Thyroid disorders in childhood cancer survivors treated with 131 I-MIBG, TKIs or immune checkpoint inhibitors: incidence, mechanisms and clinical management – systematic review

Sarah Allaert; Anne Rochtus; Brigitte Decallonne

Background: The thyroid gland is a common unintended target during and after cancer treatment in childhood cancer survivors. However, only a limited number of studies have assessed thyroid adverse events of newer or more selective anticancer drugs. The main objectives of this review are to provide an overview of thyroid disorders in children, treated with 131 I-metaiodobenzylguanidine (131 I-MIBG), tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), to provide an understanding of the pathophysiological mechanisms behind the associated thyroid disorders, and to provide practical guidance regarding screening, follow-up and treatment options.

Methods: We performed a systematic review using Medline, Embase, Cochrane and clinicaltrials.org by means of the PRISMA guidelines.

Results: Fifty-four studies met the eligibility criteria for inclusion. The Table below summarizes the therapies with their mechanisms of actions. Hypothyroidism was the most frequent thyroid disorder with an incidence ranging from 35 to 81% for 131 I-MIBG. Thyrotoxicosis was usually a transient phase of thyroiditis, related to TKIs and ICIs. ICI-treated children were more sensitive for central hypothyroidism and 131 I-MIBG was associated with highest incidence of thyroid nodules. In general, time of onset was longer for 131 I-MIBG (years) compared with TKIs and ICIs (weeks to months).


Therapy	Target	Childhood cancers	Mechanism of action	Secondary effects
131 I-MIBG	Neural crest cells	Recurrent neuroblastoma and metastatic pheochromocytoma	Local radiation after dissociation of 131 I	Anemia, hypothyroidism (35-82%), thyroid nodules (21-56%), sialadenitis, nausea
TKI	TK binding site of ATP	Chronic myeloid leukemia, Philadelphia positive acute lymphatic leukemia, unresectable or metastatic solid tumors and specific metastatic thyroid cancers	Inhibition of (de)phosphorylation of ATP and downstream pathways resulting in apoptosis and blockade of cell proliferation, differentiation, angiogenesis etc.	Hematologic toxicity, skin rashes, diarrhea, nausea, hepatotoxicity, transient thyrotoxicosis (2%), central hypothyroidism (2%)
ICI: anti-CTLA-4, anti-PD1 & anti-PD-L1	Immune checkpoint receptors or ligands	Melanoma, advanced solid tumors and refractory classic Hodgkin Lymphoma	Reactivation of anti-tumor immune responses by eliminating the inhibition of T cell activity	Immune-related adverse event: pneumonitis, colitis, hepatitis, neuropathies, transient thyrotoxicosis (3%), central hypothyroidism (3-5%)

Conclusion: Despite the limited data, thyroid disorders appear to occur frequently in childhood cancer survivors treated with 131 I-MIBG, TKIs or ICIs. Thyroid function monitoring is therefore recommended. We provide a practical guidance for surveillance of the thyroid function for the clinician taking care of childhood cancer survivors.

ESPE Abstracts

RFC12.3