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Exp Clin Endocrinol Diabetes 2013; 121(10): 581-587
DOI: 10.1055/s-0033-1355337
Article
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Hypophysitis Caused by Ipilimumab in Cancer Patients: Hormone Replacement or Immunosuppressive Therapy

A. Lammert
1   Fifth Medical Clinic, University Medical Center Mannheim, Mannheim, Germany
,
H. J. Schneider
2   Division of Endocrinology, Department of Medicine IV, Ludwig-Maximilians University, Munich, Germany
,
T. Bergmann
3   Division of Endocrinology and Diabetes, Department of Medicine I, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
,
U. Benck
1   Fifth Medical Clinic, University Medical Center Mannheim, Mannheim, Germany
,
B. K. Krämer
1   Fifth Medical Clinic, University Medical Center Mannheim, Mannheim, Germany
,
R. Gärtner
2   Division of Endocrinology, Department of Medicine IV, Ludwig-Maximilians University, Munich, Germany
,
C. Metzner
4   Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
,
C. Schöfl
3   Division of Endocrinology and Diabetes, Department of Medicine I, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
,
C. Berking
5   Department of Dermatology and Allergology, Ludwig-Maximilians University, Munich, Germany
› Author Affiliations
Further Information

Publication History

received 04 June 2013
first decision 19 July 2013

accepted 21 August 2013

Publication Date:
11 October 2013 (online)

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Abstract

Purpose:

Ipilimumab is besides the BRAF inhibitor vemurafenib the first officially approved medical treatment for metastatic melanoma, which results in improved survival. Ipilimumab leads to a release of a CTLA4-mediated inhibition of T-cell immunoreactions. Therefore, patients may also suffer from immune-related adverse events affecting different organs, which are typically treated by high-dose corticosteroids. Ipilimumab-induced hypophysitis (iH) has been reported in up to 17% of melanoma patients in clinical trials.

Methods and Results:

Here we present 5 patients with metastatic melanoma and 2 patients with prostate cancer who developed hypophysitis after ipilimumab therapy. Patients were treated by high-dose corticosteroid therapy resulting in the resolution of local inflammation but not of pituitary deficiencies. Partial or complete hypopituitarism remained in all patients. Pharmacotherapy with high-dose corticosteroids caused complications in 5 patients, necessitating hospitalization in 4. 2 of the 3 patients with progressive disease died, while 3 patients had stable disease and 1 patient showed tumor regression after discontinuation of ipilimumab.

Conclusion:

In summary, with regard to safety and simplicity of hormonal substitution therapy we have to scrutinize high-dose corticosteroid therapy, though it only improves inflammation but not neuro-endocrine function and may cause further morbidity. Regression of the tumor depends on the ipilimumab-mediated immune events, in which high-dose and long-term corticosteroid therapy for iH appears to be counter-intuitive. Herein, we discuss screening and the diagnostic as well as therapeutic management of iH in metastatic cancer patients from an endocrinologic perspective.

Key words

autoimmunity - hypopituitarism - glucocorticoids
 

  • References

  • 1 Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711-723
    CrossrefPubMedGoogle Scholar
  • 2 Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517-2526
    CrossrefPubMedGoogle Scholar
  • 3 Kryczek I, Liu R, Wang G et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res 2009; 69: 3995-4000
    CrossrefPubMedGoogle Scholar
  • 4 Subudhi SK, Alegre ML, Fu YX. The balance of immune responses: costimulation verse coinhibition. J Mol Med (Berl) 2005; 83: 193-202
    CrossrefPubMedGoogle Scholar
  • 5 Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30: 2691-2697
    Google Scholar
  • 6 Maker AV, Yang JC, Sherry RM et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother 2006; 29: 455-463
    CrossrefPubMedGoogle Scholar
  • 7 Hashimoto K, Takao T, Makino S. Lymphocytic adenohypophysitis and infundibuloneurohypophysitis. Endocr J 1997; 44: 1-10
    CrossrefPubMedGoogle Scholar
  • 8 Rivera JA. Lymphocytic hypophysitis: disease spectrum and approach to diagnosis and therapy. Pituitary 2006; 9: 35-45
    CrossrefPubMedGoogle Scholar
  • 9 Hashimoto K, Asaba K, Tamura K et al. A case of lymphocytic infundibuloneurohypophysitis associated with systemic lupus erythematosus. Endocr J 2002; 49: 605-610
    CrossrefPubMedGoogle Scholar
  • 10 Carpenter KJ, Murtagh RD, Lilienfeld H et al. Ipilimumab-induced hypophysitis: MR imaging findings. Am J Neuroradiol 2009; 30: 1751-1753
    CrossrefPubMedGoogle Scholar
  • 11 Bronstein Y, Ng CS, Hwu P et al. Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. Am J Roentgenol 2011; 197: W992-W1000
    CrossrefPubMedGoogle Scholar
  • 12 Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I et al. Hypopituitarism. Lancet 2007; 369: 1461-1470
    CrossrefPubMedGoogle Scholar
  • 13 Kaehler K, Egberts F, Lorigan P et al. Anti-CTLA-4 therapy-related autoimmune hypophysitis in a melanoma patient. Melanoma Research 2009; 19: 333-334
    CrossrefPubMedGoogle Scholar
  • 14 Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol 2011; 164: 303-307
    CrossrefPubMedGoogle Scholar
  • 15 van den Eertwegh AJ, Versluis J, van den Berg HP et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 509-517
    CrossrefPubMedGoogle Scholar
  • 16 Deutschbein T, Unger N, Mann K et al. Diagnosis of secondary adrenal insufficiency: unstimulated early morning cortisol in saliva and serum in comparison with the insulin tolerance test. Horm Metab Res 2009; 41: 834-839
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Heinze HJ, Bercu BB. Acquired hypophysitis in adolescence. J Pediatr Endocrinol Metab 1997; 10: 315-321
    PubMedGoogle Scholar
  • 18 Honegger J, Fahlbusch R, Bornemann A et al. Lymphocytic and granulomatous hypophysitis: experience with nine cases. Neurosurgery 1997; 40: 713-722
    CrossrefPubMedGoogle Scholar
  • 19 Kristof RA, Van Roost D, Klingmuller D et al. Lymphocytichypophysitis: non-invasive diagnosis and treatment by high dose methylprednisolone pulse therapy?. J Neurol Neurosurg Psychiatry 1999; 67: 398-402
    CrossrefPubMedGoogle Scholar
  • 20 Lecube A, Francisco G, Rodriguez D et al. Lymphocytic hypophysitis successfully treated with azathioprine: first case report. J Neurol Neurosurg Psychiatry 2003; 74: 1581-1583
    CrossrefPubMedGoogle Scholar
  • 21 Tubridy N, Saunders D, Thom M et al. Infundibulohypophysitis in a man presenting with diabetes insipidus and cavernous sinus involvement. J Neurol Neurosurg Psychiatry 2001; 71: 798-801
    CrossrefPubMedGoogle Scholar
  • 22 Postema PTE, von Hangen PM, de Herder WW. Treatment of aggressive, recurrent lymphocytic hypophysitis with rituximab. Presented at: 90th annual Meeting of the Endocrine Society Abstract 2008; 1–394
    PubMedGoogle Scholar
  • 23 Selch MT, DeSalles AA, Kelly DF et al. Stereotactic radiotherapy for the treatment of lymphocytic hypophysitis. Report of two cases. J Neurosurg 2003; 99: 591-596
    CrossrefPubMedGoogle Scholar
  • 24 Ray DK, Yen CP, Vance ML et al. Gamma knife surgery for lymphocytic hypophysitis. J Neurosurg 2011; 112: 118-121
    PubMedGoogle Scholar
  • 25 Ng WH, Gonzales M, Kaye AH. Lymphocytic hypophysitis. J Clin Neurosci 2003; 10: 409-413
    CrossrefPubMedGoogle Scholar
  • 26 Dillard T, Yedlinak C, Alumkal J et al. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 2010; 13: 29-38
    CrossrefPubMedGoogle Scholar
  • 27 Voskens CJ, Goldinger SM, Loquai C et al. The Price of Tumor Control: An Analysis of Rare Side Effects of Anti-CTLA-4 Therapy in Metastatic Melanoma from the Ipilimumab Network. PLoS One 2013; 53745
    PubMedGoogle Scholar
  • 28 Juszczak A, Gupta A, Karavitaki N et al. Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review. Eur J Endocrinol 2012; 167: 1-5
    CrossrefPubMedGoogle Scholar
  • 29 Shaw SA, Camacho LH, McCutcheon IE et al. Transient hypophysitis after cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade. J Clin Endocrinol Metab 2007; 92: 1201-1202
    CrossrefPubMedGoogle Scholar
  • 30 McGrail KM, Beyerl BD, Black PM et al. Lymphocytic adenohypophysitis of pregnancy with complete recovery. Neurosurgery 1987; 20: 791-793
    CrossrefPubMedGoogle Scholar
  • 31 Bitton RN, Slavin M, Decker RE et al. The course of lymphocytic hypophysitis. Surg Neurol 1991; 36: 40-43
    CrossrefPubMedGoogle Scholar
  • 32 Ozawa Y, Shishiba Y. Recovery from lymphocytic hypophysitis associated with painless thyroiditis: clinical implications of circulating antipituitary antibodies. Acta Endocrinol (Copenh) 1993; 128: 493-498
    PubMedGoogle Scholar
  • 33 Ober KP, Elster A. Spontaneously resolving lymphocytic hypophysitis as a cause of postpartum diabetes insipidus. Endocrinologist 1994; 4: 107-111
    CrossrefPubMedGoogle Scholar
  • 34 Menon PS, Shah N, Chauhan PH et al. Spontaneous resolution of a pituitary mass: probable lymphocytic hypophysitis. J Assoc Physicians India 1996; 44: 653-655
    PubMedGoogle Scholar
  • 35 Noto H, Tsukamoto K, Hayashi S et al. Spontaneous resolution of a pituitary mass: probable lymphocytic hypophysitis. Endocr J 2001; 48: 483-486
    CrossrefPubMedGoogle Scholar