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Introduction -Special Symposium on TKIs

The contemporary treatment of thyroid cancer has evolved greatly in the past 30 years. This advancement in knowledge has been more rapid than in the preceding century and continues to be a challenge to the practicing endocrinologist.  This symposium on advances in the diagnosis and treatment of thyroid cancer was developed to summarize the current state of the art in identification and management of the majority of thyroid cancers encountered while alerting the clinician to the characteristics of more advanced cases which have a far less favorable outcomes. 

The first chapter of this work focuses on the current management of differentiated thyroid cancer. An outline of the diagnostic tools commonly implemented in the assessment of patients sets the stage for a discussion of the clinical course of the most common types of differentiated thyroid cancer, culminating with an extensive review of therapeutic interventions. After selecting an appropriate initial surgical procedure, it is evident that further clinical decisions are based on the stage of disease present post operatively. The need for further interventions such as 131-I ablation and TSH suppressive therapy with l-thyroxine are determined by the extent of initial surgery, the risk predicted by the histopathologic findings and the predicted effectiveness of these interventions. Follow up strategies using available clinical laboratory and imaging techniques are laid out in detail. Restaging and further treatments based on clinical findings are detailed as are considerations for the safe administration of therapeutic interventions and the potential for side effects of the same. Long term surveillance strategies and prognoses are made clear as well as suggestions for optimal outcomes are made clear. 

The second section of this work introduces the concept of 131-I refractory (more advanced) differentiated thyroid cancer.  After a brief review of the clinical history of 131-I therapy in patients with differentiated thyroid cancer, Tuttle and Sabra review factors which are associated with suboptimal 131-I avidity in metastatic thyroid cancer and explain methods of assessing the potential for successful use of 131-I to treat patients with more advanced thyroid cancer. A thorough explanation of several methods of dosimetry are outlined including the advantages and limitations of each in predicating the effectiveness of 131-I in improving patient outcomes. This section is summarized with a set of practical findings to guide clinical decision making and defining 131-I refractory disease where further use of 131-I would not likely result in improved patient outcomes and may only be expected to be associated with the toxicities of radioactive iodine. 

The selection of patients with advanced thyroid cancer for more advanced intervention with tyrosine kinase inhibitor (TKI) therapies is the focus of the next section of this symposium. Pacini and Schlumberger re-define the limited life expectancy predicted for those with more advanced thyroid cancer as defined as 131-I refractory metastatic disease. These authors review the methods employed to assess the extent and course of the minority of differentiated thyroid cancer who have persistent of recurrent metastatic disease despite the apparently highly effective conventional treatments outlined by Pacini and DeGroot in the first chapter.  This section proposes principles of clinical management of such individuals which range from continued TSH suppressive therapy with LT4 and active surveillance, appropriate in some with non-progressive disease, to revisional surgery for symptomatic focal disease or the institution of advanced TKI interventions when progression of the thyroid cancer is clear. An introduction to TKI selection closes out this section and sets the stage for the next discussion.

Klopper and Haugen have provided us with an overview of the current state of modern systemic therapies for managing aggressive thyroid cancer when traditional interventions are no longer effective. These authors define the mechanisms of action of the of the multi-targeted tyrosine kinase inhibitors. They provide us with an overview of the current state of knowledge of TKI therapies in thyroid cancer trials with especial attribution of the targets of each of the agents utilized. Trial outcomes are detailed so as to provide a useful overview of potentially useful interventions for these unfortunate patients with advancing disease. The authors summarize the current impact that these agents have had on clinical practice and propose an algorithm for assessing candidates for advanced systemic therapy of thyroid cancer and propose a very practical construct to support the ongoing administration of these therapies with periodic re-staging and appropriate monitoring in the short and long term.

Finally, Fagin and HO have provided us with a comprehensive discussion of experience with multi-kinase inhibitors emphasizing the positives and limitations of these therapies in the current literature. They briefly discuss a limited role for cytotoxic chemotherapeutic agents especially for anaplastic thyroid cancer cases where traditional surgical and 131-I interventions are of limited value and point out that TKIs also have been demonstrated to have limited utility. The remainder of this elegant view forward is dedicated to explaining efforts to target the genetic drivers of thyroid cancer, enhance the effectiveness of 131-I in those grown refractory and overcome adaptive resistance to some small molecule inhibitors in some advanced thyroid cancers. Finally the authors explore the future of cancer immunotherapies in advanced thyroid cancer patients over all leaving us with a clear understanding of current directions in developing ever more advanced treatments for the patient presenting the dilemma of recurrent, 131-I resistant and advancing metastatic thyroid cancer.

James V. Hennessey M. D. Director, Clinical Endocrinology Division of Endocrinology Beth Israel Deaconess Medical Center