Refractory thyroid cancer is rare (45 cases/million population/year) and is responsible for most thyroid cancer related death. It includes patients with at least one tumor focus that does not concentrate radioiodine (RAI) or who progress within one year after RAI treatment despite uptake in all lesions.
Treatment consists in levothyroxine to maintain a low TSH level and focal treatment modalities (surgery, EBRT, thermo-ablation). In case of multiple metastases with demonstrated RECIST progression, systemic treatment may be indicated. Toxicity is high with a decrease in quality of life and the decision to initiate a treatment is validated by a tumor board.
Cytotoxic chemotherapy is poorly effective. Two anti-angiogenic TKIs, sorafenib and lenvatinib, are labeled by EMA and FDA. Lenvatinib is particularly effective: PFS is prolonged by 15 months, ORR is 65% and OS is improved in elderly patients, and it is used as first line treatment in the absence of contraindication.
However most patients progressed even after CR, and several possibilities can be offered as second line. Other anti-angiogenic drugs have demonstrated some efficacy, including sunitinib, pazopanib and cabozantinib. Intra-tumoral targets such as BRAF or ALK may be present in the tumor tissue, and their presence may lead to use a specific inhibitor.
Redifferentiation by inhibiting the MAPkinase pathway during 46 weeks to reinduce RAI uptake in tumor tissue and in that case to treat with RAI may be used in patients with a relatively low tumor burden and with slow tumor progression.
Immunotherapy with check point inhibitors in combination with an anti-angiogenic drug is attractive to improve response rate and duration of response, but no data is currently available.
Despite major achievements in recent years, there is a need for prospective trials, preferably in the frame of networks.