One year later, in a follow-up blood analysis he was found to have an elevated thyroglobulin level (90.4 ng/mL). A PET/CT scan showed multiple bone metastases. A neck ultrasound revealed enlarged lymph nodes in the right thyroid bed.
• How common is radioiodine-refractory thyroid cancer?
Radioiodine-refractory thyroid cancer in patients with progression of disease despite radioiodine therapy, or with non-radioiodine-avid lesions [37], is uncommon. It has a poor prognosis with a median survival of 3 to 6 years after diagnosis. It is more frequent in older patients. These lesions are often hypermetabolic and hence [F-18]FDG-avid [38], with a worse prognosis. In one study of patients with metastatic differentiated thyroid cancer, the 10-year overall survival rate was 56% in patients with radioiodine-avid lesions but only 10% in patients with non-radioiodine-avid lesions [38].
• Is the bone a common place for metastasis? Where else should we expect to find a lesion?
Metastatic Pattern
The most common sites for distant metastasis of papillary thyroid cancer are the lungs and the bone. The 10-year survival rate of papillary thyroid cancer patients with lung metastases is between 30% and 50% [38,39]; the prog-nosis is better in patients < 45 years and with radiodine uptake [40]; indeed, patients with pulmonary metastasis seen only in 131-I scans and not on CT or chest x-ray have a longer survival [41]. Pulmonary metastasis can be treated with radioiodine if they are radioiodine-avid. With this treatment complete remission is possible, although it is extremely difficult to achieve in macronodular metastasis.
Bones are the second most common place for distant metastases. Bone metastases seem to have a worse response to treatment with an unfavorable prognosis [42]. Pamidronate (a biphosphonate) and denosumab (a RANK ligand inhibitor) have been used to prevent skeletal related events, including pathologic fractures and cord compression, in bone metastases from other cancers such as breast and prostate, and may also be useful in thyroid cancer, although this has not yet been studied [43,44]. Moreover, surgical resection of isolated bone metastasis seems to improve survival [45].
Skin, liver, and brain metastasis, although uncommon, can also occur. There are also reported rare cases of metastasis in the breast, parotid, larynx, pharynx, adrenal glands, pituitary, kidney, liver, orbit, the sphenoid sinus, choroid plexus, pancreas, and skeletal muscles [46].
• Which treatments can we offer to a patient with metastatic disease refractory to radioiodine?
Chemotherapy and Treatment of Radioiodine-Resistant Disease
Therapeutic options for patients with metastatic papillary thyroid cancer resistant to radioiodine and TSH suppression are limited. Cytotoxic drugs do not play a major role in the treatment of refractory metastatic papillary thyroid cancer, and new research is mainly focused on tyrosine kinase inhibitors (TKIs) with a considerable number of clinical trials either completed or ongoing.
Tyrosine kinases are enzymes that transfer phosphate groups from adenosine triphosphate to proteins. In tumor cells their signaling paths promote proliferation, avoidance of apoptosis, invasion, angiogenesis, and metastasis. TKIs are small molecules that are able to inhibit tyrosine kinase function even at very low intracellullar concentrations. Some of them inhibit various tyrosine kinases and are known as multi-kinase inhibitors (MKIs).