstract
BackgroundPheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited.MethodsA multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4–6 weeks.ResultsBetween May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61–95%) and median PFS 13.4 (95% CI: 5.3–24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1–88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment.ConclusionAlthough the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.
Highlights
Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages
Pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGL) are uncommon neuroendocrine neoplasms arising from the adrenal medulla and sympathetic/parasympathetic paraganglia respectively
Radiological progression was defined by the presence of new lesions or a 20% increase in the sum of the longest diameter of target lesions, comparing two computedtomography (CT) scans performed within 13 months of each other
Summary
Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. In over 30% of cases of PCC/PGL, a predisposing germline mutation can be identified, the most common are inactivating mutations in subunits of the succinate dehydrogenenase (SDH) complex predominantly SDHB and SDHD.[2,3] Other hereditary susceptibility genes include RET and von Hippel-Lindau (VHL) as part of the syndromes of multiple endocrine neoplasia 2 (MEN2). VHL syndrome respectively; the tumour suppressor gene neurofibromatosis 1 (NF1),[4] MYC associated factor X (MAX) and transmembrane protein 127 (TMEM127) and a number of additional genes.[3] Recent molecular characterisation and mRNA expression profile clustering have identified germline VHL and SDH subunit mutations specific to a pseudohypoxia subgroup of PCC/PGL, or cluster 1 as previously published.[5] Both genes are important in the regulation of hypoxia inducible factor (HIF) and angiogenesis.[6,7]
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