Radioiodine-Resistant Differentiated Thyroid Cancer: Hope for the Future

In this helpful review, the authors catalog a number of the novel molecular agents now being examined for treatment of radioiodine-resistant, metastatic differentiated thyroid cancer. They also call for increased systematic study of outcomes through recruitment of patients into large-scale trials.

Differentiated thyroid cancer (DTC) is characterized by a generally excellent long-term outcome for almost everyone who is diagnosed. Mortality is rare and morbidity is largely limited to locoregional recurrence, which itself is not known to affect prognosis. The mainstay of adjuvant treatment for DTC, including advanced disease, is radioiodine (RAI) ablation, which remains the best first-line therapy as long as the cancer remains iodine-avid. There is currently no paradigm for the use of any chemotherapy for treatment of DTC that retains radioiodine avidity. If iodine avidity abates over time-which, as the authors note, occurs in up to 50% of patients with advanced disease-outcomes may be poor. Here, the authors summarize promising results of new targeted therapies that give hope to the small but very unfortunate group of patients for whom RAI no longer works.

Like many clinicians, we agree with the call for greater inclusion of patients with advanced disease into large clinical trials. However, an important set of questions exist regarding whom to include and whether such trial data can be generalized to all patients with advanced thyroid cancer. Traditional oncologic trial design employs relatively short follow-up and relies on radiographic tumor regression as the major index of treatment response. Nevertheless, even in the case of advanced DTC, clinical indolence is not unusual and even widely metastatic disease may remain clinically stable for years without specific intervention other than intentional thyroid-stimulating hormone suppression.

Because even the novel agents summarized in this article can have serious side effects, striking the right balance between who should be treated and at what point treatment should be initiated remain important issues. Until both risk-benefit and survival data exist, continued caution about appropriate selection of DTC patients for treatment is very much indicated.

Selecting Patients for Off-Label Therapy

The authors recommend off-label use of oral multikinase inhibitors such as sorafenib (Nexavar) and sunitinib (Sutent) for patients who cannot be treated as part of a trial. To date, trials for thyroid cancer are much less available than trials for other cancers, and are also typically restricted to regional centers. This results in multiple barriers to access. Until DTC trials are more accessible and systematic trial data are available to guide clinical decision-making, we agree that the use of such agents off-label can be a very good choice for selected patients with radioiodine-insensitive and advanced DTC.

Who should select patients for systemic therapies? Is this the province of the medical oncologist, the medical endocrinologist, the endocrine or head and neck surgeon, or all of the above? The fact is that in DTC, successful multidisciplinary collaboration is essential. Endocrinologists and surgeons are the ones who most frequently treat thyroid cancer, have a keenly developed sense of disease natural history, and are adept at RAI use, whereas oncologists have extensive experience with chemotherapy and an infrastructure for effective management of complications. Our recent institutional experience with a novel multidisciplinary thyroid cancer center has taught us that close active collaboration between all these specialties can be valuable, effective, and enjoyable. Moreover, the collaborative approach offers a very good way to match DTC therapeutic intensity to disease severity.

Since establishing the loss of RAI avidity is such a key step in the decision to use systemic therapies, we must disagree with the authors’ statement that “FDG avidity may be the most practical and reproducible definition of RAI-resistant disease.” In fact, non–­iodine-avid disease is best defined by simple nonvisualization of uptake on post-therapy scanning, using RAI administered at therapeutic doses. Most patients with DTC will be treated with RAI until they are cured (which happens often) or until RAI becomes ineffective (which happens much less often). Thus, there is usually ample opportunity to document the loss of iodine avidity as part of a standard DTC treatment algorithm. 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) can be very helpful in the follow-up and periodic restaging of patients with non–iodine-avid DTC. The inverse correlation between iodine avidity and FDG uptake is well established to convey very useful prognostic information.[1]

However, both the high cost of FDG-PET scanning and its imperfect sensitivity for detecting non–iodine-avid disease do not support its routine use for establishing loss of iodine avidity.

Looking Ahead

The greatest promise for optimal treatment of all thyroid cancer, including non–iodine-avid disease, may come from the recent work characterizing certain genetic defects in cell signaling that cause activation of the mitogen-activated protein kinase pathway, which is central to most cases of DTC. Reports about the high predictive utility of molecular markers such as BRAF and RAS, are already prompting paradigm changes in the management of conventional DTC.

For example, BRAF mutation can now be routinely diagnosed on fine-needle aspiration cytology,[2,3] and because its presence predicts locoregional metastasis, BRAF status can be used to tailor the extent of initial surgery for optimal treatment.[3] These same mutations also provide potential therapeutic targets to identify the very DTCs that pose the greatest clinical risk, potentially even impacting the choice of systemic therapy.[4,5] The sobering fact that DTC incidence is reportedly increasing worldwide means that the advent of targeted therapy trials couldn’t come at a better time, and to patients whose progressive disease has failed RAI, such trials offer a great deal of hope.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Robbins RJ: Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 91:498-505, 2006.
2. Xing M, Clark D, Guan H, et al: BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer. J Clin Oncol 27:2977-2982, 2009.
3. Yip L, Nikiforova MN, Carty SE, et al: Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery. In press.
4. Nikiforov YE: Thyroid carcinoma: Molecular pathways and therapeutic targets. Modern Pathology 21(suppl 2):S37-S43, 2008.
5. Sherman SI: Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab 94:1493-1499, 2009.