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.