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.

Medullary thyroid carcinoma - Adverse events during systemic treatment: risk-benefit ratio

ABSTRACT Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid and associated with mutations in the proto-oncogene REarranged during Transfection (RET). The prognosis of MTC depends on clinical stage, with a 95.6% 10-year survival rate among patients with localized disease and 40% among patients with advanced disease. Standard chemotherapy and radiotherapy have no significant impact on the overall survival of these patients and two tyrosine kinase receptor inhibitors (TKIs), vandetanib and cabozantinib, have been recently approved for the systemic treatment of locally advanced or metastatic MTC. However, since patients with MTC and residual or recurrent disease may have an indolent course with no need for systemic treatment, and since these drugs are highly toxic, it is extremely important to select the patients who will receive these drugs in a correct manner. It is also essential to carefully monitor patients using TKI regarding possible adverse effects, which should be properly managed when occurring.

Progressive Multiple Cystic Changes in Both Lungs in a Patient Treated with Gefitinib for Lung Adenocarcinoma with Multiple Lung Metastases

Gefitinib is regarded as a relatively safe agent for the treatment of an advanced non-small cell lung cancer (NSCLC). Pulmonary toxicity such as interstitial lung disease associated with gefitinib is uncommon with an estimated all time incidence around 1% worldwide. Moreover, a case of gefitinib associated with pulmonary cystic changes has not been reported yet. In this report we present a case of progressive multiple air cystic changes in both lungs in a patient with NSCLC and intrapulmonary metastases who underwent a gefitinib therapy.

Kinase inhibitors for advanced medullary thyroid carcinoma

The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.

Oral Muscle Relaxant May Induce Immediate Allergic Reactions

Eperisone and afloqualone act by relaxing both skeletal and vascular smooth muscles to improve circulation and suppress pain reflex. These drugs are typically prescribed with non-steroidal anti-inflammatory drugs (NSAIDs) as painkillers. However, there have been no reports on serious adverse reactions to oral muscle relaxants; and this is the first report to describe three allergic reactions caused by eperisone and afloqualone. All three patients had histories of allergic reactions after oral intake of multiple painkillers, including oral muscle relaxants and NSAIDs, for chronic muscle pain. An open-label oral challenge test was performed with each drug to confirm which drugs caused the systemic reactions. All patients experienced the same reactions within one hour after oral intake of eperisone or afloqualone. The severity of these reactions ranged from laryngeal edema to hypotension. To confirm that the systemic reaction was caused by eperisone or afloqualone, skin prick testing and intradermal skin tests were performed with eperisone or afloqualone extract in vivo, and basophil activity tests were performed after stimulation with these drugs in vitro. In one patient with laryngeal edema, the intradermal test with afloqualone extract had a positive result, and CD63 expression levels on basophils increased in a dose-dependent manner by stimulation with afloqualone. We report three allergic reactions caused by oral muscle relaxants that might be mediated by non-immunoglobulin E-mediated responses. Since oral muscle relaxants such as eperisone and afloqualone are commonly prescribed for chronic muscle pain and can induce severe allergic reactions, we should prescribe them carefully.

Reacções cutâneas adversas aos inibidores do receptor do factor de crescimento epidérmico: estudo de 14 doentes / Adverse cutaneous reactions to epidermal growth factor receptor inhibitors: a study of 14 patients

FUNDAMENTOS: O cetuximab e o erlotinib, inibidores do receptor do factor de crescimento epidérmico, provocam frequentemente reacções cutâneas adversas peculiares. OBJETIVOS: Caracterizar do ponto de vista clínico-evolutivo as reacções cutâneas adversas e avaliar a sua abordagem terapêutica. METODOLOGIA: Entre março/2005 e setembro/2009 foram seguidos 14 doentes com idade média de 59,6 anos, em tratamento com cetuximab (7) ou erlotinib (7), por neoplasia pulmonar (10) ou colorrectal (4). Retrospectivamente foi avaliado o padrão clínico evolutivo de reacção cutânea, o intervalo entre a introdução do fármaco e o início dos sintomas e a resposta ao tratamento. RESULTADOS: Doze doentes apresentaram erupção papulopustulosa predominantemente na face, decote e dorso, em média 13,5 dias após o início do fármaco. Efectuaram tratamento oral com minociclina ou doxiciclina e tópico com metronidazol, peróxido de benzoílo e/ou corticoide. Ocorreu melhoria das lesões em todos os doentes. Cinco doentes, em média oito semanas após o início da terapia, apresentaram granulomas piogénicos periungueais, em quatro casos associados a paroníquia, melhorados com tratamento tópico (antibióticos, corticoides e antissépticos). Observou-se xerose em alguns doentes e, de forma isolada, outros efeitos adversos, como telangiectasias e angiomas, alterações dos cabelos e cílios e nevos melanocíticos eruptivos. Na maioria dos doentes, a terapêutica com o inibidor do receptor do factor de crescimento epidérmico foi mantida. CONCLUSÃO: Com o crescente uso destas terapêuticas-alvo, torna-se obrigatório reconhecer e tratar os seus efeitos cutâneos adversos, assegurando uma intervenção atempada de forma a permitir a manutenção desta terapêutica.

BACKGROUND: Cetuximab and erlotinib, epidermal growth factor receptor inhibitors, often cause peculiar adverse cutaneous reactions. OBJECTIVES: Our aim was to evaluate adverse cutaneous reactions and their management in patients undergoing treatment with cetuximab and erlotinib. PATIENTS AND METHODS: Between March/2005 and September/2009, we observed 14 patients with a mean age of 59.6 years undergoing treatment with cetuximab (7) or erlotinib (7), due to lung(10) or colorectal cancer (4). We evaluated the interval between introduction of the drug and onset of symptoms, treatment response, and the clinical pattern of evolution of the cutaneous reaction retrospectively. RESULTS: Twelve patients presented papular-pustular eruption typically affecting the face, chest and back, which appeared in average 13.5 days after starting the drug treatment. The patients underwent oral treatment with minocycline or doxycycline and topical treatment with metronidazole, benzoyl peroxide and/or corticosteroids. All patients showed improvement of the lesions. Five patients presented periungual pyogenic granulomas, which were associated with paronychia in 4 cases, after an average of 8 weeks of treatment. There was improvement of the lesions with topical treatment (antibiotics, corticosteroids and antiseptics). Xerosis was observed in some patients. Other less frequent adverse side effects such as telangiectasia and angiomas, hair and eyelash alterations, and eruptive melanocytic nevi were also described. Treatment with epidermal growth factor receptor inhibitor was maintained in most patients. CONCLUSION: The increasing use of these targeted therapies requires knowledge of their adverse cutaneous side effects to ensure timely intervention in order to allow the continuation of the therapy.

Bowel Perforation after Erlotinib Treatment in a Patient with Non-Small Cell Lung Cancer

Erlotinib is accepted as a standard second-line chemotherapeutic agent in patients with non-small cell lung cancer who are refractory or resistant to first-line platinum-based chemotherapy. There has been no previous report of bowel perforation with or without gastrointestinal metastases related to erlotinib in patients with non-small cell lung cancer. The exact mechanism of bowel perforation in patients who received erlotinib remains unclear. In this report, we report the first case of enterocutaneous fistula in a female patient with metastatic non-small cell lung cancer 9 months, following medication with erlotinib as second-line chemotherapy.

Reações cutâneas secundárias ao uso dos inibidores do receptor de fator de crescimento epidérmico: relato de dois casos / Cutaneous reactions due to the use of epidermal growth factor receptor inhibitors: two case reports

O aumento da expressão de receptores do fator de crescimento epidérmico (EGFR) está envolvido no estímulo ao crescimento tumoral. Seus inibidores demonstraram eficácia no tratamento de neoplasias de cabeça e pescoço, cólon e pulmão.A inibição do EGFR pode determinar reações cutâneas em mais de 50 por cento dos pacientes. Em geral, são reversíveis, mas, quando graves, limitam o uso da droga. Lesões papulopustulosas em face e tronco são as mais comuns, além de xerose, alterações ungueais e dos pelos. A intensidade da toxicidade cutânea tem relação direta com a resposta antitumoral. Uma abordagem dermatológica adequada é essencial para dar continuidade à terapia contra o câncer de forma satisfatória.

An increase in the expression of epidermal growth factor receptors (EGFR) is involved in the stimulation of tumor development. EGFR inhibitors have shown efficacy in the treatment of neoplasms of the head, neck, colon and lung. EGFR when inhibited can cause cutaneous reactions in more than 50 percent of the patients. They are usually reversible, but when severe, limit the use of the drug. Papulopustulars lesions in the face and upper torso are the most common, as well as xerosis, hair and nail changes. There is a direct relationship between the degree of cutaneous toxicity and the antitumoral response. An adequate dermatologic approach is necessary for an effective therapy against cancer.

Alfuzosin-induced Acute Liver Injury / 대한간학회지

We describe a 56-year-old man who developed an acute liver injury after taking alfuzosin for 1 month to control his newly diagnosed benign prostatic hypertrophy (BPH). There was no history of alcohol consumption or the taking herbal or traditional remedies. Viral causes, autoimmune hepatitis, and biliary tree obstruction were excluded. Other rare causes of hepatitis such as hemochromatosis, primary biliary cirrhosis and Wilson's disease were also absent in this patient. His liver test results began to improve after discontinuing the alfuzosin. Two weeks later, alfuzosin was administered again because the patient complained of dysuria. After 10 days of alfuzosin reuse, his liver test results worsened. Five months later after the complete discontinuation of the drug, his liver test results had returned to normal. This clinical sequence suggests that alfuzosin caused his acute liver injury.

Gefitinib (Iressa®) in metastatic patients with non-small cell lung cancer: preliminary experience in a Brazilian center

CONTEXTO: Pacientes com carcinoma de pulmão não-pequenas células metastático são considerados incuráveis mas podem se beneficiar de quimioterapia sistêmica paliativa. Recentemente, com o advento de inibidores do receptor do fator de crescimento epitelial (EGFR), uma alternativa eficiente e menos tóxica surgiu para o tratamento destes pacientes. OBJETIVO: Testar em nosso meio a atividade e toxicidade do gefitinib. TIPO DE ESTUDO: Prospectivo, não aleatorizado e não controlado. LOCAL: Clínica de Oncologia e Hematologia (CLIOH), São Paulo, Brasil. PACIENTES E MÉTODOS: De junho de 2002 a abril de 2003, tratamos cinco pacientes com carcinoma de pulmão não-pequenas células metastático e previamente expostos a quimioterapia sistêmica (mediana do número de esquemas quimioterápicos prévios = 2) com gefitinib na dose de 250 mg ao dia, oralmente, no contexto de um protocolo de disponibilização da droga patrocinado pela AstraZeneca. A idade média dos pacientes foi de 65 anos, dois eram de sexo masculino e três tinham um estado funcional de 1, um de 2 e um de 3 na escala do ECOG (Eastern Cooperative Oncology Group). RESULTADOS: Observamos erupção cutânea em dois, diarréia em três e artralgias em dois pacientes. Notamos uma resposta parcial e um paciente teve estabilização de sua doença com durações de 11+ e 4+ meses, respectivamente, ambas acompanhadas de significativa queda em seus marcadores tumorais. Três pacientes progrediram durante o tratamento. DISCUSSAO: Novas opções de agentes quimioterápicos com perfis de toxicidade mais favoráveis são urgentemente necessárias para o tratamento de pacientes com câncer de pulmão não-pequenas células, que normalmente têm baixa expectativa de vida. Na nossa pequena série de cinco pacientes, observamos estabilização da doença em dois e reações de pele e gastrintestinais, freqüentemente descritas na literatura, em todos. Dois tiveram artralgia, não reportada até o momento. CONCLUSÕES: Concluímos que o gefitinib constitui importante adição ao armamentário terapêutico para tratamento de casos avançados de carcinoma de pulmão não-pequenas células.