Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

Replacement Dose for Overt Hypothyroidism Induced by Programmed Cell Death Protein 1 Antibodies May Be Higher than Recommended

Author(s): Qian Zhang, Yao Zhang, Huijuan Zhu, Kuanzhi Liu, Pingping Lou, Peixuan Kong, Lei Su and Shuchang Wang*

Volume 24, Issue 10, 2024

Published on: 19 September, 2023

Page: [1169 - 1179] Pages: 11

DOI: 10.2174/1871530323666230821102730

Price: $65

Abstract

Background: The present recommendations, consensus, or guidelines for the replacement dosage for hypothyroidism induced by programmed cell death protein 1 (PD-1) therapy are not uniform, and there are very few special clinical trials that have examined the replacement dosage for it.

Objectives: This article illustrates the clinical characteristics of hypothyroidism induced by PD-1 antibodies (Abs) and reports the recommended replacement dosage for hypothyroidism.

Methods: Eighteen patients with overt primary hypothyroidism induced by PD-1 Abs (group 1) were selected from 655 patients with different tumor types. Retrospective analysis was performed on patients in group 1 and 18 patients with natural courses of overt primary hypothyroidism who were age- and sex-matched with the patients in group 1 (group 2). The replacement dosages required for the patients in the two groups were compared.

Results: Thyroid dysfunction occurred in group 1 after approximately 3.0 ± 1.4 cycles of PD-1 therapy (1-6 stages), with a median time of 61.5 days. The median time of onset of hypothyroidism among all patients was 87.5 days (30-240 days). Most of the patients with hypothyroidism were asymptomatic, and the onset of hypothyroidism was independent of age, sex, TPOAb, TgAb and TSH in group 1 (P>0.05). The average replacement dosage for patients in group 1 was 1.8 ± 0.6 μg/kg/d (0.6-3.2 μg/kg/d). Multiple linear regression analysis showed that sex, age, TPOAb, TgAb and TSH were not correlated with drug dosage.

Conclusion: It seemed that the average maintenance dosage of levothyroxine might need to be 1.8 μg/kg/day for patients with overt hypothyroidism induced by PD-1 Abs.

Graphical Abstract

[1]
Ribas, A.; Hamid, O.; Daud, A.; Hodi, F.S.; Wolchok, J.D.; Kefford, R.; Joshua, A.M.; Patnaik, A.; Hwu, W.J.; Weber, J.S.; Gangadhar, T.C.; Hersey, P.; Dronca, R.; Joseph, R.W.; Zarour, H.; Chmielowski, B.; Lawrence, D.P.; Algazi, A.; Rizvi, N.A.; Hoffner, B.; Mateus, C.; Gergich, K.; Lindia, J.A.; Giannotti, M.; Li, X.N.; Ebbinghaus, S.; Kang, S.P.; Robert, C. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA, 2016, 315(15), 1600-1609.
[http://dx.doi.org/10.1001/jama.2016.4059] [PMID: 27092830]
[2]
Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; Carcereny, E.; Ahn, M.J.; Felip, E.; Lee, J.S.; Hellmann, M.D.; Hamid, O.; Goldman, J.W.; Soria, J.C.; Dolled-Filhart, M.; Rutledge, R.Z.; Zhang, J.; Lunceford, J.K.; Rangwala, R.; Lubiniecki, G.M.; Roach, C.; Emancipator, K.; Gandhi, L. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med., 2015, 372(21), 2018-2028.
[http://dx.doi.org/10.1056/NEJMoa1501824] [PMID: 25891174]
[3]
Johnson, D.B.; Jakubovic, B.D.; Sibaud, V.; Sise, M.E. Balancing cancer immunotherapy efficacy and toxicity. J. Allergy Clin. Immunol. Pract., 2020, 8(9), 2898-2906.
[http://dx.doi.org/10.1016/j.jaip.2020.06.028] [PMID: 32599218]
[4]
Iglesias, P.; Soria, A.; Díez, J.J. Autoimmune endocrinopathies induced by immunomodulating antibodies in the treatment of cancer. Med. Clin., 2015, 145(6), 264-268.
[http://dx.doi.org/10.1016/j.medcli.2015.02.010] [PMID: 25851909]
[5]
Iglesias, P. Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach. Eur. J. Intern. Med., 2018, 47, 6-13.
[http://dx.doi.org/10.1016/j.ejim.2017.08.019] [PMID: 28826822]
[6]
Wright, J.J.; Powers, A.C.; Johnson, D.B. Endocrine toxicities of immune checkpoint inhibitors. Nat. Rev. Endocrinol., 2021, 17(7), 389-399.
[http://dx.doi.org/10.1038/s41574-021-00484-3] [PMID: 33875857]
[7]
Haanen, J.B.A.G.; Carbonnel, F.; Robert, C.; Kerr, K.M.; Peters, S.; Larkin, J.; Jordan, K. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 2017, 28(S4), iv119-iv142.
[http://dx.doi.org/10.1093/annonc/mdx225] [PMID: 28881921]
[8]
Castinetti, F.; Albarel, F.; Archambeaud, F.; Bertherat, J.; Bouillet, B.; Buffier, P.; Briet, C.; Cariou, B.; Caron, P.; Chabre, O.; Chanson, P.; Cortet, C.; Do Cao, C.; Drui, D.; Haissaguerre, M.; Hescot, S.; Illouz, F.; Kuhn, E.; Lahlou, N.; Merlen, E.; Raverot, V.; Smati, S.; Verges, B.; Borson-Chazot, F. French endocrine society guidance on endocrine side effects of immunotherapy. Endocr. Relat. Cancer, 2019, 26(2), G1-G18.
[http://dx.doi.org/10.1530/ERC-18-0320] [PMID: 30400055]
[9]
Puzanov, I.; Diab, A.; Abdallah, K.; Bingham, C.O., III; Brogdon, C.; Dadu, R.; Hamad, L.; Kim, S.; Lacouture, M.E.; LeBoeuf, N.R.; Lenihan, D.; Onofrei, C.; Shannon, V.; Sharma, R.; Silk, A.W.; Skondra, D.; Suarez-Almazor, M.E.; Wang, Y.; Wiley, K.; Kaufman, H.L.; Ernstoff, M.S. Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J. Immunother. Cancer, 2017, 5(1), 95.
[http://dx.doi.org/10.1186/s40425-017-0300-z] [PMID: 29162153]
[10]
Arima, H.; Iwama, S.; Inaba, H.; Ariyasu, H.; Makita, N.; Otsuki, M.; Kageyama, K.; Imagawa, A.; Akamizu, T. Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: Clinical guidelines of the Japan Endocrine Society. Endocr. J., 2019, 66(7), 581-586.
[http://dx.doi.org/10.1507/endocrj.EJ19-0163] [PMID: 31243183]
[11]
Fleseriu, M.; Hashim, I.A.; Karavitaki, N.; Melmed, S.; Murad, M.H.; Salvatori, R.; Samuels, M.H. Hormonal replacement in hypopituitarism in adults: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab., 2016, 101(11), 3888-3921.
[http://dx.doi.org/10.1210/jc.2016-2118] [PMID: 27736313]
[12]
Slawik, M.; Klawitter, B.; Meiser, E.; Schories, M.; Zwermann, O.; Borm, K.; Peper, M.; Lubrich, B.; Hug, M.J.; Nauck, M.; Olschewski, M.; Beuschlein, F.; Reincke, M. Thyroid hormone replacement for central hypothyroidism: A randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine. J. Clin. Endocrinol. Metab., 2007, 92(11), 4115-4122.
[http://dx.doi.org/10.1210/jc.2007-0297] [PMID: 17711927]
[13]
Mosaferi, T.; Tsai, K.; Sovich, S.; Wilhalme, H.; Kathuria-Prakash, N.; Praw, S.S.; Drakaki, A.; Angell, T.E.; Lechner, M.G. Optimal thyroid hormone replacement dose in immune checkpoint inhibitor-associated hypothyroidism is distinct from hashimoto’s thyroiditis. Thyroid, 2022, 32(5), 496-504.
[http://dx.doi.org/10.1089/thy.2021.0685] [PMID: 35199588]
[14]
McDermott, M.T. Hypothyroidism. Ann. Intern. Med., 2020, 173(1), ITC1-ITC16.
[http://dx.doi.org/10.7326/AITC202007070] [PMID: 32628881]
[15]
Boelen, A.; Kwakkel, J.; Fliers, E. Beyond low plasma T3: Local thyroid hormone metabolism during inflammation and infection. Endocr. Rev., 2011, 32(5), 670-693.
[http://dx.doi.org/10.1210/er.2011-0007] [PMID: 21791567]
[16]
Lee, S.; Farwell, A.P. Euthyroid sick syndrome. Compr. Physiol., 2016, 6(2), 1071-1080.
[http://dx.doi.org/10.1002/cphy.c150017] [PMID: 27065175]
[17]
Muir, C.A.; Clifton-Bligh, R.J.; Long, G.V.; Scolyer, R.A.; Lo, S.N.; Carlino, M.S.; Tsang, V.H.M.; Menzies, A.M. Thyroid immune-related adverse events following immune checkpoint inhibitor treatment. J. Clin. Endocrinol. Metab., 2021, 106(9), e3704-e3713.
[http://dx.doi.org/10.1210/clinem/dgab263] [PMID: 33878162]
[18]
Ross, D.S.; Burch, H.B.; Cooper, D.S.; Greenlee, M.C.; Laurberg, P.; Maia, A.L.; Rivkees, S.A.; Samuels, M.; Sosa, J.A.; Stan, M.N.; Walter, M.A. 2016 american thyroid association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid, 2016, 26(10), 1343-1421.
[http://dx.doi.org/10.1089/thy.2016.0229] [PMID: 27521067]
[19]
Ma, C.; Hodi, F.S.; Giobbie-Hurder, A.; Wang, X.; Zhou, J.; Zhang, A.; Zhou, Y.; Mao, F.; Angell, T.E.; Andrews, C.P.; Hu, J.; Barroso-Sousa, R.; Kaiser, U.B.; Tolaney, S.M.; Min, L. The impact of high-dose glucocorticoids on the outcome of immune-checkpoint inhibitor-related thyroid disorders. Cancer Immunol. Res., 2019, 7(7), 1214-1220.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0613] [PMID: 31088848]
[20]
Brown, R.L. Tyrosine kinase inhibitor-induced hypothyroidism: Incidence, etiology, and management. Target. Oncol., 2011, 6(4), 217-226.
[http://dx.doi.org/10.1007/s11523-011-0197-2] [PMID: 22101606]
[21]
Wang, S.; Wang, L.; Yao, Y.; Feng, F.; Yang, H.; Liang, Z.; Deng, K.; You, H.; Sun, J.; Xing, B.; Jin, Z.; Wang, R.; Pan, H.; Zhu, H. Primary lymphocytic hypophysitis: Clinical characteristics and treatment of 50 cases in a single centre in China over 18 years. Clin. Endocrinol., 2017, 87(2), 177-184.
[http://dx.doi.org/10.1111/cen.13354] [PMID: 28423475]
[22]
Joshi, M.N.; Whitelaw, B.C.; Palomar, M.T.P.; Wu, Y.; Carroll, P.V. Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review. Clin. Endocrinol., 2016, 85(3), 331-339.
[http://dx.doi.org/10.1111/cen.13063] [PMID: 26998595]
[23]
Chaker, L.; Razvi, S.; Bensenor, I.M.; Azizi, F.; Pearce, E.N.; Peeters, R.P. Hypothyroidism. Nat. Rev. Dis. Primers, 2022, 8(1), 30.
[http://dx.doi.org/10.1038/s41572-022-00357-7] [PMID: 35589725]
[24]
Kabadi, U.M.; Kabadi, M.M. Serum thyrotropin in primary hypothyroidism: A reliable and accurate predictor of optimal daily levothyroxine dose. Endocr. Pract., 2001, 7(1), 16-18.
[http://dx.doi.org/10.4158/EP.7.1.16] [PMID: 11250763]
[25]
Olubowale, O.; Chadwick, D.R. Optimization of thyroxine replacement therapy after total or near-total thyroidectomy for benign thyroid disease. Br. J. Surg., 2005, 93(1), 57-60.
[http://dx.doi.org/10.1002/bjs.5157] [PMID: 16323163]
[26]
Gordon, M.B.; Gordon, M.S. Variations in adequate levothyroxine replacement therapy in patients with different causes of hypothyroidism. Endocr. Pract., 1999, 5(5), 233-238.
[http://dx.doi.org/10.4158/EP.5.5.233] [PMID: 15251659]
[27]
Iyer, P.C.; Cabanillas, M.E.; Waguespack, S.G.; Hu, M.I.; Thosani, S.; Lavis, V.R.; Busaidy, N.L.; Subudhi, S.K.; Diab, A.; Dadu, R. Immune-related thyroiditis with immune checkpoint inhibitors. Thyroid, 2018, 28(10), 1243-1251.
[http://dx.doi.org/10.1089/thy.2018.0116] [PMID: 30132401]
[28]
Santini, F.; Pinchera, A.; Marsili, A.; Ceccarini, G.; Castagna, M.G.; Valeriano, R.; Giannetti, M.; Taddei, D.; Centoni, R.; Scartabelli, G.; Rago, T.; Mammoli, C.; Elisei, R.; Vitti, P. Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases. J. Clin. Endocrinol. Metab., 2005, 90(1), 124-127.
[http://dx.doi.org/10.1210/jc.2004-1306] [PMID: 15483074]
[29]
Cunningham, J.J.; Barzel, U.S. Lean body mass is a predictor of the daily requirement for thyroid hormone in older men and women. J. Am. Geriatr. Soc., 1984, 32(3), 204-207.
[http://dx.doi.org/10.1111/j.1532-5415.1984.tb02003.x] [PMID: 6699335]
[30]
Roos, A.; Linn-Rasker, S.P.; van Domburg, R.T.; Tijssen, J.P.; Berghout, A. The starting dose of levothyroxine in primary hypothyroidism treatment: A prospective, randomized, double-blind trial. Arch. Intern. Med., 2005, 165(15), 1714-1720.
[http://dx.doi.org/10.1001/archinte.165.15.1714] [PMID: 16087818]
[31]
Muir, C.A.; Menzies, A.M.; Clifton-Bligh, R.; Tsang, V.H.M. Thyroid toxicity following immune checkpoint inhibitor treatment in advanced cancer. Thyroid, 2020, 30(10), 1458-1469.
[http://dx.doi.org/10.1089/thy.2020.0032] [PMID: 32264785]
[32]
Delivanis, D.A.; Gustafson, M.P.; Bornschlegl, S.; Merten, M.M.; Kottschade, L.; Withers, S.; Dietz, A.B.; Ryder, M. Pembrolizumab-induced thyroiditis: Comprehensive clinical review and insights into underlying involved mechanisms. J. Clin. Endocrinol. Metab., 2017, 102(8), 2770-2780.
[http://dx.doi.org/10.1210/jc.2017-00448] [PMID: 28609832]
[33]
Mazarico, I.; Capel, I.; Giménez-Palop, O.; Albert, L.; Berges, I.; Luchtenberg, F.; García, Y.; Fernández-Morales, L.A.; De Pedro, V.J.; Caixàs, A.; Rigla, M. Low frequency of positive antithyroid antibodies is observed in patients with thyroid dysfunction related to immune check point inhibitors. J. Endocrinol. Invest., 2019, 42(12), 1443-1450.
[http://dx.doi.org/10.1007/s40618-019-01058-x] [PMID: 31093955]
[34]
Stelmachowska-Banaś M.; Czajka-Oraniec, I. Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review. Endocr. Connect., 2020, 9(10), R207-R228.
[http://dx.doi.org/10.1530/EC-20-0342] [PMID: 33064663]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy