Individualization of therapies for patients with advanced differentiated thyroid cancers.

Although describing experience related to but a single patient, the manuscript by Crouzeix et al. (1) represents an important counterpoint to the emphasis of most current therapeutic literature pertinent to radioiodine-refractory metastatic differentiated thyroid cancer (DTC). In particular, kinase inhibitors now understandably dominate present-day discussions related to DTC therapy, in large part owing to the attainment of dramatic clinical benefit in many DTC patients treated with agents including sorafenib (2, 3), sunitinib (4), or pazopanib (5). These recent innovations are clearly exciting and should not be minimized, but it is equally important to place them into the broader therapeutic context. The Crouzeix et al. (1) manuscript helps to do so in some respects; however, because it focuses on a single patient, other aspects of the broader therapeutic context are necessarily not addressed. What the Crouzeix et al. (1) manuscript does particularly well is to illustrate that kinase inhibitors do not consistently represent the most effective therapies for at least a subset of DTC patients requiring systemic therapy beyond radioiodine—emphasizing the need to individualize therapies based not only upon tumor and patient characteristics, but also based upon patterns of response to therapies undertaken in individual patients. Although cytotoxic chemotherapy has historically been deemed ineffective in DTC, cytotoxics nevertheless clearly have a role in the therapy of anaplastic and poorly differentiated thyroid cancers—as is well illustrated in the present manuscript. As cited in the Crouzeix et al. (1) manuscript, recent reports suggest moreover that select cytotoxic approaches (e.g. GEMOX, gemcitabine oxaliplatin) (6) may also have application in somewhat less aggressive thyroid cancers. This is an important point to appreciate not only with regard to tailoring therapies for individual patients, but also with regard to designing future thyroid cancer therapeutic clinical trials. In this latter context, the application of therapies beyond just vascular endothelial growth factor receptortargeted kinase inhibitors will be important. What the present case does not illustrate as well is that the vast majority of DTC patients have excellent prognosis and will therefore at best never receive kinase inhibitor or cytotoxic therapy. Even in the presence of metastatic and radioiodine-resistant disease, most DTC patients experience an indolent course of disease that is often best observed expectantly—unless, of course, it becomes symptomatic, rapidly progressive, and/or imminently threatening. The overall mortality rate for thyroid cancers as a whole is only about 3%, with 1,780 thyroid cancer-related deaths and 56,460 new thyroid cancer cases expected in the United States in 2012 (7). As a result, it can be very challenging to use available systemic therapeutic options judiciously and to become dexterous in selectively applying expectant observation vs. locoregional approaches vs. systemic therapeutic alternatives. It is also critical to keep in mind that: 1) kinase inhibitors do not cure DTC patients, even if remarkably effective initially; 2) thereareasyetnodata todefinitively indicate that the use of kinase inhibitors in DTC improves survival; 3) not all DTC patients benefit from kinase inhibitor therapy; 4) oral bioavailability does not ensure that tyrosine kinase inhibitors are less toxic and/or safer than cytotoxic chemotherapy [acute mortality attributable to kinase inhibitor therapy is about 1.5% (8), with disagreeable side effects developing in 50%]; and 5) like other therapies that are less commonly used in a particular context, the application of kinase inhibitors in DTC patients is best relegated to those with greatest experience.