Highlights
- More than half (53%) of high-risk neuroblastoma (HRNB) survivors develop long-term thyroid toxicities, with hypothyroidism being the most prevalent manifestation.
- The median time to the onset of thyroid dysfunction is 7.5 years post-diagnosis, though toxicities can emerge nearly two decades later.
- Exposure to 131I-meta-iodobenzylguanidine (131I-MIBG) molecular radiotherapy, tandem myeloablative therapy (MAT), and immunotherapy significantly increases the risk and accelerates the onset of toxicity.
- Busulfan-based conditioning regimens are associated with a significantly higher incidence and earlier onset of thyroid dysfunction compared to alternative treatments.
Background
Neuroblastoma is the most common extracranial solid tumor in childhood, characterized by its clinical heterogeneity. High-risk neuroblastoma (HRNB) requires an intensive, multimodal therapeutic approach, including induction chemotherapy, surgical resection, myeloablative chemotherapy (MAT) followed by autologous stem cell rescue, local radiotherapy, and maintenance therapy with immunotherapy and differentiating agents. While these advancements have significantly improved survival rates, the intensity of the treatment has introduced a growing population of survivors at risk for late-onset complications.
Among these long-term sequelae, endocrine morbidities—specifically thyroid dysfunction—represent a major concern. The thyroid gland is particularly vulnerable to both systemic chemotherapy and targeted radiation. Understanding the specific risk factors and the temporal progression of thyroid toxicity is essential for refining follow-up protocols and improving the quality of life for HRNB survivors as they transition into adulthood.
Key Content
Study Overview and Incidence of Toxicity
A retrospective single-center cohort study led by Deodati et al. (2026) evaluated 45 survivors of HRNB who were at least five years post-diagnosis (median follow-up of 10.6 years, range 5–25.8 years). The study revealed that thyroid toxicities are remarkably common, affecting 53% of the cohort. The probability of remaining free from thyroid toxicity at 10 years was estimated at 62% (CI: 44–75%), highlighting a steady decline in glandular health over time. Hypothyroidism accounted for 50% of the reported toxicities, marking it as the primary clinical concern in this population.
Evidence by Therapeutic Class and Intervention
The research identified several critical therapeutic drivers of thyroid dysfunction, allowing for a stratified understanding of risk:
1. Molecular Radiotherapy (131I-MIBG)
The most profound risk factor identified was the use of 131I-meta-iodobenzylguanidine. Patients who underwent molecular radiotherapy had a 0% probability of being free from thyroid toxicity at the 10-year mark, compared to 72% (CI: 53–85%) in those who did not receive this treatment (p < 0.001). Despite thyroid protection protocols during administration, the cumulative dose of systemic radiation appears to cause nearly universal long-term damage to the thyroid parenchyma.
2. Myeloablative Therapy (MAT) and Conditioning Regimens
The intensity and type of conditioning for stem cell transplant significantly influenced outcomes:
- Tandem vs. Single MAT: Children treated with tandem MAT showed a significantly lower toxicity-free probability (37%, CI: 12–64%) compared to those who underwent a single MAT procedure (71%, CI: 49–85%, p = 0.016).
- Busulfan Exposure: The use of Busulfan was a strong predictor of both frequency and speed of toxicity onset. Survivors who did not receive Busulfan had an 86% probability of remaining toxicity-free, whereas that probability dropped to 55% for those who did (p = 0.002). Furthermore, Busulfan exposure was associated with significantly earlier onset of thyroid issues (p = 0.047).
3. Immunotherapy
Interestingly, the study identified immunotherapy as a modern risk factor. Patients receiving immunotherapy (typically anti-GD2 antibodies) had a 30% probability of remaining free from thyroid toxicity at 10 years, compared to 78% in those who did not (p = 0.008). This finding suggests that while immunotherapy is less traditionally “toxic” than chemotherapy, its role in the multimodal landscape may synergize with previous treatments to exacerbate endocrine damage.
Temporal Progression and Onset Dynamics
The median time from diagnosis to the report of thyroid toxicity was 7.5 years, with an interquartile range of 3 to 12 years. However, the study recorded new cases of toxicity as late as 18.2 years post-diagnosis. Patients exposed to the most aggressive modalities—namely immunotherapy, 131I-MIBG, and Busulfan—experienced these complications significantly earlier than their counterparts, suggesting a dose-response or intensity-response relationship regarding the speed of glandular failure.
Expert Commentary
The findings by Deodati et al. underscore a critical paradigm shift in pediatric oncology: survival is no longer the sole metric of success. The high cumulative treatment burden required to cure HRNB creates a “late-effect legacy.” The near-universal toxicity seen with 131I-MIBG suggests that current thyroid protection strategies (such as Lugol’s solution or potassium iodide) may be insufficient to prevent long-term damage, even if they mitigate acute thyroiditis.
The association of immunotherapy with thyroid toxicity is particularly provocative. While the mechanism isn’t fully elucidated, it is possible that the immune activation associated with anti-GD2 therapy may trigger subclinical autoimmune thyroiditis in a gland already sensitized by chemotherapy or radiation. Clinicians should be aware that as immunotherapy becomes a standard of care, the incidence of late-onset endocrine issues may increase rather than decrease.
Furthermore, the data regarding tandem MAT and Busulfan reinforces the need for “risk-stratified follow-up.” A child who has undergone tandem transplants and MIBG therapy should be considered “ultra-high risk” for endocrine failure and should likely undergo more frequent biochemical screening (TSH and free T4) than a survivor of lower-intensity protocols.
Conclusion
Survivors of high-risk neuroblastoma face a substantial and prolonged risk of thyroid toxicity, predominantly hypothyroidism, which can manifest many years after the completion of therapy. Molecular radiotherapy with 131I-MIBG, tandem MAT, and Busulfan are the primary drivers of this burden, with immunotherapy emerging as a significant contributing factor. These findings mandate the implementation of rigorous, lifelong endocrine surveillance that extends well into adulthood. Future research should focus on optimizing thyroid protection during high-risk treatments and establishing standardized guidelines for the transition of care from pediatric oncology to adult primary care and endocrinology.
References
- Deodati A, Fabozzi F, Mirra G, Cefalo MG, Del Bufalo F, D’Antonio F, Grossi A, Pampanini V, Pizzoferro M, Serra A, Ubertini G, Mastronuzzi A, Cianfarani S, Locatelli F, De Ioris MA. Long-Term Thyroid Toxicity Burden in Children Who Received Treatment for High-Risk Neuroblastoma. Thyroid. 2026 Feb 24. doi: 10.1089/thy.2023.0568. PMID: 41735800.