Sorafenib
Sorafenib (400 mg twice daily) is an oral MKI that targets RAF, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 2 and 3, RET and c-Kit [47]. It was approved in November 2013 for patients with radioiodine-refractory differentiated thyroid cancer [48]. Three phase II studies had previously evaluated sorafenib in papillary thyroid cancer, showing a partial response in 15% to 31% of patients and a progression-free survival up to 79 weeks [49–51]. Common adverse effects included weight loss, fatigue, rash, hypertension and the main dose-limiting toxicity—a hand-foot syndrome consisting of swelling, reddening, numbness, and desquamation on palms and soles [52].
Approval of the drug was based on the DECISION trial [52]. A total of 417 patients were randomized (207 to sorafenib and 210 to placebo), of which 57% had papillary thyroid cancer. The primary endpoint of progression-free survival (PFS) was significantly higher in the sorafenib arm, (median, 10.8 months) compared with placebo (median, 5.8 months) (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.45–0.75, P < 0.001). Median overall survival had not been reached in either arm [52]. The PFS of 5.8 months in the placebo arm confirmed that the group of patients in this study had a rapidly progressing disease, unlike the majority of patients with RAI-sensitive disease.
Selumetinib
Radioiodine re-sensitization was addressed in a study using selumitinib, an inhibitor of mitogen-activated protein kinase kinase (MAPK kinase or MEK). Preclinical models had shown that radioiodine-refractory tumors exposed to inhibitors of this enzyme were able to uptake radioiodine again. Twenty patients with radioiodine-refractory thyroid cancers were treated with selumetinib for 4 weeks and 12 showed increased radioiodine uptake following the treatment. Furthermore, 8 of these patients went on to show responses clinically to retreatment with radioiodine [53].Further studies with this agent will be needed to determine its place in treating patients with differentiated thyroid cancer.
External Beam Radiotherapy and Local Treatment for Metastases
The role of external beam radiotherapy in papillary thyroid cancer is mainly for symptom management. Local radiation can be used in patients with refractory metastatic disease or in lesions that do not uptake radioiodine. Examples include painful bone metastasis or brain metastasis that cannot be treated with surgery. In addition, radiofrequency ablation, chemo-embolization, or ethanol ablation can be used in certain patients.
Sequence of Treatments
In the setting of symptomatic metastatic, radioiodine-resistant disease, we prefer to use a TKI, normally sorafenib, as a first-line treatment. For second-line treatments, enrollment in a clinical trial is an option. Over 70% of patients with metastatic papillary thyroid cancer have mutations of the enzyme BRAF kinase. Vemurafenib is an inhibitor of this enzyme and appears to have some activity in patients with RAI-refractory thyroid cancer in early clinical trials [54–58]. Other TKIs such as sunitinib can also be used. Doxorubicin is only used in cases when a patient is not eligible for a trial and the off-label use of another TKI is contraindicated.
Further Treatment in this Patient
The patient received a trial of sorafenib. He showed disease stabilization that lasted 5 months. The treatment was stopped due to adverse effects (loss of weight and vomiting) and progression of the disease. He was then enrolled in a trial of vemurafenib. He stopped treatment because of adverse events related to the medication and currently has stable disease.