Consensus Reached in Radioactive Iodine, Thyroid Cancer Debate

Nancy A. Melville

May 01, 2019

Amid debate between thyroid and nuclear medicine communities on the use of radioactive iodine therapy (I-131; RAI) for the treatment of differentiated thyroid cancer (DTC), leaders of four societies representing the specialties have issued a joint statement ironing out key points of contention and setting goals for improving the treatment approach.

"By fostering an open, productive, and evidence-based discussion, the...meeting restored trust, confidence, and a sense of collegiality between individuals and organizations that are committed to optimal thyroid disease management," they state.

The resulting joint statement, published this month in Thyroid, sets forth nine key principles, dubbed the "Martinique Principles," that emerged from a summit meeting in Martinique of leaders of the American Thyroid Association (ATA), European Thyroid Association, European Association of Nuclear Medicine, and Society of Nuclear Medicine and Molecular Imaging, representing eight countries.

The latter two groups had declined to endorse the most recent ATA guidelines, published in 2015, because of objections about various recommendations of I-131 RAI therapy in DTC, and the meeting was called amid growing concern about patients and practitioners receiving conflicting messages on the appropriate practices.

"I think it is quite important that we have very productive crosstalk between the endocrinologist and nuclear medicine doctors to make sure we understand their points of view and what they can bring to bear for the optimal management of thyroid cancer patients," first author R. Michael Tuttle, MD, professor of medicine, and clinical director of the Endocrinology Service at Memorial Sloan Kettering Cancer Center in New York City, told Medscape Medical News.

To Give RAI Routinely or Not?

Among the key points of debate was whether patients should routinely receive RAI therapy after total thyroidectomy or if RAI therapy should be based more on a case-by-case decision, Tuttle said.

"The primary areas of contention related to whether or not some low risk and some intermediate risk thyroid cancer patients should be routinely given radioactive iodine therapy after total thyroidectomy," he explained.

"The European nuclear medicine doctors preferred a rather routine use in these low and intermediate risk patients (as opposed to) the American [ATA] more permissive approach," which states that either giving or not giving radioactive iodine can be equally appropriate.

The resulting principles from the meeting, in addition to calling for a continued collaboration, focus on points including distinguishing the specific goals of RAI therapy, clarifying the role of postoperative disease status — as well as factors beyond staging — in RAI therapy decision-making, and acknowledging the lack of evidence on the optimal I-131 dose in adjuvant treatment, as well as shortcomings in definitive evidence of what constitutes RAI-refractory disease.

Refining Postoperative Disease Assessment — and Looking Beyond

The concerns about treatment after thyroidectomy are addressed in three of the principles on the role of postoperative disease status in optimizing patient selection for RAI therapy, with one principle calling for better standardization in postoperative evaluations and their integration into routine clinical care.

Such standardization is necessary because of numerous issues, including varying results that can come from assessments such as neck ultrasound assessment — which is operator-dependent — and varying thyroglobulin (Tg) measures, which can differ according to the type of assay used, the joint statement notes.

Importantly, however, multiple factors beyond postoperative disease status are necessary to determine optimal patient selection for RAI therapy, another principle notes.

The authors point to a meta-analysis (Endocrinol Metab Clin North Am. 2008;37:457-480) that showed studies on the issue are inconsistent, and "the variability of...findings indicate that large and important sources of heterogeneity exist in patient selection and therapeutic effectiveness" of RAI therapy.

"Some authors report a benefit of giving I-131 even to patients with nonmetastasized microcarcinomas, whereas other groups find no benefit," the joint statement indicates.

Focus on Likelihood of Tumor Response to I-131

The principles further address the issue of uncertainties in I-131 dosing for adjuvant treatment, concluding that with evidence currently insufficient to definitively determine an optimal dose, recommendations for dosing should only be made based on a multidisciplinary team management decision.

And given the significant differences in criteria that constitute an I-131 refractory status, current definitions are "suboptimal," the authors assert, and the principles therefore suggest focusing instead on the likelihood of tumor response.

"Characteristics that used to classify patients as I-131 refractory should be used to risk stratify patients with regard to the likelihood that a tumor will respond to I-131 therapy and not necessarily as definitive criteria to mandate whether I-131 therapy should be recommended," the report states.

While the joint statement provides several clinical scenarios of a possible I-131-refractory status, the authors underscore that there is currently no definition, classification, or clinical scenario that is an absolute indicator that a patient has I-131-refractory DTC.

"Simply because a patient fits a particular clinical scenario does not mean that this patient's DTC should be absolutely defined or labeled as I-131 refractory but rather conveys the likelihood that a tumor will be refractory to additional I-131 therapy," they state.

"Each patient should be managed individually with a thorough understanding of the many factors that enter into the appraisal of the likelihood that a tumor will be refractory to I-131, as well as weighing the patient's specific clinical scenario and the risks and benefits of I-131 therapy."

Indolent Nature of DTC Hinders Long-Term Research

An important factor behind much of the debate over RAI therapy in the management of DTC is that the slow-growing nature of the disease makes conclusive evidence difficult to obtain, the authors point out.

"It is the comparatively indolent behavior and high survival rates of most DTCs that make prospective studies that address important oncological outcomes (eg, disease specific or overall survival) difficult if not impossible to perform," the report concludes.

"While the Martinique Principles provide a framework for many important management issues in DTC, ongoing discussions will be required to address many of the specifics that arise as one considers implementing these principles in clinical practice."

Knowledge of Nuances of Nuclear Medicine Important in Utilization

In the meantime, the debate highlights a broader issue regarding the need for a stepped-up focus on nuclear medicine in thyroid care, Tuttle stressed.

"Nuclear medicine has certainly changed over the last 10 to 20 years, and I think it really is time to re-evaluate what nuclear medicine can bring to the table for both diagnostic and therapeutic purposes," he said.

Referring to the Martinique summit, he noted: "I certainly learned a lot about the nuances of radioactive iodine scanning that I had underappreciated before."

That increased understanding has resulted in more effective utilization of radioactive iodine, Tuttle added.

"I do think a lack of knowledge, at least on my part, about some of the intricacies of nuclear medicine may have contributed to an underutilization of radioactive iodine imaging in some of my patients," he acknowledged.

No funding was received for the report. Tuttle has reported no relevant financial relationships.

Thyroid. 2019;29:461-470. Full text

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