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Rajan P Dang, Daniel McFarland, Valerie H Le, Nadia Camille, Brett A Miles, Marita S Teng, Eric M Genden, Krzysztof J Misiukiewicz
Objectives. Invasion of differentiated thyroid cancer (DTC) into surrounding structures can lead to morbid procedures such as laryngectomy and tracheal resection. In these patients, there is a potential role for neoadjuvant therapy. Methods. We identified three studies involving the treatment of DTC with neoadjuvant chemotherapy: two from Slovenia and one from Japan. Results. These studies demonstrate that in selected situations, neoadjuvant chemotherapy can have a good response and allow for a more complete surgical resection, the treatment of DTC...
2016: International Journal of Surgical Oncology
Pawel Kawalec, Iwona Malinowska-Lipień, Tomasz Brzostek, Maria Kózka
Thyroid carcinoma is the most prevalent endocrine malignancy, with an increasing incidence over the past decades. Treatment of differentiated thyroid cancer consists of surgery followed by radioactive iodine (RAI) ablation of the thyroid remnant, and TSH suppression. Among new therapeutic solutions for patients with advanced RR-DTC stage, the most promising seem to be sorafenib and lenvatinib, up to now considered to be orphan drugs. Areas covered: We performed a systematic review of medical databases to collect all eligible clinical trials referring to the topic of our analysis...
October 13, 2016: Expert Review of Anticancer Therapy
Kenji Ikeda, Masatoshi Kudo, Seiji Kawazoe, Yukio Osaki, Masafumi Ikeda, Takuji Okusaka, Toshiyuki Tamai, Takuya Suzuki, Takashi Hisai, Seiichi Hayato, Kiwamu Okita, Hiromitsu Kumada
BACKGROUND: Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC). METHODS: Patients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles...
October 4, 2016: Journal of Gastroenterology
Jörg Trojan, Oliver Waidmann
Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016...
2016: J Hepatocell Carcinoma
Haris Zahoor, Brian I Rini
The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas Covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials, which led to their approval, is presented...
October 3, 2016: Expert Opinion on Emerging Drugs
Emiliano Calvo, Manuela Schmidinger, Daniel Y C Heng, Viktor Grünwald, Bernard Escudier
Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab...
September 10, 2016: Cancer Treatment Reviews
Sebastiano Buti, Alessandro Leonetti, Alice Dallatomasina, Melissa Bersanelli
INTRODUCTION: Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, and its pathogenesis is strictly related to altered cellular response to hypoxia, in which mTOR signaling pathway is implicated. Everolimus, an mTOR serine/threonine kinase inhibitor, represents a therapeutic option for the treatment of advanced RCC. AIM: The objective of this article is to review the evidence for the treatment of metastatic RCC with everolimus. EVIDENCE REVIEW: Everolimus was approved for second- and third-line therapy in patients with advanced RCC according to the results of a Phase III pivotal trial that demonstrated a benefit in median progression-free survival of ~2 months compared to placebo after failure of previous lines of therapy, of which at least one was an anti-VEGFR tyrosine kinase inhibitor (TKI)...
2016: Core Evidence
Tatiana Kelil, Abhishek R Keraliya, Stephanie A Howard, Katherine M Krajewski, Marta Braschi-Amirfarzan, Jason L Hornick, Nikhil H Ramaiya, Sree Harsha Tirumani
Substantial improvement in the understanding of the oncogenic pathways in thyroid cancer has led to identification of specific molecular alterations, including mutations of BRAF and RET in papillary thyroid cancer, mutation of RAS and rearrangement of PPARG in follicular thyroid cancer, mutation of RET in medullary thyroid cancer, and mutations of TP53 and in the phosphatidylinositol 3'-kinase (PI3K)/AKT1 pathway in anaplastic thyroid cancer. Ultrasonography (US) and US-guided biopsy remain cornerstones in the initial workup of thyroid cancer...
September 2016: Radiographics: a Review Publication of the Radiological Society of North America, Inc
Katharina Mischler, Stefan Kneifel, Richard Cathomas
BACKGROUND: Metastatic differentiated thyroid cancer (DTC) is a rare disease that is in the first line treated with iodine-131 radioisotope therapy. Until recently, options were very limited in the case of progressive radioactive-iodine (RAI)-refractory disease. Based on new study results, tyrosine kinase inhibitors (TKIs) have attracted attention. The TKI sorafenib demonstrated significantly improved progression-free survival (PFS) in a phase III trial. Recent data from another phase III trial showed that the TKI lenvatinib achieved high response rates and a large improvement in PFS in metastatic RAI-refractory DTC patients in the first-line setting and after 1 prior line of TKI...
2016: Oncology Research and Treatment
Bruce Robinson, Martin Schlumberger, Lori J Wirth, Corina E Dutcus, James Song, Matthew H Taylor, Sung-Bae Kim, Monika K Krzyzanowska, Jaume Capdevila, Steven I Sherman, Makoto Tahara
CONTEXT: Lenvatinib improved the progression-free survival (PFS) and overall response rate (ORR) of patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) versus placebo in the Phase 3 Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT). OBJECTIVE: To characterize tumor size changes with lenvatinib treatment. DESIGN: SELECT was a phase 3, randomized, double-blind, multicenter study. SETTING: In this clinical trial, tumor assessments of lenvatinib (n=261) and placebo-treated (n=131) patients were performed by independent radiologic review per Response Evaluation Criteria In Solid Tumors version 1...
August 22, 2016: Journal of Clinical Endocrinology and Metabolism
Saori Watanabe Miyano, Yuji Yamamoto, Kotaro Kodama, Yukiko Miyajima, Masaki Mikamoto, Takayuki Nakagawa, Hiroko Kuramochi, Setsuo Funasaka, Satoshi Nagao, Naoko Hata Sugi, Kiyoshi Okamoto, Yukinori Minoshima, Yusuke Nakatani, Yuki Karoji, Isao Ohashi, Yoshinobu Yamane, Toshimi Okada, Tomohiro Matsushima, Junji Matsui, Masao Iwata, Toshimitsu Uenaka, Akihiko Tsuruoka
The fibroblast growth factor receptor (FGFR) signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib...
August 17, 2016: Molecular Cancer Therapeutics
Qingling Huang, Valentina E Schneeberger, Noreen Luetteke, Chengliu Jin, Roha Afzal, Mikalai M Budzevich, Rikesh J Makanji, Gary V Martinez, Tao Shen, Lichao Zhao, Kar-Ming Fung, Eric B Haura, Domenico Coppola, Jie Wu
RET fusions have been found in lung adenocarcinoma, of which KIF5B-RET is the most prevalent. We established inducible KIF5B-RET transgenic mice and KIF5B-RET-dependent cell lines for preclinical modeling of KIF5B-RET-associated lung adenocarcinoma. Doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET transgenic mice developed invasive lung adenocarcinoma with desmoplastic reaction. Tumors regressed upon suppression of KIF5B-RET expression. By culturing KIF5B-RET-dependent BaF3 (B/KR) cells with increasing concentrations of cabozantinib or vandetanib, we identified cabozantinib-resistant RET(V804L) mutation and vandetanib-resistant-RET(G810A) mutation...
October 2016: Molecular Cancer Therapeutics
Jun Gong, Benjamin Gerendash, Nazli Dizman, Abrar Khan, Sumanta K Pal
PURPOSE OF REVIEW: Multiple agents, including vascular endothelial growth factor (VEGF) inhibitors and mammalian target of rapamycin inhibitors have been approved over the past decade for the treatment of metastatic renal cell carcinoma (mRCC). Here, we focus on nivolumab, cabozantinib, and lenvatinib plus everolimus, agents that have recently emerged with positive clinical data leading to 'Food and Drug Administration approval or pending approval in mRCC. We also review the development of novel agents of interest showing promise in mRCC as part of combination therapy'...
September 2016: Current Opinion in Urology
Gabriel Tremblay, Christopher Livings, Lydia Crowe, Venediktos Kapetanakis, Andrew Briggs
BACKGROUND: Cost-effectiveness models for the treatment of long-term conditions often require information on survival beyond the period of available data. OBJECTIVES: This paper aims to identify a robust and reliable method for the extrapolation of overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer receiving lenvatinib or placebo. METHODS: Data from 392 patients (lenvatinib: 261, placebo: 131) from the SELECT trial are used over a 34-month period of follow-up...
2016: ClinicoEconomics and Outcomes Research: CEOR
Jolanta Krajewska, Aleksandra Kukulska, Barbara Jarzab
INTRODUCTION: Radioiodine [RAI]-resistant advanced and progressive differentiated thyroid cancer [DTC], although rare, constitutes a real challenge as its prognosis is poor and available therapeutic options, until now, have been limited. Discovery of a crucial role of distinct tyrosine kinases in DTC pathogenesis opened up new options in systemic treatment. Lenvatinib is an oral potent multi kinase inhibitor [MKI] of different growth factor receptors including VEGFR1/Flt-1, VEGFR2/KDR, VEGFR3, FGFR1,2,3,4, PDGFR-β as well as RET and KIT signaling networks...
August 2016: Expert Opinion on Pharmacotherapy
Athanasios Bikas, Shivangi Vachhani, Kirk Jensen, Vasyl Vasko, Kenneth D Burman
Introduction Patients with progressive, metastatic, RAI-refractory differentiated thyroid cancer (DTC), as well as patients with advanced medullary (MTC) and anaplastic thyroid cancer represent a cohort for which therapeutic options are limited. The recent discoveries in the molecular mechanisms implicated in TC have provided insight of the pathogenesis and progression of disease. In that respect, targeted therapies have emerged as a promising alternative for the treatment of those patients. Areas Covered Tyrosine Kinase Inhibitors (TKIs) have been studied extensively in TC: sorafenib and lenvatinib have been approved by the FDA for the treatment of metastatic, RAI-refractory DTC, while vandetanib and cabozantinib are FDA approved for use in advanced MTC...
July 1, 2016: Expert Review of Clinical Pharmacology
Hilary Glen
Despite advances in metastatic renal cell carcinoma (mRCC) treatments, patients eventually progress and develop resistance to therapies targeting a single pathway. Lenvatinib inhibits VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT proto-oncogenes. In a randomized, Phase II trial evaluating patients with mRCC who had progressed after one prior VEGF-targeted therapy, progression-free survival was significantly improved with lenvatinib alone or in combination with everolimus versus everolimus alone. This review summarizes the clinical development of lenvatinib in mRCC, and how simultaneous targeting of multiple pathways involved in carcinogenesis and/or therapeutic resistance may improve patient outcomes...
October 2016: Future Oncology
Chenjing Zhu, Xuelei Ma, Yuanyuan Hu, Linghong Guo, Bo Chen, Kai Shen, Yue Xiao
To systematically review the safety and efficacy of lenvatinib in the treatment of patients, we retrieved all the relevant clinical trials on the adverse events (AEs) and survival outcomes of lenvatinib through PubMed, Medline, Embase, Web of Science and Cochrane Collaboration's Central register of controlled trial. Fourteen eligible studies involving a total of 978 patients were included in our analysis. The most common all-grade AEs observed in patients treated with lenvatinib were hematuria (56.6%), fatigue (52...
June 14, 2016: Oncotarget
R A Werner, K Lückerath, J S Schmid, T Higuchi, M C Kreissl, I Grelle, C Reiners, A K Buck, C Lapa
Tyrosine kinase inhibitors (TKI) have shown clinical effectiveness in iodine-refractory differentiated thyroid cancer (DTC). The corresponding role of serum thyroglobulin (Tg) in iodine-refractory DTC has not been investigated yet. 9 patients (3 female, 61 ± 8y) with progressive iodine-refractory DTC starting on lenvatinib were considered. Tumor restaging was performed every 2-3 months including contrast-enhanced computed tomography (CT, RECIST 1.1). Serum Tg was measured and compared to imaging findings...
2016: Scientific Reports
Rasmus Laursen, Markus Wehland, Sascha Kopp, Jessica Pietsch, Manfred Infanger, Jirka Grosse, Daniela Grimm
BACKGROUND: Thyroid cancer is the most common type of endocrine neoplasia. Differentiated thyroid carcinoma (DTC) represents 94% of all thyroid cancer types. Approximately 20% experience local recurrence and 10% distant metastasis. The recurrent DTC often becomes less differentiated, loses the iodine uptake capability and consequently loses the radioactive iodine treatment option. Under these circumstances survivability drops below 10% at 10 years. The treatment options for dedifferentiated thyroid cancers are extremely limited...
June 13, 2016: Current Pharmaceutical Design
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