Abstract


Introduction:
Paragangliomas are rare vascular endocrine tumors that highly express vascular endothelium growth factor (VEGF). Anti-angiogenic agents may thus play a role in the treatment of these tumors. We herein report a dramatic clinical response to the oral VEGFR 1-3 and multi-kinase inhibitor lenvatinib.
Clinical Case: view more

Introduction:
Paragangliomas are rare vascular endocrine tumors that highly express vascular endothelium growth factor (VEGF). Anti-angiogenic agents may thus play a role in the treatment of these tumors. We herein report a dramatic clinical response to the oral VEGFR 1-3 and multi-kinase inhibitor lenvatinib.
Clinical Case:
A 49-year-old female with longstanding metastatic pelvic paraganglioma who presented during pregnancy with SDHB (p.V140F--c.418G>T) mutation was treated with multiple surgical resections. She also underwent systemic and localized therapeutic approaches including multiple chemotherapeutic regimens (etoposide and cisplatin; cyclophosphamide, doxorubicin, and cisplatin; cyclophosphamide, vincristine, and dacarbazine) as well as an array of local therapies at metastatic sites (radiation, cryoablation). Given octreotide avidity (no MIBG avidity) and progressing bony metastasis and pelvic fistulae after multiple pelvic surgeries, she was initiated on octreotide therapy and RANK-Ligand-directed bone therapy. She also benefited from pazopanib (VEGFR and multi-kinase inhibitor) therapy for about 2 years, attaining profound disease regression initially, but ultimately incurring disease progression on pazopanib therapy.
Upon disease progression, she developed hypertension. Laboratory values showed metanephrine level < 0.20 nmol/L (<0.50 nmol/L), normetanephrines 5.7 nmol/L (<0.90 nmol/L), norepinephrine 3542 pg/ml (200-1700 pg/ml), dopamine 3919 pg/ml (< 30 pg/ml). CT scans of chest, abdomen and pelvis showed new and increasing pulmonary nodules and progression of hilar, pelvic and peritoneal metastatic lymphadenopathy. After focal radiotherapy to a right hilar mass, alpha and beta blockade using phenoxybenzamine and atenolol as well as calcium channel blockers to control blood pressure, lenvatinib was started, 24 mg daily.
Within 48 hours of lenvatinib initiation, she incurred dramatic nodal clinical tumor regression associated with fever and she was evaluated. Work up revealed no infectious source for fever. Laboratory evaluation was unremarkable with normal blood counts, except for elevated uric acid at 7 mg/dl (2.7-6.1 mg/dl), deemed potentially consistent with tumor lysis syndrome.  She was treated briefly with allopurinol 300 mg per day.  Follow up imaging showed interval decreases in hilar and retroperitoneal adenopathy, with subsequent imaging indicating a confirmed RECIST response. Side effects prominently included fatigue.
Conclusion: We describe a promising clinical response to lenvatinib therapy in a patient with widely metastatic malignant paraganglionoma who had experienced disease progression through both prior cytotoxic and pazopanib therapy.  Like other VEGFR-targeted kinase inhibitors, lenvatinib may represent a promising drug for further development in treating refractory metastatic paraganglioma.

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