Phase II Trial of Sorafenib in Patients with Advanced Anaplastic Carcinoma of the Thyroid

Savvides, P.; Nagaiah, Govardhanan; Lavertu, Pierre; Fu, Pingfu; Wright, John J.; Chapman, Robert A.; Wasman, Jay; Dowlati, Afshin; Remick, Scot C.

doi:10.1089/thy.2012.0103

Cited by 185 publications

(134 citation statements)

References 19 publications

(21 reference statements)

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…Our findings show that the NIR NP platform can facilitate the in vivo delivery of siBRAF into ATC xenograft tumors, eliciting robust BRAF silencing in the tumor tissue and effective suppression of tumor growth without obvious side effects. Although several small molecule inhibitors of BRAF have recently been approved by the Food and Drug Administration for the treatment of late-stage melanoma with BRAF mutation, a phase II trial in patients with ATC has shown that the BRAF inhibitor sorafenib only modestly extends overall survival and allows relapse (29), largely because of the inevitable drug resistance. In addition, because of the need for long-term administration of inhibitors, patients often develop significant side effects, such as arthralgia, skin rash, and photosensitivity.…”

Section: Discussionmentioning

confidence: 99%

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Liu

Gunda

Zhu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Anaplastic thyroid cancer (ATC), one of the most aggressive solid tumors, is characterized by rapid tumor growth and severe metastasis to other organs. Owing to the lack of effective treatment options, ATC has a mortality rate of ∼100% and median survival of less than 5 months. RNAi nanotechnology represents a promising strategy for cancer therapy through nanoparticle (NP) -mediated delivery of RNAi agents (e.g., siRNA) to solid tumors for specific silencing of target genes driving growth and/or metastasis. Nevertheless, the clinical success of RNAi cancer nanotherapies remains elusive in large part because of the suboptimal systemic siRNA NP delivery to tumors and the fact that tumor heterogeneity produces variable NP accumulation and thus, therapeutic response. To address these challenges, we here present an innovative theranostic NP platform composed of a near-infrared (NIR) fluorescent polymer for effective in vivo siRNA delivery to ATC tumors and simultaneous tracking of the tumor accumulation by noninvasive NIR imaging. The NIR polymeric NPs are small (∼50 nm), show long blood circulation and high tumor accumulation, and facilitate tumor imaging. Systemic siRNA delivery using these NPs efficiently silences the expression of V-Raf murine sarcoma viral oncogene homolog B (BRAF) in tumor tissues and significantly suppresses tumor growth and metastasis in an orthotopic mouse model of ATC. These results suggest that this theranostic NP system could become an effective tool for NIR imaging-guided siRNA delivery for personalized treatment of advanced malignancies.T hyroid cancer has been continuously increasing in worldwide incidence for the past few decades and is now the fifth most common malignancy in females (1). Notably, the most aggressive form of thyroid cancer, anaplastic thyroid cancer (ATC), has a mortality rate of nearly 100%, with median survival time of 3-5 months, mainly because of local invasion and metastasis to lung, lymph nodes (LNs), and other tissues (2). The mechanisms that mediate metastasis in ATC strongly depend on the activation of genetic mutations, such as V-Raf murine sarcoma viral oncogene homolog B (BRAF), TP53, RAS, PIK3CA, and AKT1 (3). Current treatments for ATC rely on various combinations of surgical resection with adjuvant therapies, such as chemotherapy and radiotherapy, but have shown only limited survival benefits (4). Therefore, there are compelling reasons to establish new strategies for more effective treatment of metastatic ATC.RNAi is a powerful means for specific silencing of virtually any target gene of interest, thus offering an enormous opportunity to treat cancers and suppress metastases (5). By improving the in vivo delivery of RNAi agents (e.g., siRNA) to solid tumor tissues through the enhanced permeability and retention (EPR) effect (6), nanotechnology has drastically facilitated the clinical translation of RNAi for cancer therapy (5). However, RNAi nanoparticles (NPs) at the clinical stage for cancer treatment (7, 8) may still face challenging obstacles, such ...

show abstract

Section: Discussionmentioning

confidence: 99%

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Liu

Gunda

Zhu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Savvides et al conducted a phase II trial of another tyrosine kinase inhibitor, sorafenib, in patients with advanced ATC, and they reported that 2 of 20 patients (10%) showed a partial response [20].…”

Section: Discussionmentioning

confidence: 99%

Anaplastic Thyroid Carcinoma Treated with Lenvatinib

et al. 2017

View full text Add to dashboard Cite

Anaplastic thyroid carcinoma (ATC), which accounts for 1%-2% of all malignant tumors of the thyroid, is known to be highly resistant to any therapy and has a 1-year survival rate of 5%-20% [1][2][3]. ATC patients are limited in number, and most die within 6 months after diagnosis, making it difficult to establish a standard treatment protocol. Multimodal therapy including surgery, radiotherapy and chemotherapy has been introduced, but survival times remain poor [4][5][6].The use of molecular-targeted drugs as cancer therapy has been rapidly increasing over the past decade. Lenvatinib, a new molecular-targeted anticancer drug, is a multi-targeted receptor tyrosine kinase inhibitor that inhibits the activities of vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet-derived growth factor receptors, KIT, and RET [7,8]. Lenvatinib exerts its anticancer activity via the suppression of tumor angiogenesis, and it is generally indicated for unresectable radioiodine-refractory differentiated thyroid cancers [9]. However, the evidence of the clinical effect of this drug on ATC is very limited. We herein report a case of ATC with local recur- Kurume Medical Journal, 64, 00-00, 2017 Summary: Objective: We report a case of anaplastic thyroid carcinoma (ATC) with local recurrence and distant metastasis that responded very well to treatment with lenvatinib, a new molecular-targeted anticancer drug. Case Report: A 91-year-old Japanese woman presented with a 5-month history of a painless mass in her left anterior neck. She had a past history of total thyroidectomy and neck dissection for papillary carcinoma of the thyroid. Here she underwent neck dissection, and the histopathological diagnosis was lymph node metastasis of papillary carcinoma with anaplastic transformation. Five months later, a cervical lymph node swelled up again.Computed tomography demonstrated an enhanced mass in the neck and multiple nodules in both lungs. Recurrent ATC with multiple lung metastases was diagnosed, and molecular-targeted therapy with lenvatinib was initiated. The neck tumor reduced in 1 week, and the pulmonary nodules became completely hollow within 1 month. However, we had to discontinue lenvatinib because of severe side effects including high blood pressure, hypocalcemia, and hypoalbuminemia. Soon after discontinuation, the side effects subsided, but the tumor rapidly regrew. The patient died of lymphangiosis carcinomatosa 6 days after discontinuation. Conclusion: Although recent advances in molecular-targeted therapy have provided powerful cancer therapy tools, the negative side of this therapy must be addressed.

show abstract

“…Other than pazopanib, several other TKIs have been studied in the treatment of ATC but almost exclusively in phase 2 studies (Savvides et al 2013). The major limit of these studies is that the rarity of ATC that does not allow trials to enroll large numbers of patients in a short period of time.…”

Section: :4mentioning

confidence: 99%

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

Viola

Valerio

Molinaro

et al. 2016

Endocrine-Related Cancer

164

130

View full text Add to dashboard Cite

Thyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15-20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

show abstract

Phase II Trial of Sorafenib in Patients with Advanced Anaplastic Carcinoma of the Thyroid

Abstract: Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.

Cited by 185 publications

References 19 publications

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Anaplastic Thyroid Carcinoma Treated with Lenvatinib

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

Contact Info

Product

Resources

About