Rare complications of multikinase inhibitor treatment

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Guía práctica para el manejo de efectos adversos por inhibidores multicinasas (sorafenib y vandetanib) en pacientes con cáncer de tiroides avanzado / Practice guidelines for the management of adverse effects due to multikinase inhibitors (sorafenib and vandetanib) in patients with advanced thyroid cancer

El advenimiento de la terapia con inhibidores multicinasas (IMK) representó un cambio radical en el tratamiento de pacientes con carcinoma avanzado de tiroides. Hasta la fecha, 2 fármacos se encuentran aprobados por la Asociación Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) en Argentina: sorafenib, para pacientes con carcinoma diferenciado de tiroides radiorresistente, y vandetanib, para aquellos con carcinoma medular de tiroides (enfermedad progresiva y/o sintomática). Los estudios de fase III han demostrado que estos fármacos aumentan significativamente la supervivencia libre de progresión en este grupo de pacientes. Si bien tienen una indicación precisa, su manejo requiere de un equipo multidisciplinario en contacto estrecho con un paciente involucrado en su tratamiento. Los efectos adversos de sorafenib y vandetanib son frecuentes, sin embargo, muchos de ellos disminuyen con el tiempo y la mayoría puede manejarse a menudo sin disminuir la dosis ni suspender el fármaco. El conocimiento del correcto manejo de los efectos adversos por parte del equipo tratante constituye una herramienta fundamental para poder educar al paciente y, consecuentemente, poder prevenirlos o minimizarlos, y de esta manera evitar complicaciones severas. El objetivo de esta publicación es brindar una guía para el diagnóstico y tratamiento de los efectos adversos de estos IMK y, por otro lado, presentar la iniciativa del Hospital de Clínicas de la Universidad de Buenos Aires en cuanto a la implementación de la misma.

The advent of multikinase inhibitors therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The ANMAT (the Argentinian regulatory health agency) has currently approved sorafenib for patients with radioiodine resistant differentiated thyroid carcinoma, and vandetanib for patients with medullary thyroid carcinoma (progressive and/or symptomatic disease). It has been demonstrated by phase III clinical trials that these drugs improve progression free survival in this group of patients. Although they have a precise indication, an interdisciplinary team in close contact with a committed patient, are required for their effective management. The adverse events of these drugs are common, but many of them may ameliorate over time, and most of them are manageable, even without the need for dose reduction or drug withdrawal. Knowledge of the correct management of the adverse events is a fundamental tool for the medical team and for the patient to prevent or minimise them, to avoid serious complications and to obtain better patient compliance. The primary objective of this article is to provide a guideline for the diagnosis and treatment of the adverse events produced by the multikinase inhibitors, and to present the initiative of the Hospital de Clinicas in order to implement these guidelines.

Uso de inhibidores de tirosina quinasa en carcinoma medular de tiroides. Experiencia Institucional / Use of tyrosine kinase inhibitors in medullary thyroid carcinoma. Institutional Experience

El cáncer medular de tiroides (CMT) correspondeal 5% de los tumores de la glándula tiroides. El único tratamiento curativo es la cirugía. En pacientes con compromiso locorregional o a distancia, la enfermedad puede evolucionar en forma indolente o bien con una rápida progresión de síntomas, requiriendo tratamiento sistémico. Si bien el CMT se caracteriza por tener escasa respuesta a la quimioterapia (QT), la evidencia actual en estudios aleatorizados demostró que los inhibidores de tirosina quinasa (ITQ) han demostrado beneficio en supervivencia libre de progresión (SLP). Se analizaron 6 pacientes con un seguimiento mediano de 29 meses. Todos presentaron más de dos sitios metastásicos. Dos requirieron tratamientos locorregionales (quimioembolización y RT). Los ITQ más utilizados fueron: vandetanib (3), sorafenib (2) y sunitinib (1). Un 50% inició tratamiento con dosis plenas y 3 requirieron reducción de dosis debido a toxicidad G3-G4. El intervalo libre de progresión (ILP) mediano, luego del inicio con ITQ, fue de 4.1 meses (AU)

Medullary thyroid cancer (CMT) accounts for 5% of thyroid tumors. The only curative treatment is surgery. In patients with locally or distal involvement, the disease may evolve indolently or with rapid progression of symptoms, requiring systemic treatment. Although CMT is characterized by a poor response to chemotherapy, current evidence in randomized trials has shown that tyrosine kinase inhibitors (ITKs) have demonstrated benefit in progressionfree survival. Six patients with a median follow-up of 29 months were analyzed. All had more than two metastatic sites. Two patients required locoregional treatments (chemoembolization and radio therapy). The most commonly used ITKs were: vandetanib (3), sorafenib (2) and sunitinib (1). The 50% initiated treatment with full dose and 3 required reduction of the dose due to G3- G4 toxicity. The median progression-free interval after initiation with ITK was 4.1 months (AU)

Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome

Medullary thyroid carcinoma (MTC) may rarely present with paraneoplastic syndromes. Among the most frequent ones are the appearance of diarrhea and ectopic Cushing syndrome (ECS). The ECS in the context of MTC is usually present in patients with distant metastatic disease. The use of drugs such as ketoconazole, metyrapone, somatostatin analogs and etomidate have been ineffective alternatives to control hypercortisolism in these patients. Bilateral adrenalectomy is often required to manage this situation. Recently, the use of tyrosine kinase inhibitors has been shown to be a useful tool to achieve eucortisolism in patients with metastatic MTC and ECS. We present a patient with sporadic advanced persistent and progressive MTC with lymph node and liver metastases, which after 16 years of follow-up developed an ECS. After one month of 300 mg/day vandetanib treatment, a biochemical and clinical response of the ECS was achieved but it did not result in significant reduction of tumor burden. However the patient reached criteria for stable disease according to response evaluation criteria in solid tumors (RECIST 1.1) after 8 months of follow-up.

Vortex Keratopathy in a Patient Receiving Vandetanib for Non-Small Cell Lung Cancer

We report a case of vortex keratopathy in a patient treated with vandetanib for non-small cell lung cancer (NSCLC). A 44-year-old female who underwent two cycles of chemotherapy for NSCLC complained of visual blurring in both eyes after the initiation of vandetanib, an anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor receptor 2 protein tyrosine kinase inhibitor. On ophthalmic examination, visual acuities were 20 / 20 OU and, with the exception of diffuse vortex keratopathy in both eyes, other findings were unremarkable. Vandetanib is believed to have caused vortex keratopathy in this patient. Anti-EGFR properties affecting normal corneal epithelial cell migration and wound healing or drug associated metabolite deposition, which is the case in numerous drug-associated vortex keratopathies, may be possible underlying mechanisms in the formation of this corneal complication.

Photosensitivity Reactions to Vandetanib: Redevelopment after Sequential Treatment with Docetaxel

Vandetanib (ZD6474, Zactima(TM)) is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis, including vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. The most frequently reported adverse events attributed to vandetanib include diarrhea, elevated aminotransferase, asymptomatic corrected QC interval prolongation, and hypertension. In a few randomized, double-blinded studies, cutaneous adverse events including these general symptoms have been reported, but there are only a few reports on the photosensitivity reaction to vandetanib domestically as conducted by dermatologists. In this report, we describe two cases of photosensitivity reactions induced by vandetanib. After improvement with steroid and antihistamine, the photosensitivity reaction was redeveloped by sequential treatment with docetaxel.

Stevens-Johnson Syndrome Induced by Vandetanib

Vandetanib is a once-daily oral anticancer drug that selectively inhibits key signaling pathways in cancer by targeting vascular endothelial growth factor receptors, epidermal growth factor receptors tyrosine kinase, and rearranged during transfection-dependent tumor cell proliferation and survival. The most frequently reported adverse events attributed to vandetanib include diarrhea, elevated aminotransferase, asymptomatic corrected QT interval prolongation, and hypertension. Though a number of randomized, doubleblind studies, including cutaneous adverse events attributed to vandetanib, have been reported along with these general symptoms, no case of Stevens-Johnson syndrome (SJS) has been reported. This paper demonstrates a case of SJS induced by vandetanib.