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Revista chilena de pediatría

versión impresa ISSN 0370-4106

Rev. chil. pediatr. vol.91 no.3 Santiago jun. 2020

http://dx.doi.org/10.32641/rchped.v91i3.1237 

ORIGINAL ARTICLE

Thyroid dysfunction due to 131I-metaiodobenzylguanidine in patients with neuroblastoma

Eulalia Garrido Magaña1 

Jorge Alberto Silva Estrada2 

Elisa Nishimura Meguro1 

Aleida de Jesús Rivera Hernández1 

Jessie Nallely Zurita Cruz3  4 

1 Pediatric Endocrinology Division, UMAE Hospital de Pediatría Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.

2 Pediatrid Division, Hospital Central Sur de Alta Especialidad de Petróleos Mexicanos (PEMEX), Ciudad de México, México.

3 Facultad de Medicina, Universidad Nacional Autónoma de México, México.

4 Hospital Infantil de México Federico Gómez, Secretaria de Salud. México.

Abstract:

Introduction:

The treatment of advanced neuroblastoma includes chemotherapy, surgery, and radiotherapy with 131-I-Metaiodobenzylguanidine (131-I-MIBG). Despite strategies to protect thyroid function, its dysfunction is reported between 12 and 85%.

Objective:

To identify the frequency of thyroid dys function in cases of neuroblastoma treated with 131-I-MIBG.

Patients and Method:

Cross-sectional study. We included all the cases with neuroblastoma treated with 131-I-MIBG between 2002 and 2015, with complete somatometry, and complete thyroid profile (TSH, free and total T3 and T4, and anti-thyroglobulin and antiperoxidase antibodies).

Results:

27 patients were identified out of which eleven died (40%). Out of the 16 surviving cases, 9 (56%) presented thyroid dysfunction: 2 (13%) cases with subclinical hypothyroidism and 7 (44%) cases with clinical hypothyroidism (3 cases due to psychomotor developmental delay and 4 due to growth deceleration). The patients presented cli nical manifestations at 16.1 months (1.2-66.3 months) after receiving the radiopharmaceutical at acumulative dose of 142 mCi (96-391.5 mCi). No differences were found in the age at diagnosis, age at the start of treatment with 131-I-MIBG, the cumulative dose of 131-I-MIBG, and the time elapsed between the dose and the thyroid profile among the cases with or without thyroid dysfunction.

Con clusions:

56% of patients with neuroblastoma had thyroid dysfunction. Most of the cases with hypothyroidism were referred when thyroid dysfunction was clinically evident. A thyroid profile should be performed every 6 months, along with an annual endocrinological evaluation during the next 5 years in these patients.

Keywords: Neuroblastoma; hypothyroidism; thyroid; chemotherapy; Metaiodo benzylguanidine

What do we know about the subject matter of this study?

In patients with neuroblastoma, thyroid dysfunction following I131- MIBG therapy is a common complication. Inadequate follow-up can have serious consequences, including neurodevelopmental de lay.

What does this study contribute to what is already known?

The frequency of hypothyroidism after I131-MIBG therapy was 56%. Thyroid profile should be performed twice a year and evaluated annually by a pediatric endocrinologist during the first 5 years after the diagnosis of neuroblastoma.

Introduction

Neuroblastoma is an embryonal tumor of the peri pheral sympathetic nervous system. It is the most com mon extracranial solid tumor in children and shows a very heterogeneous biological and clinical behavior1.

Worldwide, it presents an incidence of 7 to 14 cases per million children per year2, whereas in Mexico bet ween 1995 and 2005, it was reported an incidence of 3.8 cases per million children per year in a population with health insurance3. In 80% of the cases the age at presentation is under 4 years2,4.

In a study conducted in Mexico between 1996 and 2001, it was determined that 70% of patients admit ted with neuroblastoma presented advanced stages (III and IV) at diagnosis, with a survival of 27% at 5 years5.

Treatment for advanced stages is multidisciplinary, including chemotherapy, surgery, radiation therapy, and I131-metaiodobenzylguanidine (I131-MIBG) therapy6, a radioisotope used for diagnostic and therapeutic purposes6,7.

MIBG is a guanethidine derivative and a norepine phrine analog with specific affinity towards the cells in the neural crest. Neuroblastoma cells express the no repinephrine transporter. Hence, when MIBG is mar ked with Iodine-131, neuroblastoma cells are selectively targeted and destroyed by the radioisotope, adding effectiveness to the induction, consolidation, and re lapse chemotherapy regimens8,9 with response rates for refractory disease that range from 20% to 40%7.

This radiopharmaceutical has presented short- and long-term adverse effects such as nausea, vomiting10, hepatotoxicity11, myelotoxicity, thyroid dysfunction, and second neoplasms14.

The thyroid dysfunction after I131-MIBG treatment ranges from 12% to 85%, depending on the therapeutic protocols and the grade of blockage of thyroid function12,15,16,17. Multiple studies have shown that, des pite performing thyroid blockage with oral stable io dine, thyroid dysfunction presents a high incidence15.

Patients with neuroblastoma have factors inherent to the treatment received (chemotherapy, radiothera py, I131-MIBG therapy) that increase the risk of thyroid disease, therefore, the early identification of the dys function is essential for hormone replacement and follow-up.

In addition, the risk of developing a second ma lignancy, such as leukemia, thyroid cancer, rhabdomyosarcoma, or schwannoma, is 20% higher than the general population and they can occur up to 10 years later14.

There are very few studies reporting the inciden ce of thyroid dysfunction in patients with neuroblastoma and their results are highly variable. Therefore, the objective of our study was to identify the frequency of thyroid dysfunction in neuroblastoma patients who received I131-MIBG at therapeutic doses.

Patients and Methods

Design

Between January 2012 and December 2015, we conducted a cross-sectional study in a tertiary referral pediatric hospital. We identified in the hospital databa se all pediatric patients with neuroblastoma who were diagnosed according to the histopathological study performed at disease onset and that received I131-MIBG as part of their treatment in January 2012 to Decem ber 2015 period. Patients with incomplete biochemical studies or who did not agree to participate in the study were excluded. From the medical record, we registered the date of diagnosis, age, initial anthropometry measurement, stage of neuroblastoma, cumulative dose of I131-MIBG, and hormonal studies performed.

In those patients who did not have a thyroid profile after the administration of I131-MIBG, a complete phy sical examination and thyroid profile was performed during the study period.

Chemotherapy protocol

The chemotherapy regimen included Cyclo phosphamide and Epirubicin, alternated with Cisplatin, Ifosfamide, and Etoposide every 3 weeks for a period of 12 months. No patient received cranial radiotherapy. After completing 6 cycles of chemothera py, the therapeutic dose of I131-MIBG was administe red at 100 to 150 mCi/dose. Two days before the administration of I131-MIBG, the patient was prescribed a 1% lugol solution, one drop per kilogram of body weight per day, with a maximum of 40 drops per day, divided into 2 doses, which continued for 5 days after the administration of I131-MIBG therapeutic dose.

Measurement of blood thyroid hormone levels

Through venipuncture sampling, serum thyroid hormone levels were collected between 7 and 8 hours in the morning after 12 hours of fasting. Using elec- trochemiluminescence immunoassay (ECLIA), the following levels were measured: thyroid-stimulating hormone (TSH), total and free triiodothyronine (T3 - FT3), and total and free thyroxine (T4 - FT4). The cobas® 6000 analyzer e601 module (Roche Diagnostics GmbH, Indianapolis, IN, USA) was used according to the manufacturer’s recommendations. The intra- and inter-assay coefficients of variation for all measure ments were < 7%. A standard curve was included in each test.

Diagnosis determined by hormone profile

We defined subclinical hypothyroidism as having high TSH blood levels (between 6 mu/ml and 9.9 mu/ ml) and normal serum levels of thyroid hormones; and hypothyroidism as having serum levels of TSH > 10 mu/ml and normal or low serum levels of thyroid hor mones.

Statistical analysis

We calculated median, minimum, and maximum for the quantitative variables, and for the qualitative oneswe used percentages and frequencies. Mann Whitney’s U was applied to estimate the difference of quantitative variables between patients with and without thyroid dysfunction. P < 0.05 was considered statistically significant. STATA v.12.0 software was used for statistical analysis.

Ethical aspect

The protocol was approved by the Hospital’s Re search and Ethics Committee. The parents signed the informed consent and, if patients were over 8 years old, they signed informed assent according to the recom mendations of the Declaration of Helsinki.

Results

We identified 27 patients, with a median age at diagnosis of neuroblastoma of 8 years (minimum age 1 month and maximum 12 years 9 months). At the time of diagnosis, 33% were in stage III and 67% in stage IV (Table 1).

Table 1 Demographic, diagnostic and treatment characteristics of children with neuroblastoma who received I131-MIBI. 

Regarding the administration of I131-MIBG, the median age of patients receiving the first dose was 3.6 years (minimum 8 months, maximum 13 years). Out of the total patients, 13 (48%) received a single dose of I131-MIBG, 7 (26%) received two doses, 5 patients (19%) received three doses, and 1 patient (4%) recei ved four doses, resulting in a cumulative median dose of 116 mCi (minimum 84, maximum 392 mCi). Out of the 27 patients who received the I131-MIBG, 11 (41%) died, with a median survival of 14 months at a 5-year follow-up, 6 patients died in the first year of diagnosis, and 5 at three years of follow-up (Table 1).

Out of the 16 surviving patients, 8 had no post-I131- MIBG thyroid function tests, thus they were scheduled for laboratory studies and clinical evaluation. 9 of the 16 (56.2%) patients presented an abnormal thyroid profile, which was performed at a median of 16 months after the I131-MIBG dose (minimum 1 month, maxi mum 66 months). The median age at treatment was 3 years (minimum 9 months, maximum 7 years). The median cumulative dose of I131-MIBG was 142 mCi, minimum 96 mCi and maximum 392 mCi (Table 2).

Table 2 Comparison between surviving patients with and without thyroid dysfunction. 

All patients presented hypothyroidism, with a me dian TSH of 75 mU/l (minimum 13.7 and maximum 605). Anti-peroxidase and anti-thyroglobulin antibo dies were negative in all of them.

The 7 survivor euthyroid patients (43.8%) had their thyroid profiles done at 40 months (minimum 14, maximum 100) after the I131-MIBG dose. The me dian cumulative dose was 216 mCi, with a minimum of 84 mCi and a maximum of 223 mCi (Table 2).

Seven out of the 9 children with thyroid dys function presented clinical manifestations before the biochemical diagnosis of hypothyroidism, 3 with de layed psychomotor development, and 4 with stunted growth.

We compared the age at diagnosis of neuroblas toma, the age at the beginning of treatment with I131- MIBG, the cumulative dose of I131-MIBG, and the time elapsed between dose and thyroid profile, without finding statistical differences between cases with or without thyroid dysfunction (Table 2).

Discussion

In our study, we observed that half of the patients with neuroblastoma had thyroid dysfunction and 19% presented neurodevelopmental delay due to a late diagnosis of hypothyroidism.

MIBG does not cause any adverse effect on the thyroid gland, but I131 does. I131-MIBG is excreted almost entirely in urine, however, a percentage is me tabolized by the liver and produces free I131. Consequently, the thyroid will also concentrate radioactive iodine that will lead to thyrocyte destruciton and in crease risk of thyroid tumors19.

Hence the importance of protecting the thyroid gland by administering high doses of oral stable iodi ne which stimulates the Wolff-Chaikoff effect20,21. The Wolff-Chaikoff effect is a self-regulatory mechanism of the thyroid gland when there is a sudden increase in the availability of circulating iodine, causing suppres sion in the response of the thyroid cells to TSH, decre asing the synthesis of thyroglobulin, its iodization and the release of thyroid hormones21.

The recommendations for the management of patients with neuroblastoma treated with I131-MIBG include the administration of oral stable iodine, two days before and up to 10 days after22; however, our pa tients were only treated for 5 days, similar to other case series11,12,15,16,17,23,24,25. Even though the thyroid gland was protected in some degree, we detected 56% of frequen cy of thyroid dysfunction26,27.

In our patients, the average time of detection of hy pothyroidism was 16 months, longer than that repor ted by other studies13. It should be noted that in some cases the diagnosis was made up to 5 years after recei ving the I131-MIBG.

Other drugs can block iodine uptake (oral stable iodine), block the binding of iodine to thyroglobulin (methimazole), decrease iodine uptake (levothyroxine), block the sodium/iodide transporter (perchlorate), and some groups have attempted to perform conjugate blockade with the administration of methimazole and levothyroxine, however, the risk of mye lotoxicity caused by methimazole may outweigh the benefit15.

While the use of multiple drugs to block iodine uptake may improve the chance of not developing hy pothyroidism (although not by 100%), the monothe rapy with only oral stable iodine, may have been a de termining factor in the high number of cases detected in the patients studied.

Chemotherapy may be another mechanism that causes thyroid dysfunction in these patients. Specifica lly, vincristine interferes with the microtubule-micro- filament system of the thyrocyte and inhibits thyroglobulin endocytosis by thyroid cells and thyroid hor mone secretion, while cisplatin has a direct cytotoxic effect on thyrocytes28. In patients with neuroblastoma who were not treated with I131-MIBG doses, whole-body radiotherapy has been reported as a risk factor for hypothyroidism27.

Although we do not have a thyroid profile before the start of chemotherapy and administration of I131- MIBG, all patients had a normal neonatal screening, including thyroid profile, thus we can be sure that none of them had congenital hypothyroidism and that acquired hypothyroidism was secondary to oncologi cal treatment.

Since thyroid hormones have a primary function for adequate global and neurological development du ring the first 2 years of extra-uterine life in humans, their dysfunction can result in growth failure and inte llectual disability29.

According to what has been observed in this series, we recommend that every patient with neuroblastoma should have their thyroid profile done at the beginning and on an annual basis, and whenever therapeutic dose of I131-MIBG is administered, thyroid function should be monitored every six months for up to 5 years after the oncological diagnosis, in order to detect alterations early. It is important to note that in this type of patient, in addition to follow-up for thyroid function, there are other endocrine disorders such as growth hormone de ficiency, hypogonadism, and diabetes, which should be early identified27,30.

As limitations of the study, we consider that a prospective study is required to better assess the factors involved in the development of hypothyroi dism. The sample size is limited, so this should be approached cautiously. Finally, due to its retrospec tive nature, it was not possible to perform serial measurements of the thyroid profile that would allow a stronger association between risk factors and thyroid dysfunction.

Conclusion

In conclusion, the frequency of hypothyroidism fo llowing I131-MIBG administration was 56%. We were unable to identify all factors influencing the develop ment of thyroid dysfunction in children with neuro blastoma, however, inadequate follow-up can have serious consequences, such as neurodevelopmental delay. Therefore, in patients with neuroblastoma, a thyroid profile should be performed every six months and an annual evaluation by a pediatric endocrinolo gist is warranted during the first 5 years after the onco logical diagnosis.

Ethical Responsibilities

Human Beings and animals protection: Disclosure the authors state that the procedures were followed ac cording to the Declaration of Helsinki and the World Medical Association regarding human experimenta tion developed for the medical community.

Data confidentiality: The authors state that they have followed the protocols of their Center and Local regu lations on the publication of patient data.

Rights to privacy and informed consent: The authors have obtained the informed consent of the patients and/or subjects referred to in the article. This docu ment is in the possession of the correspondence author.

Conflicts of Interest: Authors declare no conflict of interest regarding the present study.

Financial Disclosure: Authors state that no economic support has been asso ciated with the present study.

Referencias:

1. Speleman F, Park JR, Henderson TO. Neuroblastoma: A Tough Nut to Crack. Am Soc Clin Oncol Educ B. 2016;35:e548-57. [ Links ]

2. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007;369:2106-20. [ Links ]

3. Palma V, Juárez S, González G, et al. Incidencia y tendencia del neuroblastoma en niños derechohabientes del IMSS. Rev Med Inst Mex Seguro Soc. 2010;48(2):151-8. [ Links ]

4. Marshall GM, Carter DR, Cheung BB, Liu T, Mateos MK, Meyerowitz JG, Weiss WA. The prenatal origins of cancer. Nat Rev Cancer. 2014;14:277-89. [ Links ]

5. López E, Cerecedo F, Rivera H, et al. Neuroblastoma: factores pronósticos y sobrevida. Experiencia en el Hospital de Pediatria del Centro Médico Nacional Siglo XXI y revisión de la literatura. Gac Méd Mex. 2003;139(3):209-14. [ Links ]

6. Newman EA, Nuchtern JG. Recent biologic and genetic advances in neuroblastoma: Implications for diagnostic, risk stratification, and treatment strategies. Semin Pediatr Surg. 2016;25:257-64. [ Links ]

7. Parisi MT, Eslamy H, Park JR, Shulkin BL, Yanik GA. 131I-Metaiodobenzylguanidine Theranostics in Neuroblastoma: Historical Perspectives; Practical Applications. Semin Nucl Med. 2016;46:184-202. [ Links ]

8. Gaze MN, Gains JE, Walker, C Bomani JB. Optimization of molecular radiotherapy with [131I]-meta Iodobenzylguanidine for high-risk neuroblastoma. Q J Nucl Med Mol Imaging. 2013;57(1):66-78. [ Links ]

9. Kraal KC, van Dalen EC, Tytgat GA, Van Eck-Smit VLF. Iodine-131-meta-iodobenzylguanidine therapy for patients with newly diagnosed high-risk neuroblastoma. Cochrane Database Syst Rev. 2017;4:CD010349. [ Links ]

10. Modak S, Pandit-Taskar N, Kushner BH, et al. Transient sialoadenitis: A complication of 131I-metaiodobenzylguanidine therapy. Pediatr Blood Cancer. 2008;50:1271-3. [ Links ]

11. Quach A, Ji L, Mishra V, Sznewajs A, Veatch J, et al. Thyroid and Hepatic Function After High-Dose 131I-Metaiodobenzylguanidine (131I-MIBG) Therapy for Neuroblastoma. Pediatr Blood Cancer. 2011;56:191-201. [ Links ]

12. van Santen HM, de Kraker J, van Eck BL, de Vijlder JJ, Vulsma T. High incidence of thyroid dysfunction despite prophylaxis with potassium iodide during (131) I-meta-iodobenzylguanidine treatment in children with neuroblastoma. Cancer. 2002;94:2081-9. [ Links ]

13. Bhandari S, Cheung N, Kushner B, et al. Hypothyroidism After 131I-Monoclonal Antibody Treatment of Neuroblastoma. Pediatr Blood Cancer. 2010;55:76-80. [ Links ]

14. Garaventa A, Gambini C, Villavecchia G, et al. Second malignancies in children with neuroblastoma after combined treatment with 131I-metaiodobenzylguanidine. Cancer. 2003;97:1332-8. [ Links ]

15. Van Santen HM, de Kraker J, van Eck BLF, de Vijlder JJM, Vulsma T. Improved radiation protection of the thyroid gland with thyroxine, methimazole, and potassiumiodide during diagnostic and therapeutic use of radiolabeled metaiodobenzylguanidine in children with neuroblastoma. Cancer. 2003;98:389-96. [ Links ]

16. Brans B, Monsieurs M, Laureys G, Kaufman J-M, Thierens H, Dierckx R. Thyroidal uptake and radiation dose after repetitive I-131-MIBG treatments: influence of potassium iodide for thyroid blocking. Med Pediatr Oncol. 2002;38:41-6. [ Links ]

17. Picco P, Garaventa A, Claudiani F, Gattorno M, De Bernardi B, Borrone C. Primary hypothyroidism as a consequence of 131-Imetaiodobenzylguanidine treatment for children with neuroblastoma. Cancer. 1995;76:1662-4. [ Links ]

18. Bongers-Schokking J, de Muinck Keizer-Schrama SM. Influence of timing and dose of thyroid hormone replacement on mental psychomotor, and behavioral development in children with congenital hypothyroidism. J Pediatr. 2005;147:768-74. [ Links ]

19. Clement SC, van Eck-Smit BLF, van Trotsenburg ASP, Kremer LCM, Tytgat GAM, van Santen HM. Long-term follow-up of the thyroid gland after treatment with (131) I-metaiodobenzylguanidine in children with neuroblastoma: importance of continuous surveillance. Pediatr Blood Cancer. 2013;60:1833-8. [ Links ]

20. Picco P, Garaventa A, Claudiani F, Garibaldi L, Borrone C. Primary hypothyroidism and 131I-MIBG therapy in neuroblastoma. Lancet. 1993;342:57. [ Links ]

21. Matthay KK, DeSantes K, Hasegawa B, et al. Phase I dose escalation of 131I -metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol. 1998;16:229-36. [ Links ]

22. Clement SC, van Rijn RR, van Eck-Smit BL, et al. Long-term efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma. Eur J Nucl Med Mol Imaging. 2015;42(5):706-15. [ Links ]

23. Cohen LE, Gordon JH, Popovsky EY, Gunawardene S, Duffey-Lind E, Lehmann LE, Diller LR. Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma: high incidence of endocrine and growth problems. Bone Marrow Transplant. 2014;49(4). [ Links ]

24. Perwein T, Lackner H, Sovinz P, Benesch M, Schmidt S, Schwinger W, Urban C. Survival and late effects in children with stage 4 neuroblastomae. Pediatr Blood Cancer. 2011;57(4):629-35. [ Links ]

Received: May 13, 2019; Accepted: March 26, 2020

Correspondence: Jessie Nallely Zurita Cruz. E-mail: zuritajn@hotmail.com.

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