Discussion
While disease-specific mortality for pediatric patients with DTC is very low, and surgery with adjuvant RAI is curative for most patients, approaches are not without associated toxicity. The American Thyroid Association has recommended selective use of RAI in children with DTC, including those with distant metastases which occurs in upwards of 30% of patients.10-12 Early toxicities of RAI administration in children can include radiation thyroiditis, xerostomia and transient bone marrow suppression, with late complications of permanent salivary gland dysfunction, bone marrow suppression, pulmonary fibrosis, and secondary cancers.13 Furthermore, no standard limit for cumulative RAI therapy in pediatrics exists.14 Consideration of usage and appropriate timing of alternative therapeutic approaches may not be needed to decrease mortality, but may reduce morbidity and improve quality of life in patients with DTC.
RET fusions retaining the kinase domain are drivers of PTC withCCDC6-RET and NCOA4-RET reported as the most common rearrangements.15 Inhibition of RET was previously achieved by multi-tyrosine kinase inhibitors such as lenvatinib and cabozantinib, but the emergence of selective RET-inhibitors has provided a targeted approach with a potentially reduced side effect profile.16,17 In our patient with metastatic PTC who was not achieving desired response to repeated doses of RAI, discovery of a NCOA4-RET fusion allowed for initiation of systemic therapy with selpercatinib, which quickly provided clinical, radiographic, and biochemical response. She has not experienced the more common selpercatinib-related adverse events, such as hypertension, transaminitis, diarrhea or constipation,5-9 but was noted to have weight gain which while likely multifactorial, has been reported with selpercatinib18 and was deemed to be possibly related to medication use.
Our patient’s treatment response has continued despite two dose reductions of selpercatinib, allowing us to minimize possible associated toxicity without compromising efficacy. Given the chronic need for targeted therapy without knowledge of long-term side effects, understanding the minimal dose required for desired effect is of utmost importance. More precise administration of tyrosine kinase inhibitors is being studied, and it is proposed that the wider therapeutic index of targeted agents may allow for pediatric dosing to be less than the maximum tolerated dose documented in adults.19 In summation, a better understanding of the molecular landscape of pediatric PTC offered an effective systemic treatment modality, and we will continue to closely observe the dose response in our patient.