Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience.
Cabanillas ME , Waguespack SG , Bronstein Y , Williams MD , Feng L , Hernandez M , Lopez A , Sherman SI , Busaidy NL
J Clin Endocrinol Metab. 2010 Jun;95(6):2588-95. Epub 2010 Apr 14.
Cabanillas et al describe the M. D. Anderson experience with off-label use of sorafenib and sunitinib tyrosine kinase inhibitors in 15 patients with RAI refractory DTC. The primary endpoints were radiographic response and progression-free survival (PFS). Secondary objectives were tissue-specific radiographic responses and correlation of Tg with overall response. All patients had evidence of progressive disease (PD) before start of therapy. Best response in target lesions was partial response (PR) in three (20%), stable disease (SD) in nine (60%), and PD in three (20%). Clinical benefit (PR+SD) was 80%. The most noticeable organ-specific response was observed in lung . All histological subtypes had similar responses. The median PFS was 19 months. The overall survival at 2 yr of follow-up is 67%. The agents appear to be effective in patients with widely metastatic, progressive DTC, with most patients achieving stable disease or partial response. Log Tg significantly correlated with response to treatment and therefore may have value as a surrogate marker of response.
Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer.
Robinson BG , Paz-Ares L , Krebs A , Vasselli J , Haddad R
J Clin Endocrinol Metab. 2010 Jun;95(6):2664-71
Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases that also inhibits RET kinase activity. This study investigated the efficacy and safety of 100 mg/d vandetanib in patients with advanced hereditary MTC. Eligible patients with unresectable, measurable, locally advanced, or metastatic hereditary MTC received 100 mg/d vandetanib. The primary objective was to assess the objective response rate by response evaluation criteria in solid tumors. The study comprised 19 patients. Confirmed objective partial responses were observed in three patients, yielding an objective response rate of 16% Stable disease lasting 24 wk or longer was reported in a further 10 patients (53%); the apparent benefit rate was therefore 68%. Serum levels of calcitonin and carcinoembryonic antigen showed a sustained 50% or greater decrease from baseline in 21%. Adverse events were predominantly grade 1 or 2 and consistent with previous vandetanib monotherapy studies. Vandetanib at a once-daily dose of 100 mg has clinically relevant antitumor activity in patients with locally advanced or metastatic hereditary MTC and an overall acceptable safety profile
Harvesting the low-hanging fruit: kinase inhibitors for therapy of advanced medullary and nonmedullary thyroid cancer.
Fagin JA, Tuttle RM, Pfister DG.
J Clin Endocrinol Metab. 2010 Jun;95(6):2621-4.
Fagin and coworkers evaluate these results in an accompanying editorial, pointing out the current poor prognosis among the >10% of the 37000 annual new cases that develop RAI refractory distant mets, especially if the mets are FDG-PET positive. The rational of treatment is the high percentage of tumors that have BRAF or RAS mutations, (and activation of RET kinase in MTC). Although not FDA approved for this use, the Comprehensive Cancer Center Network has recommended consideration of use in patients unable or unwilling to enter a clinical trial. Side effects are significant in part because of generalized inhibition of tyrosine kinases, their action as ATP competitors, and under some circumstances a potential for paradoxical tumor activation. Sorafenib use has been associated with development of squamous cell carcinomas and keratoacanthomas.
The exact mechanism of action in relation to specific oncogene mutations in tumors remains uncertain, and this information should become crucial for selecting a particular therapeutic agent. Results of treatment so far are very encouraging, and overall side effects are reasonable considering the gravity of the illnesses. Many newer and more selective agents are under study. However it should be noted that studies have not as yet proven a survival benefit from therapy with the kinase inhibitors. (Summarized by L De Groot, MD)