Redifferentiation Therapy for Iodine Refractory Differentiated Thyroid Cancers: Current Status

Radioiodine (RAI) has been used as an effective treatment for differentiated thyroid cancer for >80 years. ¹ While a significant number of patients, even with advanced disease, are cured by RAI, a proportion will develop iodine refractory differentiated thyroid cancer (IRDTC). Despite recent developments, including the advent of multikinase inhibitors, ^2,3 and more recently more targeted therapies such as neurotrophic tyrosine receptor kinase ⁴ and rearranged during transfection ⁵ inhibitors for subgroups of patients with specific molecular alterations, outcomes of patients with IRDTC remain poor and there is a need for novel treatment approaches.

There has long been an interest in the possibility of redifferentiation in IRDTC to allow the reintroduction of RAI therapy as a useful treatment. Earlier studies involving the use of lithium ⁶ and retinoids ⁷ failed to translate into meaningful clinical benefit, but with greater understanding of the molecular mechanisms of iodine resistance, and in particular the role of disruption the mitogen-activated protein kinase signaling pathway in preventing sodium iodide symporter expression, more targeted approaches have become possible. ^8,9

Van Nostrand et al. ¹⁰ present a narrative review of the existing literature in this field. It is striking that of 14 articles identified, 8 are retrospective studies and 6 articles report the outcomes of only 1 or 2 patients. None of the studies are randomized. In total the 14 articles include 101 patients who have received redifferentiation therapy, using 7 different agents. While some promising results are reported, more robust data are required to establish how such treatment approaches can be used to maximum clinical benefit, and how they compare with currently available therapies.

Van Nostrand et al. helpfully emphasize the importance of establishing a clear nomenclature for both categories of patients and treatment strategies. It is vital that clear definitions are established to inform trial design and facilitate comparison of results across studies. The distinction between attempts to restimulate iodine uptake where it has been completely lost (redifferentiation) and those aiming to increase iodine uptake where there remains some visible uptake but perhaps not in all lesions, or where there is evidence of disease progression despite iodine uptake (uptake enhancement), is particularly helpful and this distinction should be made in future studies.

The study of the International Committee on the Classifications of Radioiodine Refractory Differentiated Thyroid Cancer is certainly to be welcomed in providing clarification in this area.

With increasing understanding of the molecular mechanisms behind thyroid cancer development, and rapidly increasing access to routine molecular pathology testing, information regarding the presence of specific alterations such as BRAF mutations and NTRK or RET fusions is now routinely available for patients with IRDTC. Where such alterations are present, the most effective approach is likely to use a specific targeted agent, where available and there are certainly reports of enhanced iodine uptake in such circumstances. ^9,11 Determining the benefit of further RAI in these situations is complicated by the fact that there are often significant responses to such targeted agents when given alone, and this must be factored into any future study design.

While ultimately the impact of treatment on patients' quality of life and overall survival is of greatest importance, alternative endpoints are required in early phase studies to select therapies suitable for further investigation. In particular, the ability to quantify changes in absorbed dose delivered to target lesions by accurate dosimetry after RAI therapy is important. Some studies have set an absorbed dose target to warrant further RAI after a course of redifferentiation therapy, ⁸ but such target doses are essentially arbitrary and further study is needed to determine whether there is an absorbed dose threshold required to achieve meaningful clinical benefit.

Van Nostrand et al. comment on issues of access to novel therapies, and specifically redifferentiation therapy. Given the current limited all-be-it promising data on this treatment approach, they correctly recommend that patients in this situation should, where possible, be offered entry into prospective clinical trials. Management within a clinical trial protocol is clearly the safest option for the individual patient. It also allows acquisition of more robust data to answer the many outstanding questions regarding the clinical benefits, and how to optimize this treatment strategy to benefit future patients.

The current paucity of clinical trial options for this group of patients is however highlighted. It is incumbent on the clinical community to design high-quality multicenter ideally randomized phase 3 trials to test this treatment approach. Given the relative rarity of this disease, this will be challenging and will require an international effort, but previous drug trials ^2,3 have demonstrated that this is possible.

Comment is also made regarding alternative means of access, including the U.S. “right to try” law. ¹² This is clearly only relevant to practice in the United States, and legitimate concerns have been raised about this route, regarding patient safety, lack of oversight, and unrealistic expectations on the part of patients of unproven treatments, not to mention an often very significant financial burden. ¹³ Careful consideration is required before adopting this approach, being mindful of the Hippocratic imperative “primum non nocere”—first do no harm.

In summary, there is a growing body of evidence to suggest that there may be value in therapies that redifferentiate IRDTC to allow further RAI therapy. However, further international collaborative research is required to optimize treatment strategies using developments in molecular pathology, drug design, and molecular radiotherapy dosimetry, to determine which groups of patients stand to benefit, and to determine the clinical benefits of this approach when compared with other available treatment options.