Long-term results of suppressing thyroid-stimulating hormone during radiotherapy to prevent primary hypothyroidism in medulloblastoma/PNET and Hodgkin lymphoma: a prospective cohort study

Abstract

Primary hypothyroidism commonly occurs after radiotherapy (RT), and coincides with increased circulating thyroid-stimulating hormone (TSH) levels. We tested therefore the protective effect of suppressing TSH with L-thyroxine during RT for medulloblastoma/PNET and Hodgkin lymphoma (HL) in a prospective cohort study. From 1998 to 2001, a total of 37 euthyroid children with medulloblastoma/PNET plus 14 with HL, scheduled for craniospinal irradiation and mediastinum/neck radiotherapy, respectively, underwent thyroid ultrasound and free triiodothyronine (FT3), free thyroxine (FT4), and TSH evaluation at the beginning and end of craniospinal iiradiation. From 14 days before and up to the end of radiotherapy, patients were administered L-thyroxine checking every 3 days TSH to ensure a value<0.3 μIU/mL. During follow-up, blood tests and ultrasound were repeated; primary hypothyroidism was considered an increased TSH level greater than normal range. Twenty-two/37 patients with medulloblastoma/PNET and all the 14 patients with HL were alive after a median 231 months from radiotherapy with 7/22 and 8/14 having correctly reached TSH levels ˂ 0.3 μIU/mL and well matched for other variables. Twenty years on, hypothyroidism-free survival rates differed significantly, being 60%±15% and 15.6%±8.2% in TSH-suppressed vs. not-TSH suppressed patients, respectively (P=0.001). These findings suggest that hypothyroidism could be durably prevented in two populations at risk of late RT sequelae, but it should be confirmed in a larger cohort.

Keywords

iatrogenic primary hypothyroidism / late effects of radiotherapy / long-term follow-up / medulloblastoma / Hodgkin lymphoma

References

[1] Waguespack SG. Thyroid sequelae of pediatric cancer therapy. Horm Res Paediatr 2019; 91(2): 104–117

[2] Inskip PD, Veiga LHS, Brenner AV, Sigurdson AJ, Ostroumova E, Chow EJ, Stovall M, Smith SA, Weathers RE, Leisenring W, Robison LL, Armstrong GT, Sklar CA, Lubin JH. Hypothyroidism after radiation therapy for childhood cancer: a report from the Childhood Cancer Survivor Study. Radiat Res 2018; 190(2): 117–132

[3] Massimino M, Gandola L, Collini P, Seregni E, Marchianò A, Serra A, Pignoli E, Spreafico F, Pallotti F, Terenziani M, Biassoni V, Bombardieri E, Fossati-Bellani F. Thyroid-stimulating hormone suppression for protection against hypothyroidism due to craniospinal irradiation for childhood medulloblastoma/primitive neuroectodermal tumor. Int J Radiat Oncol Biol Phys 2007; 69(2): 404–410

[4] Massimino M, Gandola L, Pignoli E, Seregni E, Marchianò A, Pecori E, Catania S, Cefalo G. TSH suppression as a possible means of protection against hypothyroidism after irradiation for childhood Hodgkins lymphoma. Pediatr Blood Cancer 2011; 57(1): 166–168

[5] Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016; 131(6): 803–820

[6] Wémeau JL, Caron P, Schvartz C, Schlienger JL, Orgiazzi J, Cousty C, Vlaeminck-Guillem V. Effects of thyroid-stimulating hormone suppression with levothyroxine in reducing the volume of solitary thyroid nodules and improving extranodular nonpalpable changes: a randomized, double-blind, placebo-controlled trial by the French Thyroid Research Group. J Clin Endocrinol Metab 2002; 87(11): 4928–4934

[7] Biondi B, Cooper DS. Thyroid hormone suppression therapy. Endocrinol Metab Clin North Am 2019; 48(1): 227–237

[8] Massimino M, Gandola L, Mattavelli F, Pizzi N, Seregni E, Pallotti F, Spreafico F, Marchianò A, Terenziani M, Cefalo G, Biassoni V, Meazza C, Trecate G, Collini P. Radiation-induced thyroid changes: a retrospective and a prospective view. Eur J Cancer 2009; 45(14): 2546–2551

[9] Green DM, Brecher ML, Yakar D, Blumenson LE, Lindsay AN, Voorhess ML, MacGillivray M, Freeman AI. Thyroid function in pediatric patients after neck irradiation for Hodgkin disease. Med Pediatr Oncol 1980; 8(2): 127–136

[10] Ogilvy-Stuart AL, Shalet SM, Gattamaneni HR. Thyroid function after treatment of brain tumors in children. J Pediatr 1991; 119(5): 733–737

[11] Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin’s disease. N Engl J Med 1991; 325(9): 599–605

[12] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53(282): 457–481

[13] Miller R, Siegmund D. Maximally selected chi-square statistics. Biometrics 1982; 38(4): 1101–1106

[14] Hancock SL, McDougall IR, Constine LS. Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys 1995; 31(5): 1165–1170

[15] Ron E, Lubin JH, Shore RE, Mabuchi K, Modan B, Pottern LM, Schneider AB, Tucker MA, Boice JD Jr. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. 1995. Radiat Res 2012; 178(2): AV43–AV60

[16] Clausen Clausen CT, Hasle H, Holmqvist AS, Madanat-Harjuoja L, Tryggvadottir L, Wesenberg F, Bautz A, Winther JF, de Fine Licht S. Hyperthyroidism as a late effect in childhood cancer survivors — an adult life after childhood cancer in Scandinavia (ALiCCS) study. Acta Oncol 2019; 58(2): 227–231

[17] Clement SC, Kremer LCM, Verburg FA, Simmons JH, Goldfarb M, Peeters RP, Alexander EK, Bardi E, Brignardello E, Constine LS, Dinauer CA, Drozd VM, Felicetti F, Frey E, Heinzel A, van den Heuvel-Eibrink MM, Huang SA, Links TP, Lorenz K, Mulder RL, Neggers SJ, Nieveen van Dijkum EJM, Oeffinger KC, van Rijn RR, Rivkees SA, Ronckers CM, Schneider AB, Skinner R, Wasserman JD, Wynn T, Hudson MM, Nathan PC, van Santen HM. Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treat Rev 2018; 63: 28–39

[18] van Santen HM, van Dijk JE, Rodermond H, Vansenne F, Endert E, de Vijlder JJ, Haveman J, Vulsma T. Endocrine intervention during irradiation does not prevent damage to the thyroid gland. Thyroid 2006; 16(4): 387–395

[19] Bantle JP, Lee CK, Levitt SH. Thyroxine administration during radiation therapy to the neck does not prevent subsequent thyroid dysfunction. Int J Radiat Oncol Biol Phys 1985; 11(11): 1999–2002

[20] Nishiyama K, Tanaka E, Tarui Y, Miyauchi K, Okagawa K. A prospective analysis of subacute thyroid dysfunction after neck irradiation. Int J Radiat Oncol Biol Phys 1996; 34(2): 439–444

[21] Bhatti P, Veiga LH, Ronckers CM, Sigurdson AJ, Stovall M, Smith SA, Weathers R, Leisenring W, Mertens AC, Hammond S, Friedman DL, Neglia JP, Meadows AT, Donaldson SS, Sklar CA, Robison LL, Inskip PD. Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res 2010; 174(6): 741–752

[22] Wijnen M, van den Heuvel-Eibrink MM, Medici M, Peeters RP, van der Lely AJ, Neggers SJ. Risk factors for subsequent endocrine-related cancer in childhood cancer survivors. Endocr Relat Cancer 2016; 23(6): R299–R321

[23] Harris J, Barber B, Almarzouki H, Scrimger R, Romney J, O’Connell D, Urken M, Seikaly H. Free thyroid transfer: short-term results of a novel procedure to prevent post-radiation hypothyroidism. Head Neck 2017; 39(6): 1234–1238

Acknowledgments

This research received a Grant by AIRC (Associazione Italiana per la Ricerca sul Cancro) in 1998.

Compliance with ethics guidelines

Maura Massimino, Marta Podda, Lorenza Gandola, Emanuele Pignoli, Ettore Seregni, Carlo Morosi, Filippo Spreafico, Andrea Ferrari, Emilia Pecori, and Monica Terenziani have no conflicts of interest to disclose. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

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