Abstract

Cancer is one of the main causes of mortality worldwide. Thanks to scientific research, new methods of cancer treatment, including molecularly targeted therapy, are being developed. Monoclonal antibodies are used to treat many diseases, including some types of cancer, and affect various systems of the human body. The presented article aims to present the adverse effects of molecularly targeted cancer therapy on the endocrine system based on the current literature data. Immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 or its ligand PD-L1, can cause a variety of autoimmune adverse effects, among others, thyroid dysfunction, hypophysitis, and diabetes mellitus. The authors also paid attention to monitoring selected diagnostic parameters to prevent endocrine adverse effects during a therapy with monoclonal antibodies. The development of adverse effects may sometimes progress atypically and rapidly, and may be a life-threatening condition. Clinicians should choose individual schemes of treatment for particular patients. The patient’s condition should also be monitored before, during and after the therapy. The decision about the continuation of treatment with monoclonal antibodies should be based especially on a risk connected with the cessation of treatment. Clinical trials should be continued to improve knowledge about the side effects of monoclonal antibodies.

References

• 1. Agata Y., Kawasaki A., Nishimura H., Ishida Y., TsubataT., Yagita H., Honjo T.: Expression of the PD-1 antigen onthe surface of stimulated mouse T and B lymphocytes. Int.Immunol., 1996; 8: 765–772
  Google Scholar
• 2. Arima H., Iwama S., Inaba H., Ariyasu H., Makita N., OtsukiM., Kageyama K., Imagawa A., Akamizu T.: Managementof immune-related adverse events in endocrine organs inducedby immune checkpoint inhibitors: Clinical guidelinesof the Japan Endocrine Society. Endocr. J., 2019; 66: 581–586
  Google Scholar
• 3. Armand P., Chen Y.B., Redd R.A., Joyce R.M., Bsat J., JeterE., Merryman R.W., Coleman K.C., Dahi P.B., Nieto Y., LaCasceA.S., Fisher D.C., Ng S.Y., Odejide O.O., Freedman A.S., etal.: PD-1 blockade with pembrolizumab for classical Hodgkinlymphoma after autologous stem cell transplantation.Blood, 2019; 134: 22–29 4 Bavencio – Summary of Product Characteristics. https://www.ema.europa.eu/en//documents/product-information/bavencio-epar-product-information_en.pdf(25.09.2020)
  Google Scholar
• 4. mediates hypophysitis secondary to administration ofCTLA-4 blocking antibody. Sci. Transl. Med., 2014; 6: 230ra45
  Google Scholar
• 5. Bhasin S., Brito J.P., Cunningham G.R., Hayes F.J., HodisH.N., Matsumoto A.M., Snyder P.J., Swerdloff R.S., Wu F.C.,Yialamas M.A.: Testosterone therapy in men with hypogonadism:An Endocrine Society Clinical Practice Guideline.J. Clin. Endocrinol. Metab., 2018; 103: 1715–1744
  Google Scholar
• 6. Bornstein S.R., Allolio B., Arlt W., Barthel A., Don-WauchopeA., Hammer G.D., Husebye E.S., Merke D.P., MuradM.H., Stratakis C.A., Torpy D.J.: Diagnosis and treatment ofprimary adrenal insufficiency: An Endocrine Society ClinicalPractice Guideline. J. Clin. Endocrinol. Metab., 2016;101: 364–389
  Google Scholar
• 7. Carlé A., Pedersen I.B., Knudsen N., Perrild H., OvesenL., Andersen S., Laurberg P.: Hypothyroid symptoms fail topredict thyroid insufficiency in old people: A populationbasedcase-control study. Am. J. Med., 2016; 129: 1082–1092
  Google Scholar
• 8. Caturegli P., Di Dalmazi G., Lombardi M., Grosso F., LarmanH.B., Larman T., Taverna G., Cosottini M., Lupi I.: Hypophysitissecondary to cytotoxic T-lymphocyte-associatedprotein 4 blockade: Insights into pathogenesis from an autopsyseries. Am. J. Pathol., 2016; 186: 3225–3235
  Google Scholar
• 9. Caturegli P., Newschaffer C., Olivi A., Pomper M.G., BurgerP.C., Rose N.R.: Autoimmune hypophysitis. Endocr. Rev.,2005; 26: 599–614
  Google Scholar
• 10. Cha E., Klinger M., Hou Y., Cummings C., Ribas A., FahamM., Fong L.: Improved survival with T cell clonotypestability after anti-CTLA-4 treatment in cancer patients.Sci. Transl. Med., 2014; 6: 238ra70
  Google Scholar
• 11. Chabner B.A., Roberts T.G. Jr.: Timeline: Chemotherapyand the war on cancer. Nat. Rev. Cancer, 2005; 5: 65–72
  Google Scholar
• 12. Chalan P., Di Dalmazi G., Pani F., De Remigis A., CaturegliP.: Thyroid dysfunctions secondary to cancer immunotherapy.J. Endocrinol. Invest., 2018; 41: 625–638
  Google Scholar
• 13. Chamberlain J.J., Rhinehart A.S., Shaefer C.F. Jr, NeumanA.: Diagnosis and management of diabetes: Synopsis ofthe 2016 American Diabetes Association standards of medicalcare in diabetes. Ann. Intern. Med., 2016; 164: 542–552
  Google Scholar
• 14. Chang L.S., Barroso-Sousa R., Tolaney S.M., Hodi F.S,Kaiser U.B., Min L.: Endocrine toxicity of cancer immunotherapytargeting immune checkpoints. Endocr. Rev.,2019; 40: 17–65
  Google Scholar
• 15. Chau C.H., Steeg P.S, Figg W.D.: Antibody-drug conjugatesfor cancer. Lancet, 2019; 394: 793–804
  Google Scholar
• 16. Corsello S.M., Barnabei A., Marchetti P., De Vecchis L.,Salvatori R., Torino F.: Endocrine side effects induced byimmune checkpoint inhibitors. J. Clin. Endocrinol. Metab.,2013; 98: 1361–1375
  Google Scholar
• 17. Darvin P., Toor S.M., Nair V.S., Elkord E.: Immune checkpointinhibitors: Recent progress and potential biomarkers.Exp. Mol. Med., 2018; 50: 1–11
  Google Scholar
• 18. De Filette J., Andreescu C.E., Cools F., Bravenboer B.,Velkeniers B.: A systematic review and meta-analysis ofendocrine-related adverse events associated with immunecheckpoint inhibitors. Horm. Metab. Res., 2019; 51: 145–156
  Google Scholar
• 19. Dillard T., Yedinak C.G., Alumkal J., Fleseriu M.: Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis:Serious immune related adverse events acrossa spectrum of cancer subtypes. Pituitary, 2010; 13: 29–38 20 Dyrka K., Miedziaszczyk M., Szałek E., Łącka K.: Drugsused in viral diseases – their mechanism of action, selectedadverse effects and safety during pregnancy and lactation.Postępy Hig. Med. Dośw., 2019; 73: 491–507
  Google Scholar
• 20. years of clinical experience. Ann. Oncol., 2016; 27: 2168–2172
  Google Scholar
• 21. Emens L.A., Cruz C., Eder J.P., Braiteh F., Chung C., TolaneyS.M., Kuter I., Nanda R., Cassier P.A., Delord J.P., GordonM.S., ElGabry E., Chang C.W., Sarkar I., Grossman W.,et al.: Long-term clinical outcomes and biomarker analysesof atezolizumab therapy for patients with metastatictriple-negative breast cancer: A phase 1 study. JAMA Oncol.,2019; 5: 74–82
  Google Scholar
• 22. Faje A.T., Sullivan R., Lawrence D., Tritos N.A., FaddenR., Klibanski A., Nachtigall L.: Ipilimumab-induced hypophysitis:A detailed longitudinal analysis in a large cohortof patients with metastatic melanoma. J. Clin. Endocrinol.Metab., 2014; 99: 4078–4085
  Google Scholar
• 23. Fassett D.R., Couldwell W.T.: Metastases to the pituitarygland. Neurosurg. Focus., 2004; 16: E8
  Google Scholar
• 24. Ferlay J., Colombet M., Soerjomataram I., Dyba T., RandiG., Bettio M., Gavin A., Visser O., Bray F.: Cancer incidenceand mortality patterns in Europe: Estimates for 40 countriesand 25 major cancers in 2018. Eur. J. Cancer, 2018;103: 356–387
  Google Scholar
• 25. Ferrari S.M., Fallahi P., Galetta F., Citi E., Benvenga S.,Antonelli A.: Thyroid disorders induced by checkpoint inhibitors.Rev. Endocr. Metab. Disord., 2018; 19: 325–333
  Google Scholar
• 26. Freeman-Keller M., Kim Y., Cronin H., Richards A., GibneyG., Weber J.S.: Nivolumab in resected and unresectablemetastatic melanoma: Characteristics of immune-relatedadverse events and association with outcomes. Clin. CancerRes., 2016; 22: 886–894
  Google Scholar
• 27. Gauci M.L., Laly P., Vidal-Trecan T., Baroudjian B., GottliebJ., Madjlessi-Ezra N., Da Meda L., Madelaine-ChambrinI., Bagot M., Basset-Seguin N., Pages C., Mourah S., BoudouP., Lebbé C., Gautier J.F.: Autoimmune diabetes induced byPD-1 inhibitor-retrospective analysis and pathogenesis: Acase report and literature review. Cancer Immunol. Immunother.,2017; 66: 1399–1410
  Google Scholar
• 28. Gharwan H., Groninger H.: Kinase inhibitors and monoclonalantibodies in oncology: Clinical implications. Nat.Rev. Clin. Oncol., 2016; 13: 209–227
  Google Scholar
• 29. Ha D., Tanaka A., Kibayashi T., Tanemura A., SugiyamaD., Wing J.B., Lim E.L., Teng K.W., Adeegbe D., Newell E.W.,Katayama I., Nishikawa H., Sakaguchi S.: Differential controlof human Treg and effector T cells in tumor immunity byFc-engineered anti-CTLA-4 antibody. Proc. Natl. Acad. Sci.USA, 2019; 116: 609–618
  Google Scholar
• 30. Haanen J.B., Carbonnel F., Robert C., Kerr K.M., PetersS., Larkin J., Jordan K., ESMO Guidelines Committee: Managementof toxicities from immunotherapy: ESMO ClinicalPractice Guidelines for diagnosis, treatment and follow-up.Ann. Oncol., 2017; 28: iv119–iv142
  Google Scholar
• 31. Haanen J.B., Robert C.: Immune checkpoint inhibitors.Prog. Tumor Res., 2015; 42: 55–66
  Google Scholar
• 32. Hafeez U., Gan H.K., Scott A.M.: Monoclonal antibodiesas immunomodulatory therapy against cancer and autoimmunediseases. Curr. Opin. Pharmacol., 2018; 41: 114–121
  Google Scholar
• 33. Hodi F.S., Chesney J., Pavlick A.C., Robert C., GrossmanK.F., McDermott D.F., Linette G.P., Meyer N., GiguereJ.K., Agarwala S.S., Shaheen M., Ernstoff M.S., Minor D.R.,Salama A.K., Taylor M.H., et al.: Combined nivolumab andipilimumab versus ipilimumab alone in patients with advancedmelanoma: 2-year overall survival outcomes ina multicentre, randomised, controlled, phase 2 trial. LancetOncol., 2016; 17: 1558–1568
  Google Scholar
• 34. Horn L., Mansfield A.S., Szczęsna A., Havel L., KrzakowskiM., Hochmair M.J., Huemer F., Losonczy G., JohnsonM.L., Nishio M., Reck M., Mok T., Lam S., Shames D.S.,Liu J., et al.: First-line atezolizumab plus chemotherapyin extensive-stage small-cell lung cancer. N. Engl. J. Med.,2018; 379: 2220–2229
  Google Scholar
• 35. Iglesias P.: Cancer immunotherapy-induced endocrinopathies:Clinical behavior and therapeutic approach.Eur. J. Intern. Med., 2018; 47: 6–13
  Google Scholar
• 36. Illouz F., Briet C., Cloix L., Le Corre Y., Baize N., UrbanT., Martin L., Rodien P.: Endocrine toxicity of immunecheckpoint inhibitors: Essential crosstalk between endocrinologistsand oncologists. Cancer Med., 2017; 6: 1923–1929
  Google Scholar
• 37. Imfinzi – Summary of Product Characteristics. https://www.ema.europa.eu/en//documents/product-information/imfizi-epar-product-information_en.pdf (25.09.2020)
  Google Scholar
• 38. Iwama S., De Remigis A., Callahan M.K., Slovin S.F.,Wolchok J.D., Caturegli P.: Pituitary expression of CTLA-
  Google Scholar
• 39. Iyer P.C., Cabanillas M.E., Waguespack S.G., Hu M.I.,Thosani S.N., Lavis V.R., Busaidy N.L., Subudhi S.K., Diab A.,Dadu R.: Immune-related thyroiditis with immune checkpointinhibitors. Thyroid, 2018; 28: 1243–1251
  Google Scholar
• 40. Joo W.D., Visintin I., Mor G.: Targeted cancer therapy– Are the days of systemic chemotherapy numbered? Maturitas,2013; 76: 308–314
  Google Scholar
• 41. Joshi M.N., Whitelaw B.C., Palomar M.T., Wu Y., CarrollP.V.: Immune checkpoint inhibitor-related hypophysitis andendocrine dysfunction: Clinical review. Clin. Endocrinol.,2016; 85: 331–339
  Google Scholar
• 42. June C.H., Warshauer J.T., Bluestone J.A.: Is autoimmunitythe Achilles’ heel of cancer immunotherapy? Nat.Med., 2017; 23: 540–547
  Google Scholar
• 43. Kalogeras K.T., Nieman L.K., Friedman T.C., DoppmanJ.L., Cutler G.B. Jr, Chrousos G.P., Wilder R.L., Gold P.W.,Yanovski J.A.: Inferior petrosal sinus sampling in healthysubjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated withipsilateral adrenocorticotropin secretion. J Clin Invest.,1996; 97: 2045–2050
  Google Scholar
• 44. Katzke V.A., Kaaks R., Kühn T.: Lifestyle and cancer risk.Cancer J., 2015; 21: 104–110
  Google Scholar
• 45. Keytruda – Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-information_en.pdf(25.09.2020)
  Google Scholar
• 46. Konda B., Nabhan F., Shah M.H.: Endocrine dysfunctionfollowing immune checkpoint inhibitor therapy. Curr. Opin.Endocrinol. Diabetes Obes., 2017; 24: 337–347
  Google Scholar
• 47. Lam K.Y., Lo C.Y.: Metastatic tumours of the adrenalglands: A 30-year experience in a teaching hospital. Clin.Endocrinol., 2002; 56: 95–101
  Google Scholar
• 48. Lee Y.T., Tan Y.J, Oon C.E.: Molecular targeted therapy:Treating cancer with specificity. Eur. J. Pharmacol., 2018;834: 188–196
  Google Scholar
• 49. Liu M., Guo F.: Recent updates on cancer immunotherapy.Precis Clin. Med., 2018; 1: 65–74
  Google Scholar
• 50. Lupi I., Zhang J., Gutenberg A., Landek-Salgado M.,Tzou S.C., Mori S., Caturegli P.: From pituitary expansion toempty sella: Disease progression in a mouse model of autoimmunehypophysitis. Endocrinology, 2011; 152: 4190–4198
  Google Scholar
• 51. Manohar S., Kompotiatis P., Thongprayoon C., CheungpasitpornW., Herrmann J., Herrmann S.M.: Programmedcell death protein 1 inhibitor treatment is associated withacute kidney injury and hypocalcemia: Meta-analysis.Nephrol. Dial. Transplant., 2019; 34: 108–117
  Google Scholar
• 52. Marin-Acevedo J.A., Soyano A.E., Dholaria B., KnutsonK.L., Lou Y.: Cancer immunotherapy beyond immune checkpointinhibitors. J. Hematol. Oncol., 2018; 11: 8
  Google Scholar
• 53. Min L., Hodi F.S., Giobbie-Hurder A., Ott P.A., Luke J.J.,Donahue H., Davis M., Carroll R.S., Kaiser U.B.: Systemichigh-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: A retrospectivecohort study. Clin. Cancer Res., 2015; 21: 749–755
  Google Scholar
• 54. Molitch M.E., Clemmons D.R., Malozowski S., MerriamG.R., Vance M.L., Endocrine Society: Evaluation and treatmentof adult growth hormone deficiency: An EndocrineSociety clinical practice guideline. J. Clin. Endocrinol. Metab.,2011; 96: 1587–1609
  Google Scholar
• 55. Ni J., Qiu L.J., Zhang M., Wen P.F., Ye X.R., Liang Y., PanH.F., Ye D.Q.: CTLA-4 CT60 (rs3087243) polymorphism andautoimmune thyroid diseases susceptibility: A comprehensivemeta-analysis. Endocr. Res., 2014; 39: 180–188
  Google Scholar
• 56. Oelkers W.: Hyponatremia and inappropriate secretionof vasopressin (antidiuretic hormone) in patients with hypopituitarism.N. Engl. J. Med., 1989; 321: 492–496
  Google Scholar
• 57. Opdivo – Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf (25.09.2020)
  Google Scholar
• 58. Parakh S., King D., Gan H.K., Scott A.M.: Current developmentof monoclonal antibodies in cancer therapy. RecentRes. Cancer Res., 2020; 214: 1–70
  Google Scholar
• 59. Pardoll D.M.: The blockade of immune checkpoints incancer immunotherapy. Nat. Rev. Cancer, 2012; 12: 252–264
  Google Scholar
• 60. Persani L., Ferretti E., Borgato S., Faglia G., Beck-PeccozP.: Circulating thyrotropin bioactivity in sporadic centralhypothyroidism. J. Clin. Endocrinol. Metab., 2000; 85:3631–3635
  Google Scholar
• 61. Peters C., Brown S.: Antibody-drug conjugates as novelanti-cancer chemotherapeutics. Biosci. Rep., 2015; 35:e00225
  Google Scholar
• 62. Piranavan P., Li Y., Brown E., Kemp E.H., Trivedi N.: Immunecheckpoint inhibitor-induced hypoparathyroidismassociated with calcium-sensing receptor-activating autoantibodies.J. Clin. Endocrinol. Metab., 2019; 104: 550–556
  Google Scholar
• 63. Puar T.H., Stikkelbroeck N.M., Smans L.C., Zelissen P.M.,Hermus A.R.: Adrenal crisis: Still a deadly event in the 21stcentury. Am. J. Med., 2016; 129: 339.e1–9
  Google Scholar
• 64. Raghavan R., Brady M.L., Sampson J.H.: Delivering therapyto target: Improving the odds for successful drug development.Ther. Deliv., 2016; 7: 457–481
  Google Scholar
• 65. Rakoff-Nahoum S.: Why cancer and inflammation? YaleJ. Biol. Med., 2006; 79: 123–130
  Google Scholar
• 66. Ruggeri R.M., Campennì A., Giuffrida G., Trimboli P.,Giovanella L., Trimarchi F., Cannavò S.: Endocrine and metabolicadverse effects of immune checkpoint inhibitors: Anoverview (what endocrinologists should know). J. Endocrinol.Invest., 2019; 42: 745–756
  Google Scholar
• 67. Scott E.S., Long G.V., Guminski A., Clifton-Bligh R.J.,Menzies A.M., Tsang V.H.: The spectrum, incidence, kineticsand management of endocrinopathies with immunecheckpoint inhibitors for metastatic melanoma. Eur. J. Endocrinol.,2018; 178: 173–180
  Google Scholar
• 68. Socinski M.A., Jotte R.M., Cappuzzo F., Orlandi F.,Stroyakovskiy D., Nogami N., Rodríguez-Abreu D., Moro-Sibilot D., Thomas C.A., Barlesi F., Finley G., Kelsch C., LeeA., Coleman S., Deng Y., et al.: Atezolizumab for first-linetreatment of metastatic nonsquamous NSCLC. N. Engl. J.Med., 2018; 378: 2288–2301
  Google Scholar
• 69. Song M., Giovannucci E.: Preventable incidence andmortality of carcinoma associated with lifestyle factorsamong white adults in the United States. JAMA Oncol., 2016;2: 1154–1161
  Google Scholar
• 70. Suzuki M., Kato C., Kato A.: Therapeutic antibodies:Their mechanisms of action and the pathological findingsthey induce in toxicity studies. J. Toxicol. Pathol., 2015;28: 133–139
  Google Scholar
• 71. Tecentriq – Summary of Product Characteristics. https://www.ema.europa.eu/en//documents/product-information/tecentriq-epar-product-information_en.pdf(25.09.2020)
  Google Scholar
• 72. Tolcher A.W.: Antibody drug conjugates: Lessons from
  Google Scholar
• 73. Toporcov T.N., Wünsch Filho V.: Epidemiological scienceand cancer control. Clinics, 2018; 73: e627s
  Google Scholar
• 74. Torino F., Corsello S.M., Salvatori R.: Endocrinologicalside-effects of immune checkpoint inhibitors. Curr. Opin.Oncol., 2016; 28: 278–287
  Google Scholar
• 75. U.S. Cancer Statistics Working Group. 1999–2013 Incidenceand mortality web-based report. www.cdc.gov/uscs (25.09.2020)
  Google Scholar
• 76. Venetsanaki V., Boutis A., Chrisoulidou A., PapakotoulasP.: Diabetes mellitus secondary to treatment with immunecheckpoint inhibitors. Curr. Oncol., 2019; 26: e111–e114
  Google Scholar
• 77. Weber J.S., Postow M., Lao C.D., Schadendorf D.: Managementof adverse events following treatment with antiprogrammeddeath-1 agents. Oncologist, 2016; 21: 1230–1240
  Google Scholar
• 78. Weiner L.M., Surana R., Wang S.: Monoclonal antibodies:Versatile platforms for cancer immunotherapy. Nat.Rev. Immunol., 2010; 10: 317–327
  Google Scholar
• 79. Win M.A., Thein K.Z., Qdaisat A., Yeung S.C.: Acutesymptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. Am. J. Emerg. Med., 2017;35: 1039.e5–1039.e7
  Google Scholar
• 80. World Health Organization. Cancer fact sheet. http://www.who.int/mediacentre//factsheets/fs297/en/(25.09.2020)
  Google Scholar
• 81. Yamazaki N., Kiyohara Y., Uhara H., Fukushima S., UchiH., Shibagaki N., Tsutsumida A., Yoshikawa S., Okuyama R.,Ito Y., Tokudome T.: Phase II study of ipilimumab monotherapyin Japanese patients with advanced melanoma. CancerChemother. Pharmacol., 2015; 76: 997–1004
  Google Scholar
• 82. Yervoy-Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/yervoy-epar-product-information_en.pdf (25.09.2020)
  Google Scholar
• 83. Zhao C., Tella S.H., Del Rivero J., Kommalapati A.,Ebenuwa I., Gulley J., Strauss J., Brownell I.: Anti-PD-L1treatment induced central diabetes insipidus. J. Clin. Endocrinol.Metab., 2018; 103: 365–369
  Google Scholar

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