Skip to main content

Advertisement

SpringerLink
Log in

Temozolomide for corticotroph pituitary adenomas refractory to standard therapy

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

To highlight the potential of temozolomide (TMZ) to induce rapid tumor regression in patients with aggressive corticotroph adenomas (CA) that are refractory to surgery and radiation therapy and to review use of TMZ in other pituitary tumors. We present a case of a 56-year-old male with a 3 cm CA treated with transphenoidal surgery (TSS) and conventional radiotherapy in the same year. His hypercortisolemia recurred 11 years later with rapid tumor growth (to 4.2 × 2.5 cm) and he underwent a second TSS with good resection. The tumor recurred 6 months later with ophthalmoplegia. Over 16 months he underwent an additional three surgeries (two TSS, one craniotomy) and repeated conventional radiotherapy. Ki67 staining index on surgical specimens was 5–6%. Temozolomide is an oral alkylating agent approved for glioblastoma multiforme treatment that has only recently shown promise in treating some pituitary tumors. In this patient TMZ was started at 150 mg/m2/day, titrated to 200 mg/m2/day, taken 5 days per month. The only significant side effect was moderate nausea. After 10 weeks, the tumor showed a remarkable 60% regression with objective improvement in ophthalmoplegia. Treatment of aggressive CAs represents a therapeutic challenge and in some cases surgical debulking and radiotherapy are of limited success. Few reports of CAs responsive to TMZ have been reported in the literature. To our knowledge, this case represents the most rapid robust CA shrinkage response reported to date. Further randomized clinical trials of TMZ in the treatment of aggressive pituitary adenomas are warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Assié G, Bahurel H, Coste J, Silvera S, Kujas M, Dugué M-A, Karray F, Dousset B, Bertherat J, Legmann P, Bertagna X (2007) Corticotroph tumor progression after adrenalectomy in Cushing’s Disease: a reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 92:172–179

    Article  PubMed  Google Scholar 

  2. Blevins LS, Sanai N, Kunwar S, Devin JK (2009) An approach to the management of patients with residual Cushing’s disease. J Neuro-Oncol 94:313–319

    Article  CAS  Google Scholar 

  3. Bobola MS, Kolstoe DD, Blank A, Silber JR (2010) Minimally cytotoxic doses of temozolomide produce radiosensitization in human glioblastoma cells regardless of MGMT expression. Mol Cancer Ther 9:1208–1218

    Article  CAS  PubMed  Google Scholar 

  4. Bobola MS, Silber JR, Ellenbogen RG, Geyer JR, Blank A, Goff RD (2005) O6-methylguanine-DNA methyltransferase, O6-benzylguanine, and resistance to clinical alkylators in pediatric primary brain tumor cell lines. Clin Cancer Res 11:2747–2755

    Article  CAS  PubMed  Google Scholar 

  5. Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes HP, Thome C (2010) SOM230 (Pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Exp Clin Endocrinol Diabetes, 2010 May 21 [Epub ahead of print]

  6. Burrow GN, Wortzman G, Rewcastle NB, Holgate RC, Kovacs K (1981) Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. N Engl J Med 304:156–158

    Article  CAS  PubMed  Google Scholar 

  7. Bush ZM, Longtine JA, Cunningham T, Schiff D, Jane JA, Jr., Vance ML, Thorner MO, Laws ER, Jr., Lopes MB (2010) Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O6-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab, 2010 Jul 28 [Epub ahead of print]

  8. Byrne S, Karapetis C, Vrodos N (2009) A novel use of temozolomide in a patient with malignant prolactinoma. J Clin Neurosci 16:1694–1696

    Article  PubMed  Google Scholar 

  9. Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A (2006) High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege. Belgium J Clin Endocrinol Metab 91:4769–4775

    Article  CAS  Google Scholar 

  10. de Bruin C, Pereira AM, Feelders RA, Romijn JA, Roelfsema F, Sprij-Mooij DM, van Aken MO, van der Lelij A-J, de Herder WW, Lamberts SWJ, Hofland LJ (2009) Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. J Clin Endocrinol Metab 94:1118–1124

    Article  PubMed  Google Scholar 

  11. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. New England J Med 343:1350–1354

    Article  CAS  Google Scholar 

  12. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797

    CAS  PubMed  Google Scholar 

  13. Estrada J, Boronat M, Mielgo M, Magallon R, Millan I, Diez S, Lucas T, Barcelo B (1997) The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. New England J Med 336:172–177

    Article  CAS  Google Scholar 

  14. Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, Eskey CJ, Simmons NE (2006) Long-term response of pituitary carcinoma to temozolomide. Report Two Cases J Neurosurg 105:621–626

    Google Scholar 

  15. Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, Zelissen PM, van Heerebeek R, de Jong FH, van der Lely A-J, de Herder WW, Hofland LJ, Lamberts SW (2010) Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. The New England J Med 362:1846–1848

    Article  CAS  Google Scholar 

  16. Fleseriu M, Loriaux DL, Ludlam WH (2007) Second-line treatment for Cushing’s disease when initial pituitary surgery is unsuccessful current opinion in endocrinology. Diabetes Obes 14:323–328

    Article  Google Scholar 

  17. Guzel A, Tatli M, Senturk S, Guzel E, Cayli SR, Sav A (2008) Pituitary carcinoma presenting with multiple metastases: case report. J Child Neurol 23:1467–1471

    Article  PubMed  Google Scholar 

  18. Hagen C, Schroeder HD, Hansen S, Andersen M (2009) Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy. Eur J Endocrinol Eur Federation Endocrine Soc 161:631–637

    CAS  Google Scholar 

  19. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH (1994) Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 120:817–820

    CAS  PubMed  Google Scholar 

  20. Hegi ME, Diserens A-C, Godard S, Dietrich P-Y, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res Official J Am Assoc Cancer Res 10:1871–1874

    CAS  Google Scholar 

  21. Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M, Grossman AB (2005) Diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab 90:3089–3099

    Article  CAS  PubMed  Google Scholar 

  22. Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–617; discussion 617–618

    Article  CAS  PubMed  Google Scholar 

  23. Kovacs K, Horvath E, Syro LV, Uribe H, Penagos LC, Ortiz LD, Fadul CE (2007) Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings. Hum Pathol 38:185–189

    Article  CAS  PubMed  Google Scholar 

  24. Kovacs K, Scheithauer B, Lombardero M, McLendon R, Syro L, Uribe H, Ortiz L, Penagos L (2008) MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy. Acta Neuropathol 115:261–262

    Article  PubMed  Google Scholar 

  25. Kurzen H, Schmitt S, Näher H, Möhler T (2003) Inhibition of angiogenesis by non-toxic doses of temozolomide. Anti-Cancer Drugs 14:515–522

    Article  CAS  PubMed  Google Scholar 

  26. Lim S, Shahinian H, Maya MM, Yong W, Heaney AP (2006) Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncol 7:518–520

    Article  PubMed  Google Scholar 

  27. Liu JK, Fleseriu M, Ciric IS, Delashaw J, Johnny B, Couldwell WT (2007) Treatment options for Cushing disease after unsuccessful transsphenoidal surgery. Neurosurg Focus 23:E8

    Article  PubMed  Google Scholar 

  28. Lloyd R, Kovacs K, Young W Jr, Farrel W, Asa S, Truillas J, Kontogeorgos G, Sano T, Scheithauer B, Horvath E, DeLellis R, Heitz P (2004) Pituitary tumors. In: DeLellis R et al (eds) WHO classification of tumors of the endocrine organs: Pathology and genetics of endocrine organs. IARC Press, Lyon, pp 10–13

    Google Scholar 

  29. Maiza JC, Caron P (2009) Carcinomes et adenomes hypophysaires agressifs : mise au point et nouvelles options therapeutiques. Ann Endocrinol (Paris) 70(Suppl 1):S12–S19

    CAS  Google Scholar 

  30. McCormack AI, McDonald KL, Gill AJ, Clark SJ, Burt MG, Campbell KA, Braund WJ, Little NS, Cook RJ, Grossman AB, Robinson BG, Clifton-Bligh RJ (2009) Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol 71:226–233

    Article  CAS  Google Scholar 

  31. Mohammed S, Cusimano MD, Scheithauer BW, Rotondo F, Horvath E, Kovacs K (2010) O-methylguanine-DNA methyltransferase immunoexpression in a double pituitary adenoma. Neurosurgery 66:E421–E422

    Article  PubMed  Google Scholar 

  32. Mohammed S, Kovacs K, Mason W, Smyth H, Cusimano MD (2009) Use of temozolomide in aggressive pituitary tumors: case report. Neurosurgery 64:E773–E774; discussion E774

    Article  PubMed  Google Scholar 

  33. Morin E, Berthelet F, Weisnagel J, Bidlingmaier M, Serri O (2010) Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly. Pituitary 1–4

  34. Moyes VJ, Alusi G, Sabin HI, Evanson J, Berney DM, Kovacs K, Monson JP, Plowman PN, Drake WM (2009) Treatment of Nelson’s syndrome with temozolomide. Eur J Endocrinol 160:115–119

    Article  CAS  PubMed  Google Scholar 

  35. Natelson EA, Pyatt D (2010) Temozolomide-induced myelodysplasia. Adv Hematol 2010:760402

    PubMed  Google Scholar 

  36. Neff LM, Weil M, Cole A, Hedges TR, Shucart W, Lawrence D, Zhu J-J, Tischler AS, Lechan RM (2007) Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists. Pituitary 10:81–86

    Article  PubMed  Google Scholar 

  37. Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF Jr, Lloyd RV, Davis DH, Guthrie BL, Schoene WC (1997) Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79:804–812

    Article  CAS  PubMed  Google Scholar 

  38. Quinn JA, Jiang SX, Reardon DA, Desjardins A, Vredenburgh JJ, Rich JN, Gururangan S, Friedman AH, Bigner DD, Sampson JH, McLendon RE, Herndon JE, Walker A, Friedman HS (2009) Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol Official J Am Soc Clin Oncol 27:1262–1267

    CAS  Google Scholar 

  39. Ram Z, Nieman LK, Cutler GB Jr, Chrousos GP, Doppman JL, Oldfield EH (1994) Early repeat surgery for persistent Cushing’s disease. J Neurosurg 80:37–45

    Article  CAS  PubMed  Google Scholar 

  40. Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, Chabre O, Chanson P, Cortet-Rudelli C, Assaker R, Dufour H, Gaillard S, Francois P, Jouanneau E, Passagia J-G, Bernier M, Cornelius A, Figarella-Branger D, Trouillas J, Borson-Chazot F, Brue T (2010) Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a french multicenter experience. J Clin Endocrinol Metab. doi:10.1210/jc.2010-0644

  41. Saveanu A, Gunz G, Guillen S, Dufour H, Culler MD, Jaquet P (2006) Somatostatin and dopamine-somatostatin multiple ligands directed towards somatostatin and dopamine receptors in pituitary adenomas. Neuroendocrinology 83:258–263

    Article  CAS  PubMed  Google Scholar 

  42. Saveanu A, Jaquet P, Brue T, Barlier A (2008) Relevance of coexpression of somatostatin and dopamine D2 receptors in pituitary adenomas. Mol Cell Endocrinol 286:206–213

    Article  CAS  PubMed  Google Scholar 

  43. Shaikh A, Masood N (2010) Acute lymphoblastic leukemia subsequent to temozolomide use in a 26-year-old man: a case report. J Med Case Reports 4:274

    Article  PubMed  Google Scholar 

  44. Sheehan JM, Vance ML, Sheehan JP, Ellegala DB, Laws ER (2000) Radiosurgery for Cushing’s disease after failed transsphenoidal surgery. J Neurosurg 93:738–742

    Article  CAS  PubMed  Google Scholar 

  45. Starke RM, Williams BJ, Vance ML, Sheehan JP (2010) Radiation therapy and stereotactic radiosurgery for the treatment of Cushing’s disease: an evidence-based review. Curr Opin Endocrinol Diabetes Obes 17:356–364

    Article  PubMed  Google Scholar 

  46. Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S (2002) Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375–1382

    Article  CAS  PubMed  Google Scholar 

  47. Syro LV, Scheithauer BW, Ortiz LD, Fadul CE, Horvath E, Rotondo F, Kovacs K (2009) Effect of temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma. Hormones (Athens, Greece) 8:303–306

    Google Scholar 

  48. Syro LV, Uribe H, Penagos LC, Ortiz LD, Fadul CE, Horvath E, Kovacs K (2006) Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm. Clin Endocrinol 65:552–553

    Article  Google Scholar 

  49. Takeshita A, Inoshita N, Taguchi M, Okuda C, Fukuhara N, Oyama K, Ohashi K, Sano T, Takeuchi Y, Yamada S (2009) High incidence of low O(6)-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing’s disease European. J Endocrinol Eur Federation Endocrine Soc 161:553–559

    CAS  Google Scholar 

  50. Thearle MS, Freda PU, Bruce JN, Isaacson SR, Lee Y, Fine RL (2009) Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor. Pituitary 1–7. doi:10.1007/s11102-009-0211-1

  51. Wedge SR, Porteous JK, Newlands ES (1997) Effect of single and multiple administration of an O6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model. Cancer Chemother Pharmacol 40:266–272

    Article  CAS  PubMed  Google Scholar 

  52. Wedge SR, Porteus JK, May BL, Newlands ES (1996) Potentiation of temozolomide and BCNU cytotoxicity by O(6)-benzylguanine: a comparative study in vitro. Br J Cancer 73:482–490

    Article  CAS  PubMed  Google Scholar 

  53. Widhalm G, Wolfsberger S, Preusser M, Woehrer A, Kotter MR, Czech T, Marosi C, Knosp E (2009) O(6)-methylguanine DNA methyltransferase immunoexpression in nonfunctioning pituitary adenomas: are progressive tumors potential candidates for temozolomide treatment? Cancer 115:1070–1080

    Article  CAS  PubMed  Google Scholar 

  54. Yildiz F, Zorlu F, Erbas T, Atahan L (1999) Radiotherapy in the management of giant pituitary adenomas. Radiother Oncol 52:233–237

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Case presented at the American Association of Clinical Endocrinologists 19th Annual Meeting and Clinical Congress, April 21–25, 2010, Boston, MA. Troy H. Dillard, MD, Johnny B. Delashaw, MD, Edward A. Neuwelt, MD, Chris Yedinak, NP, and Maria Fleseriu, MD: Temozolomide for Corticotroph Adenomas Refractory to Surgery and Radiation: A Case of Rapid Tumor Regression. The authors thank Shirley McCartney, Ph.D., for editorial assistance in preparing this manuscript.

Author information

Authors and Affiliations

  1. Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, OR, 97239, USA

    Troy H. Dillard & Maria Fleseriu

  2. Divisions of Neuropathology and Surgical Pathology, Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA

    S. Humayun Gultekin

  3. Department of Neurological Surgery and Northwest Pituitary Center, Oregon Health & Science University, Portland, OR, 97239, USA

    Johnny B. Delashaw Jr., Chris G. Yedinak & Maria Fleseriu

  4. Departments of Neurological Surgery and Neurology, Oregon Health & Science University, Portland, OR, 97239, USA

    Edward A. Neuwelt

Authors
  1. Troy H. Dillard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Humayun Gultekin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johnny B. Delashaw Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chris G. Yedinak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edward A. Neuwelt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Fleseriu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Fleseriu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dillard, T.H., Gultekin, S.H., Delashaw, J.B. et al. Temozolomide for corticotroph pituitary adenomas refractory to standard therapy. Pituitary 14, 80–91 (2011). https://doi.org/10.1007/s11102-010-0264-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-010-0264-1

Keywords

Search

Navigation