Second-line treatment for advanced thyroid cancer: an indication in need of randomized clinical trials.

The incidence of thyroid cancer has grown over the last three decades, and in the United States, it has increased more than any other cancer (1, 2). Differentiated thyroid cancer (DTC) is the most common of all thyroid cancers, accounting for approximately 90% of cases, and includes papillary, follicular, and hurthle cell histologies (3). Although most patients with DTC have a favorable prognosis with standard treatments, including surgery, radioactive iodine (RAI), and TSH suppression, 10–15% of patients will develop disease refractory to RAI therapy (4, 5). These patients have a median overall survival of 2.5 to 3.5 years (6, 7). For decades, standard therapy for RAI-refractory DTC consisted of cytotoxic chemotherapy with doxorubicin, with unsatisfactory results and side effects (8). The discovery of oncogenic v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations in papillary thyroid cancer in 2003 and the recognition that thyroid cancers are also highly vascular paved the way for the use of sorafenib in metastatic RAI-refractory DTC. A serine-threonine kinase inhibitor, sorafenib, has been found to have multiple targets including VEGFR1–3, platelet derived growth factor receptor beta (PDGFR ), V-Raf-1 murine Leukemia viral oncogene homolog (RAF-1), and BRAF (9). Its activity in DTC, first shown in phase II studies, resulted in the design and execution of DECISION: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic RAI-refractory DTC (10–12). DECISION was important in helping to define patients with RAI-refractory DTC that were in need of systemic therapy in addition to determining the benefit of sorafenib. Patients were eligible if they met criteria for RAI-refractory disease, defined either as: 1) Having received a total lifetime dose of greater than or equal to 600mCi, 2) The presence of progressing lesions that were RAI non-Avid, or 3) The presence of lesions that had progressed in the period immediately after a therapeutic dose of RAI (12). Furthermore, patients needed to have met RECIST (Response Evaluation Criteria In Solid Tumors) criteria for progressive disease in the year before going on study, which included progression of target lesions by 20% or the development of new lesions (12). The study met its primary endpoint; the median progression free survival (PFS) in the sorafenib arm was 10.8 months, compared to 5.8 months in the placebo arm (hazard ratio, 0.587; P .0001) (12). In November of 2013, based on the data from DECISION, sorafenib became the first multikinase inhibitor (MKI) to be approved by the Food and Drug Administration for the treatment of RAI-refractory progressive DTC. This was practice changing; patients now had a tolerable systemic therapy to manage progressive, RAI-refractory disease. However, the median PFS for patients who receive sorafenib in the first-line setting is 10.8 months (12), leaving open the question of which therapies to consider in the second-line setting. This is especially important because most patients who stop treatment because of disease progression or the development of intolerable or unmanageable adverse events often maintain a good performance status and are candidates for subsequent therapy. In this issue of the JCEM, Dadu et al (13) report results of their retrospective analysis examining the efficacy of second-line therapy in patients with metastatic, RAI-refractory DTC previously treated with sorafenib.