Abstract
KEY POINTS
Current treatment of high-risk neuroblastoma (HRNB) has improved long-term survival outcomes, but the increased risk for subsequent late toxicities, including both thyroid dysfunction and secondary thyroid malignancy, has not been fully elucidated.
In this retrospective cohort study of pediatric HRNB survivors, thyroid toxicities occurred in 53% of patients after a median of 7.5 years, with toxicity reported in 24 of 45 patients (53%) at a median of 7.5 years, generally occurring early in patients treated with immunotherapy, 131I-meta-iodobenzylguanidine therapy, or busulfan.
At a median follow-up of 10.6 years after diagnosis, 37% had one or more thyroid nodules.
These data help in understanding the long-term risk of thyroid toxicity in patients treated for HRNB and provide insights into the risk factors and timing of thyroid disease.
SUMMARY
Background
Neuroblastoma is the most common extracranial solid tumor in children. About 35% of patients present initially with high-risk disease. Treatment of high-risk neuroblastoma (HRNB) includes a combination of therapies that together have improved long-term survival outcomes. However, aggressive therapeutic strategies increase the risk for subsequent late effects and toxicities, particularly the development of thyroid sequelae, including thyroid dysfunction or a secondary thyroid malignancy. This study aimed to evaluate the incidence of, and risk factors associated with, long-term thyroid toxicity in HRNB survivors. 1
Methods
This was a retrospective cohort study of pediatric cancer survivors who were diagnosed with and treated for HRNB at a tertiary medical center in Italy. Included patients had been followed for at least 5 years from the time of diagnosis. Patients had serum thyroid function (TSH and FT4) and thyroid ultrasound imaging assessed annually. Data on chemotherapy regimens, 131I-meta-iodobenzylguanidine (131I-MIBG) therapy (including the number of scans and assessment of thyroid visualization), immunotherapy, surgery, and radiotherapy were collected. Thyroid toxicity was defined as the occurrence of overt hypothyroidism (elevated TSH [reference range, 0.51–4.30 mIU/mL] combined with low FT4 [reference range, 0.98–1.64 ng/dL]), overt hyperthyroidism (low TSH combined with high FT4), thyroid nodules, or thyroid carcinoma. Only late treatment-related toxicities were considered.
Results
This study reviewed 45 long-term HRNB survivors, a median of 10.6 years after diagnosis (range, 5.0–25.8), with a median age at last follow-up of 13.3 years (range, 7.5–27.0). Long-term thyroid toxicity was noted in 24 of 45 patients (53%) at a median of 7.5 years from diagnosis (range, 1.2–18.2). Primary hypothyroidism was diagnosed in 12 of 24 affected patients. On thyroid ultrasound, 11 of 24 patients (45%) were noted to have reduced thyroid volumes, and 9 patients (37%) had one or more thyroid nodules that measured between 0.6 and 1.4 cm. One patient was diagnosed with papillary thyroid carcinoma 10 years after their neuroblastoma diagnosis; their HRNB treatment included chemotherapy, though no history of cervical radiotherapy or 131I-MIBG. The 10-year probability of remaining free from thyroid toxicity was 62% (95% CI, 44–75). Statistically significant differences in the probability of survival free from thyroid toxicity were noted to be statistically lower in patients who had been treated with immunotherapy, treated with 131I-MIBG, treated with tandem myeloablative chemotherapy (MAT; compared to single MAT), or treated with busulfan. Although only tandem MAT demonstrated a statistically significant association with the occurrence of thyroid toxicity (p = 0.019), time to analysis events noted a significantly earlier appearance of thyroid toxicities in those treated with immunotherapy, 131I-MIBG, or busulfan.
Conclusions
HRNB survivors are at an increased risk for thyroid abnormalities. Long-term endocrine surveillance of HRNB survivors is important to identify the development of thyroid dysfunction and/or thyroid nodules.
COMMENTARY
Advances in treatment strategies and the development of novel therapies have led to impressive increases in the number of childhood cancer survivors in recent decades. Consequently, approximately half of survivors will experience at least one endocrine complication over the course of their lifetime. 2 Management goals continue to aim to improve cure rates while decreasing both short- and long-term treatment burden.
In the past, HRNB was considered one of the most lethal pediatric malignancies. As a result, past studies of childhood cancer survivors included few survivors of HRNB. 3 Since the year 2000, however, disease-free survival rates have improved significantly for these patients owing to an intensive multimodal treatment strategy of therapies including chemotherapy, surgery, stem-cell transplantation, radiotherapy, and additional maintenance therapies. 4 More patients are now at risk for late toxicities and the development of chronic conditions.
The study by Deodati et al. identified a high rate of long-term thyroid toxicities, which included thyroid dysfunction (50%), thyroid nodules (37%), and in one instance, thyroid cancer. These results are similar to those reported in a previous study of 51 children with HRNB from a different institution, which also identified that just over half of children developed subsequent hypothyroidism after completion of treatment. 3 Both of these studies report higher rates of thyroid toxicities as compared to the rate of hypothyroidism reported in a larger cohort of HRNB survivors from the Children’s Oncology Group (the LEAHRN study). 5 In this LEAHRN study, whereas only 22% of patients were identified as having hypothyroidism, thyroid dysfunction was assessed as a one-time screening of eligible patients, and previous screening strategies were not reviewed.
Deodati et al. acknowledge their small cohort size as a study limitation; however, their more detailed longitudinal assessment of thyroid sequelae is a valuable contribution. This study further increases awareness about the risk of endocrinopathies in this patient population and highlights the important role of dedicated endocrine screening and management as the population of cancer survivors ages and grows over time.