TARGETED THERAPY IN REFRACTORY THYROID CANCER

Abstract

The large majority (>85%) of patients with differentiated thyroid carcinoma (DTC) and many (40%) patients with medullary thyroid carcinoma (MTC) can be cured, others may survive for decades despite persistent disease, and few patients with advanced disease may require novel therapeutic modalities [1,2]. Very few patients with anaplastic carcinoma survive over one year. These refractory thyroid cancer patients are rare, with an estimated annual incidence in France of 350 cases that is stable with time, including 200 patients with DTC, 50 with MTC and 100 patients with anaplastic thyroid carcinoma. In most patients, an initiating carcinogenic event can be found and molecular targeted therapy can be given with a scientific rationale. Patients with progressive thyroid cancer should preferably be included in prospective trials, and even phase I trials that are testing the newest therapies should be considered for these patients, as these protocols may allow early identification of possibly effective drugs. Although response criteria in these contemporary trials differ markedly from those evaluating cytotoxic chemotherapy, anti-tumour efficacy of these agents in MTC patients is likely to be much greater than that of earlier chemotherapies (ORR 30.5 months in the treatment arm (median not reached) versus 19.3 months in the placebo arm) counterbalance toxic effects and justify its use in MTC patients with progressive or symptomatic disease and those with large tumour burden [4]. Vandetanib is available in France within the framework of an Autorisation Temporaire d’Utilisation (ATU) and has been labelled in the USA by the FDA. Results of the ongoing phase III trial with XL-184 are expected to confirm promising results obtained in the phase I trial in which 29% of 35 patients had a confirmed partial tumour response. There is apparently no cross resistance between drugs. Drugs used up to now have similar mechanisms of action, all being antiangiogenic and some (including vandetanib and XL184) targeting the RET tyrosine kinase. The relative role of the inhibition of each target or of their combined inhibition is currently unknown, but because axitinib and pazopanib are thought to be only antiangiogenic drugs, responses suggest that the antiangiogenic effects of these compounds might play an important role. Also, responses to vandetanib or XL-184 have been observed in patients without RET mutation. Even among patients with an RET mutation, tumour responses were partial and were observed in only a fraction of patients. This may indicate that targeting RET may not be sufficient in all MTC patients. Future studies should explore the interest in effective inhibition of the MAPkinase pathway downstream of the RET kinase, and of other pathways such as the PI3K-AKT-mTOR pathway, and search for other relevant targets that may indicate the use of other drugs. Toxicities of the drugs used in these patients led to dose reduction in 11−73% of patients and to drug withdrawal in 7−25%. There were no unexpected toxicities with long-term treatment. In DTC patients, refractory disease is defined by the presence of at least one tumour focus without any uptake of radioiodine, or by progressive disease following radioiodine treatment or by persistent disease after six treatments with radioiodine [5–7]. Among these cancers, histology (papillary and variants, follicular and poorly differentiated) and genetic defects may differ. Anti-tumour efficacy of these agents is likely to be greater than that of earlier chemotherapies, with partial responses observed in 8−32% of patients and long-term stable disease in at least another half. Comparison of the outcome among these compounds is at the present time not