New approaches for patients with advanced radioiodine-refractory thyroid cancer

Abstract

The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient’s features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.

Molecular features of aggressive thyroid cancer

“…RAI refractoriness can be defined by different scenarios, such as the absence of RAI uptake at the initial whole body scan (WBS) or in metastatic lesions, or the loss of the capacity to uptake RAI after a previous WBS showing avidly uptake RAI metastases; a progression of the disease in a subject who has previously received RAI, or a cumulative activity of 600 mCi of 131 I; the presence of locally advanced disease that cannot be treated by surgery or evaluated by RAI uptake ( 95 , 96 ). Genetic and epigenetic alterations in the RTK/BRAF/MAPK/ERK and PI3K-AKT-mTOR pathways underly the diminished NIS signalling/activity that lead to RAI refractoriness and to a more aggressive behaviour ( 97 ): their identification can be useful to investigate new compounds able to act against these aberrant molecular mechanisms overcoming the standard cancer therapy resistance.…”

Prognostic factors to predict the efficacy of surgical interventions against brain metastasis secondary to thyroid cancer

“…found that the TKI agent significantly increased survival in 12 patients ( 25 ). Recently, the effect of selective kinase inhibitors on diverse DTC targets has been reported ( 26 ). Variable percentages of DTC patients (2–25%) have been reported to have neurotrophic tropomyosin receptor kinase (NTRK) fusions ( 27 ).…”

“…Pitoia reported a complete response to larotrectinib in a patient with RAI refractory DTC who had a rapid progression on TKI therapy and the disappearance of multiple brain metastases ( 29 ). Additionally, it is known that 5–25% of DTCs contain RET rearrangements ( 26 ). In the open-label, phase 1/2 clinical trial, 20 RET-fusion-positive thyroid cancer patients were included, showing an overall response rate (ORR) of 89% ( 30 ).…”

Real-world Treatment Patterns and Clinical Outcomes in Patients With Radioiodine-refractory Differentiated Thyroid Cancer (Rai-r Dtc) Treated With First Line Lenvatinib Monotherapy in the United States

“…In our study cohort, the median rwPFS was estimated to be 49 months, and more than half of the patients were expected to be alive past 6 years. Previous real-world studies of lenvatinib conducted in the US and other countries reported median PFS ranging from 10 to 35 months, although there could be differences in the patient populations as some of these studies included patients with more than one prior multi-kinase inhibitor treatments [14][15][16].…”