Dr. Kunadharaju and Dr. Goyal are house officers in the Department of Internal Medicine, and Dr. Silberstein is a professor and chief of hematology/oncology, all at CHI Creighton University Medical Center in Omaha,Nebraska. Dr. Rudraraju is a house officer at MacNeal Hospital in Berwyn, Illinois. Dr. Silberstein is also chief of oncology at the VA Nebraska-Western Iowa Healthcare System in Omaha.
References
that lead to activation of the mitogen-activated protein kinase (MAPK), which promotes cell division. The sequential components leading to activation of MAPK include rearrangements of RET and NTRK1 tyrosine kinases, activating mutations of BRAF, and activating mutations of RAS.8,9 Similarly, overexpression of normal c-myc and c-fos genes, as well as mutations of HRAS, NRAS, and KRAS genes, is found in follicular adenomas, follicular cancers, and occasionally papillary cancers. 10-14 Increased expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) might have a role in thyroid carcinoma as well. 15
These kinases (the serine kinase BRAF and tyrosine kinases RET and RAS, and the contributory roles of tyrosine kinases in growth factor receptors such as the VEGFR) stimulate tumor proliferation, angiogenesis, invasion, metastasis, and inhibit tumor cell apoptosis. Kinase inhibitors target these signaling kinases, affecting tumor cell biology and its microenvironment. 16,17
A wide variety of multitargeted kinase inhibitors (MKIs) have entered clinical trials for patients with advanced or progressive metastatic thyroid cancers. Two such agents, sorafenib and lenvatinib, are approved by the FDA for use in selected patients with refractory metastatic DTC, whereas many other drugs remain investigational for this disease. In phase 2 and 3 trials, most of the treatment responses for MKIs were partial. Complete responses were rare, and no study has reported a complete analysis of overall survival (OS) outcomes. Results from some new randomized trials indicate an improvement in progression-free survival (PFS) compared with placebo, and additional trials are underway.
Sorafenib
Sorafenib was approved by the FDA in 2013 for the treatment of locally recurrent or metastatic, progressive DTC that no longer responds to radioactive iodine treatment. 18 Sorafenib is an oral, small molecule MKI. It works on VEGFRs 1, 2, and 3; platelet-derived growth factor receptor (PDGFR); common RET/PTC subtypes; KIT; and less potently, BRAF.19 The recommended dose is 400 mg orally twice a day.
In April 2014, Brose and colleagues published the phase 3 DECISION study on sorafenib. 20 It was a multicenter, randomized, double-blinded, placebo-controlled trial of 417 patients with radioactive iodine-refractory locally advanced or metastatic DTC that had progressed within the previous 14 months. 20 The results of the trial were promising. The median PFS was 5 months longer in the sorafenib group (10.8 mo) than in the placebo group (5.8 mo; hazard ratio [HR], 0.59; 95% conidence interval [CI], 0.45-0.76; P < .0001). The primary endpoint of the trial was PFS, and crossover from placebo to sorafenib was permitted upon progression. Overall survival did not differ significantly between the treatment groups (placebo vs sorafenib) at the time of the primary analysis data cutoff. However, OS results may have been confounded by postprogression crossover from placebo to open-label sorafenib by the majority of placebo patients.
