Year in review: Five studies changing thyroidology practice

ByRegina Schaffer

In an update on notable, recently conducted thyroid studies, a speaker reviewed the latest treatments and imaging modalities for children and adults that have the potential to change thyroidology practice.

Megan R. Haymart

“As a clinician-researcher, I focused on studies that are novel and potentially practice-changing,” Megan R. Haymart, MD, professor of medicine, metabolism, endocrinology and diabetes and the Nancy Wigginton Endocrinology Research Professor of Thyroid Cancer at the University of Michigan and Endocrine Today Editorial Board Member, told Healio. “There were many fantastic publications between November 2019 and August 2021, but these five stood out. Two of the publications focus on new or more tailored treatment options for select patients, and three of the publications challenge current practice paradigms and/or suggest a need for new research directions.”

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In a literature review presented at the American Thyroid Association annual meeting, Haymart highlighted clinical research on thyroid disease published between November 2019 and August 2021. Meta-analyses, reviews, consensus statements and guidelines were excluded, as were manuscripts that focused on surgery and procedures.

Selpercatinib for medullary thyroid cancer

As Healio reported, researchers reported in August 2020 that selpercatinib (Retevmo, Eli Lilly), a highly selective anti-RET kinase inhibitor, was effective and safe for adults with RET-altered medullary thyroid cancer (MTC).

Selpercatinib was administered orally in 28-day cycles; phase 2 enrollees received 160 mg twice daily. The cohort included participants with RET-mutant MTC who received prior treatment with (n = 55) or without (n = 88) the multikinase inhibitors vandetanib (Caprelsa, Sanofi Genzyme) and/or cabozantinib (Cometriq/Cabometyx, Exelixis), as well as among patients with previously treated RET fusion-positive thyroid cancer (n = 19). Primary endpoint was complete or partial response; secondary endpoints were duration of response, progression-free survival (PFS) and safety.

Among the 55 participants with RET-mutant MTC, those previously treated with vandetanib and/or cabozantinib showed an objective response rate of 69% (95% CI, 55-81), with a 1-year PFS rate of 82% (95% CI, 69-90). Among those with RET-mutant MTC who did not receive prior treatment, 73% (95% CI, 62-82) achieved an objective response, with a 1-year PFS rate of 92% (95% CI, 82-97).

Haymart noted that most related adverse events were grade 1 or 2; the most common grade 3 or 4 adverse events were hypertension (21%), increased alanine transaminase (11%) and increased aspartate transaminase (9%). Treatment discontinuation due to treatment-related adverse events occurred in only 2% of participants, she said.

Based on the results, published in The New England Journal of Medicine, the FDA granted accelerated approval to selpercatinib for adults and children aged 12 years and older with advanced or metastatic RET-mutant MTC who require systemic therapy and adults and children aged 12 years and older with advanced or metastatic RET fusion-positive thyroid cancer that requires systemic therapy and has stopped responding to or is not appropriate for radioactive iodine therapy.

“This is a clinically important study that suggests there may be treatment options with excellent risk-benefit ratios for select patients,” Haymart said.

Teprotumumab for thyroid eye disease

Adults with thyroid eye disease assigned the human monoclonal antibody teprotumumab-trbw (Tepezza, Horizon Therapeutics) were significantly more likely to experience a meaningful improvement in proptosis after 21 weeks of treatment compared with those who received placebo, according to findings from a randomized controlled trial published in The New England Journal of Medicine.

As Healio reported in January 2020 , adults with Graves’ disease and active, moderate to severe thyroid eye disease were assigned an IV infusion of teprotumumab (n = 41) or placebo (n = 42) once every 3 weeks for 21 weeks. Primary outcome was reduction in proptosis of at least 2 mm at 24 weeks. Within the cohort, 82% of participants treated with teprotumumab had proptosis response vs. 10% in the placebo group (P < .001).

The FDA approved teprotumumab for the treatment of adults with thyroid eye disease in January 2020, marking the first drug approved for the condition.

“Again, when you think about risk vs. benefits, there was an excellent response, and most adverse events were grade 1 or 2,” Haymart said. “This is another therapeutic option, and it may change clinical practice.”

Risks with overtreatment during pregnancy

A cohort of pregnant women in Canada who were overtreated for hypothyroidism with levothyroxine were more likely to have a preterm delivery than women with normal thyroid-stimulating hormone, according to a study published in Thyroid.

As Healio reported, the goal of the retrospective study was to determine testing and treatment patterns and relationships between over- and undertreatment with adverse pregnancy outcomes among women prescribed thyroid hormone replacement. Researchers used multiple logistic regression analysis to determine if a TSH level of less than 0.1 mIU/L (overtreatment) or at least 10 mIU/L (undertreatment) was associated with adverse pregnancy or neonatal outcomes.

Researchers found that pregnant women with at least one TSH measurement of less than 0.1 mIU/L (n = 351 pregnancies) were more than twice as likely to experience preterm delivery vs. controls (OR = 2.14; 95% CI, 1.51-2.78). Undertreatment was not associated with adverse pregnancy or neonatal outcomes.

“This is a manuscript that resonated with me because it made me question some of my practices,” Haymart said. “This could be practice-changing or at least stimulate additional studies.”

Thyroid imaging in children

The thyroid imaging reporting and data system (TI-RADS) of ultrasound scoring has not been previously validated in pediatric patients, Haymart said. A retrospective analysis published in Radiology in 2020 assessed data from 314 children (mean age, 15 years; 82.8% girls) from a single center who underwent fine-needle aspiration biopsy between 2004 and 2017; the number of nodules that would be biopsied based on TI-RADS was compared with the number of nodules biopsied in clinic. Researchers observed that 19.1% of nodules were malignant and the use of TI-RADS alone would have missed 22% of cancers (17 of 77), Haymart said.

“A limitation of this was the retrospective design; TI-RADS was bound to fail,” Haymart said. “But there is a signal from this [study] that suggests additional work is needed. Maybe we need to think about modifications to TI-RADS for children.”

Race disparities in hypothyroidism treatment

A study published in the Journal of the Endocrine Society in March analyzed data from adults who underwent thyroid function testing as part of the 2007-2012 waves of the National Health and Nutrition Examination Survey and had hypothyroidism (n = 698). Within the cohort, 536 adults were treated, 115 were untreated with subclinical hypothyroidism and 47 were untreated with clinical hypothyroidism. Researchers stratified participants as undertreated (TSH > 5.6 mIU/L), overtreated (TSH < 0.3 mIU/L) and adequately treated. Within the cohort, 10.4% were undertreated and 12.7% were overtreated.

“I chose this because most of the disparities research done today focuses on thyroid cancer and thyroid surgery, and a lot of it has been conducted by our surgical colleagues,” Haymart said. “There is more work that can be done in thyroid function, in thyroid and pregnancy and in other areas of thyroid.”

Researchers found male sex, age younger than 45 years and lack of access to routine health care was associated with lack of treatment with thyroid hormone; race, income level and education level were not associated with treatment, Haymart said. However, in multivariate regression analyses combining over- and undertreated adults, Hispanic race was associated with increased risk for inadequate treatment compared with non-Hispanic white adults (OR = 2.42; 95% CI, 1.14-5.14).

“Why is this clinically important?” Haymart said. “First, further work is needed to understand if downstream, Hispanic adults are experiencing adverse outcomes or events because of this; more osteoporosis or arrythmia. Are young women who are pregnant experiencing more adverse pregnancy outcomes related to under- or overtreatment? Are there systemic-level barriers that we are unaware of? Are there issues with patient-physician communication? This suggests an area for future research.”