Sorafenib in metastatic radioactive iodine-refractory differentiated thyroid cancer: A pilot study

Abstract

Abstract. The incidence and mortality of thyroid cancer are on the increase worldwide and the treatment options for progressive, radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC) patients are currently limited. Sorafenib is a multikinase inhibitor that targets several molecular signals, which are believed to be involved in the pathogenesis of DTC. In this study, we reported our experience with the off-label use of sorafenib in Chinese cancer patients. A total of 8 patients (7 with papillary and 1 with follicular thyroid cancer) were recruited in this study. The partial response (PR) rate was 50.0% and 5 of the 8 patients (62.5%) achieved a durable response. The median progression-free survival (PFS) and overall survival (OS) were 40.1 and 55.0 weeks, respectively. Lung metastases were more sensitive to sorafenib compared to lymph nodes. The tumor marker response was not in accordance with the radiological response, although patients with tumor marker complete response (CR) exhibited a longer PFS and OS compared to those without a CR. Common adverse events (AEs) included palmar-plantar erythrodysesthesia, hypertension, diarrhea, weight loss and alopecia. Grade 4 AEs comprised hypocalcemia (1 patient) and elevated amylase levels (1 patient). A dose reduction was required in 62.5% of the patients. In conclusion, sorafenib exhibited a clinically relevant antitumor activity in patients with progressive metastatic RAI-refractory DTC, although the majority of the patients required a dose reduction due to intolerable toxicity. IntroductionThe incidence and mortality of thyroid cancer are increasing worldwide. Differentiated thyroid cancer (DTC), namely papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), comprise ~94% of these cases (1). Despite the majority of the DTC patients having indolent disease, ~5-10% of these patients will eventually develop metastatic disease, no longer responding to radioiodine (RAI) therapy or thyroid-stimulating hormone (TSH) suppression and exhibiting a more aggressive course and short survival (2-4). Doxorubicin is the only currently available treatment option that has been approved by the Food and Drug Administration (FDA) for such patients, with a progression-free survival (PFS) of only 2 months and a median overall survival (OS) of 8 months; however, it is accompanied by severe myelosuppression and cumulative cardiotoxicity (5). Therefore, RAI-refractory DTC is a disease requiring novel therapeutic options exhibiting better efficacy and less toxicity.Activating mutations in certain genes were previously reported to play a critical role in the development of DTC and the majority of DTCs may be due to single activating somatic mutations in one of three genes: BRAF mutations, RET̸PTC rearrangements and Ras mutations (6-9). Sorafenib is a small-molecule multikinase inhibitor that targets several molecular signals which have been proven as potential therapeutic targets in DTC. Four phase II trials using sorafenib for metastatic thyroid c...

Modulation of Autophagy by Sorafenib: Effects on Treatment Response

“…Sorafenib (BAY 43-9006, Nexavar®), which was developed in 1995 (Gauthier and Ho, 2013 ), is the only chemotherapeutic drug which has demonstrated to improve survival rate in patients with HCC (Llovet et al, 2008 ; Abdel-Rahman and Fouad, 2014 ). Recent studies have also proven that sorafenib has therapeutic effects in other cancer types, such as thyroid cancer, acute myeloid leukemia, advanced renal cell carcinoma or prostate cancer (Escudier et al, 2007 ; Gollob et al, 2007 ; Chi et al, 2008 ; Antar et al, 2014 ; Luo et al, 2014 ; Alonso-Gordoa et al, 2015 ; Yamamoto et al, 2015 ). Sorafenib targets the RAF serine/threonine kinases, a family of three members (A-RAF, B-RAF, and C-RAF/Raf-1) that play a key role in the transduction of mitogenic and oncogenic signals through the Raf/Mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, resulting in a lower cyclin D1 expression and in cell cycle arrest (Wellbrock et al, 2004 ; Adnane et al, 2006 ; Liu et al, 2006 ).…”

Synergistic Activity of N-hydroxy-7-(2-naphthylthio) Heptanomide and Sorafenib Against Cancer Stem Cells, Anaplastic Thyroid Cancer

“…The USFDA recently expanded the permitted use of sorafenib in treating advanced thyroid cancer [12] . Sorafenib is a multi-kinase inhibitor that obstructs different signaling pathways, including Raf kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptors (PDGFRs) [13] .…”

Lenvatinib-induced hypocalcaemia due to transient primary hypoparathyroidism

“…As for other toxicities, the prevalence of hypocalcemia is highly variable among registration and real-life studies (Table 1), likely due to the low number of enrolled patients, as well as to the variable presentation of this AE, which can be asymptomatic in milder cases [7]. Despite being seldomly reported, hypocalcemia during treatment with sorafenib appears to be common, with an estimated frequency of 8-41% [8][9][10]. In particular, Cabanillas et al reported severe hypocalcemia in one patient with post-surgical hypoparathyroidism, out of 8 subjects treated with sorafenib [10].…”