Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma

Frank‐Raue, Karin; Fabel, M.; Delorme, Stefan; Haberkorn, Uwe; Raue, Friedhelm

doi:10.1530/eje-06-0695

Cited by 93 publications

(34 citation statements)

References 19 publications

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“…No objective responses were observed, four patients had SD over 24 months (de Groot et al 2007). In another open-label clinical trial of nine patients with sporadic or hereditary MTC with unresectable, progressive metastases, SD was observed in five patients lasting up to 6 months; and in one patient for up to 12 months; median PFS was 6 months (Frank-Raue et al 2007). Overall, therapeutic efficacy of imatinib appears low in MTC patients.…”

Section: Imatinibmentioning

confidence: 93%

New drugs for medullary thyroid cancer: new promises?

Spitzweg¹,

Morris²,

Bible³

2016

Endocrine-Related Cancer

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Medullary thyroid cancer (MTC) is a rare tumor arising from the calcitonin-producing parafollicular C cells of the thyroid gland, occurring either sporadically or alternatively in a hereditary form based on germline RET mutations in approximately one-third of cases. Historically, patients with advanced, metastasized MTC have had a poor prognosis, partly due to limited response to conventional chemotherapy and radiation therapy. In the past decade, however, considerable progress has been made in identifying key genetic alterations and dysregulated signaling pathways paving the way for the evaluation of a series of multitargeted kinase inhibitors that have started to meaningfully impact clinical practice. Two drugs, vandetanib and cabozantinib, are now approved in the US and EU for use in advanced, progressive MTC, with additional targeted agents also showing promise or awaiting results from clinical trials. However, the potential for toxicities with significant reduction in quality of life and lack of curative outcomes has to be carefully weighed against potential for benefit. Despite significant PFS prolongation observed in randomized clinical trials, most patients even with metastatic disease enjoy indolent courses with slow progression observed over years, wherein watchful waiting is still the preferred strategy. As advanced, progressive MTC is a rare and complex disease, a multidisciplinary approach centered in specialized centers providing interdisciplinary expertise in the individualization of available therapeutic options is preferred. In this review, we summarize current concepts of the molecular pathogenesis of advanced MTC and discuss results from clinical trials of targeted agents and also cytotoxic chemotherapy in the context of clinical implications and future perspectives.

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Section: Imatinibmentioning

confidence: 93%

New drugs for medullary thyroid cancer: new promises?

Spitzweg¹,

Morris²,

Bible³

2016

Endocrine-Related Cancer

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“…Table 5 summarizes the main available drugs, as well as their corresponding targets and outcomes (222,(228)(229)(230)(231)(232)(233)(234)(235)(236)(237)(238)(239)(240)(241)(242) (B/B/B/C/B/C/B/C/C/B/C/B/C/C/B/C).…”

Section: What New Drugs Are Available For the Management Of Individuamentioning

confidence: 99%

Diagnóstico, tratamento e seguimento do carcinoma medular de tireoide: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia

Maia

Siqueira

Kulcsar

et al. 2014

Arq Bras Endocrinol Metab

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Introduction: Medullary thyroid carcinoma (MTC) originates in the thyroid parafollicular cells and represents 3-4% of the malignant neoplasms that affect this gland. Approximately 25% of these cases are hereditary due to activating mutations in the REarranged during Transfection (RET) proto-oncogene. The course of MTC is indolent, and survival rates depend on the tumor stage at diagnosis. The present article describes clinical evidence-based guidelines for the diagnosis, treatment, and follow-up of MTC. Objective: The aim of the consensus described herein, which was elaborated by Brazilian experts and sponsored by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism, was to discuss the diagnosis, treatment, and follow-up of individuals with MTC in accordance with the latest evidence reported in the literature. Materials and methods: After clinical questions were elaborated, the available literature was initially surveyed for evidence in the MedLine-PubMed database, followed by the Embase and Scientific Electronic Library Online/Latin American and Caribbean Health Science Literature (SciELO/Lilacs) databases. The strength of evidence was assessed according to the Oxford classification of evidence levels, which is based on study design, and the best evidence available for each question was selected. Results: Eleven questions corresponded to MTC diagnosis, 8 corresponded to its surgical treatment, and 13 corresponded to follow-up, for a total of 32 recommendations. The present article discusses the clinical and molecular diagnosis, initial surgical treatment, and postoperative management of MTC, as well as the therapeutic options for metastatic disease. Conclusions: MTC should be suspected in individuals who present with thyroid nodules and family histories of MTC, associations with pheochromocytoma and hyperparathyroidism, and/or typical phenotypic characteristics such as ganglioneuromatosis and Marfanoid habitus. Fine-needle nodule aspiration, serum calcitonin measurements, and anatomical-pathological examinations are useful for diagnostic confirmation. Surgery represents the only curative therapeutic strategy. The therapeutic options for metastatic disease remain limited and are restricted to disease control. Judicious postoperative assessments that focus on the identification of residual or recurrent disease are of paramount importance when defining the follow-up and later therapeutic management strategies. Arq Bras Endocrinol Metab. 2014;58(7):667-700

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“…Two small open-label, phase II studies that examined a total of 24 patients with metastatic MTC treated with imatinib, starting at 600 mg daily have been completed (54,55). No objective tumor responses were reported, and a minority of patients achieved stable disease as their best tumor response.…”

Section: Imatinibmentioning

confidence: 99%

Advances in Chemotherapy of Differentiated Epithelial and Medullary Thyroid Cancers

Sherman

2009

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context: Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes.Evidence Acquisition: The PubMed and Google Scholar search engines were used to identify publications and peer-reviewed meeting presentations addressing chemotherapy and targeted therapy for differentiated or medullary carcinoma.Evidence Synthesis: Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single agent studies, but prolonged disease stabilization is more commonly seen. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. Randomized trials for several agents are underway that may lead to eventual drug approval for thyroid cancer. thyroid carcinomas have limited effectiveness, with response rates typically 25% or less (1). With such poor outcomes, results from few clinical trials of new therapies for thyroid carcinomas were published during the latter half of the 20th century (2). Plaguing these early trials was the practice of lumping patients with all histologies of thyroid carcinoma (differentiated, medullary, and anaplastic), confounding interpretation of the results. The definitions of response used in these earlier studies varied as well, and none are comparable with the currently used standard RECIST methodology [for detailed description of RECIST, see Refs. 3, 4). Thus, treatment with cytotoxic chemotherapy is generally limited to patients with symptomatic or rapidly progressive metastatic disease unresponsive to or unsuitable for surgery, radioiodine (for tumors derived from differentiated carcinomas), and external beam radiotherapy. ConclusionDuring the past decade, biological discoveries sparked trials testing novel therapies for advanced thyroid carcinomas. Of prime importance has been recognition of key oncogenic mutations in papillary (PTC) and medullary (MTC) carcinomas. BRAF and RAS genes code for kinases that activate signaling through the MAPK pathway, regulating growth and function in many cells both normal and neoplastic. Evidence from various tumor models support the contention that most PTCs arise as a result of single activating somatic mutations in one of three genes: BRAF, RAS, and translocations producing RET/PTC oncogenes (5). The resultant RET/PTC proteins signal upstream from RAS, thus activating the same MAPK pathway. For MTC,

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Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma

Cited by 93 publications

References 19 publications

New drugs for medullary thyroid cancer: new promises?

New drugs for medullary thyroid cancer: new promises?

Diagnóstico, tratamento e seguimento do carcinoma medular de tireoide: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia

Advances in Chemotherapy of Differentiated Epithelial and Medullary Thyroid Cancers

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