Evolving Approaches in Managing Radioactive Iodine-refractory Differentiated Thyroid Cancer

Wendy Sacks, MD; Glenn D. Braunstein, MD


Endocr Pract. 2014;20(3):263-275. 

In This Article

Abstract and Introduction


Objective: To discuss the approach to care of patients with advanced differentiated thyroid cancer (DTC), in particular those with radioactive iodine (RAI)-refractory disease, and the transition to systemic treatment.

Methods: A PubMed search was conducted using the search terms "radioactive iodine-refractory, differentiated thyroid cancer and treatment" restricted to a 2000–2012 timeframe, English language, and humans. Relevant articles were identified from the bibliographies of selected references. Four patient cases are presented to illustrate the clinical course of RAI-refractory DTC.

Results: The current standard of care for early stage DTC could include surgery, RAI in some cases, and thyroid hormone suppression. For advanced RAI-refractory DTC, clinical practice guidelines established by the National Comprehensive Cancer Network and the American Thyroid Association recommend, as one option, the use of systemic therapy, including kinase inhibitors. Numerous trials are underway to evaluate the clinical benefit of these targeted therapies.

Conclusion: Preliminary results are encouraging with respect to the clinical benefit of targeted systemic therapies. However, at present there is no consensus on the criteria that define RAI-refractory disease and the optimal timing for transition to systemic therapy. There remains a need to establish common criteria to enhance patient care and enable better comparison across clinical studies.


In 2013, thyroid cancer is expected to account for approximately 3.6% of all new cancer diagnoses in the United States.[1] Differentiated thyroid cancer (DTC), classified as papillary (PTC), follicular (FTC), or Hürthle cell, accounts for >90% of thyroid cancers.[2] The prognosis for patients diagnosed with DTC is quite favorable[2] because most DTC is highly treatable and frequently curable with surgery, postoperative radioactive iodine (RAI) treatment in some cases, and thyroid-stimulating hormone (TSH) suppression.[3]

Despite the effectiveness of standard care for DTC, approximately 10 to 20% of patients will experience disease recurrence within 5 to 15 years after primary therapy.[4,5] When tumors recur, surgery, RAI treatment, and sometimes external beam radiation therapy (EBRT) are used to decrease tumor burden and curtail growth. However, for patients whose tumors are nonresectable and/or RAI-nonresponsive, disease management becomes more challenging. Systemic therapy may then be indicated, which in many instances shifts the responsibility of care from the endocrinologist to a medical oncologist. Identifying tumors that are no longer likely to respond to RAI treatment and pinpointing the most appropriate time to transition patients from localized to systemic therapy are critical for optimal patient care.

Here we review the literature focusing on existing and investigational approaches to the management of RAI-refractory metastatic DTC. We then present 4 patient cases that illustrate the challenges an endocrinologist might encounter in recognizing and treating RAI-resistant tumors in clinical practice and discuss the rationale for choices regarding implementation of targeted systemic therapy regimens.