, Volume 22, Issue 6, pp 607–613 | Cite as

Outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy for refractory Cushing’s disease

  • Alexander D. Sherry
  • Mohamed H. KhattabEmail author
  • Mark C. Xu
  • Patrick Kelly
  • Joshua L. Anderson
  • Guozhen Luo
  • Andrea L. Utz
  • Lola B. Chambless
  • Anthony J. Cmelak
  • Albert Attia



Hypofractionated stereotactic radiotherapy (HSRT) for refractory Cushing’s disease may offer a condensed treatment schedule for patients with large tumors abutting the optic chiasm unsuitable for stereotactic radiosurgery (SRS). To-date only four patients have been treated by HSRT in the published literature. We investigated the feasibility, toxicity, and efficacy of HSRT compared to SRS.


After approval, we retrospectively evaluated patients treated at our institution for refractory Cushing’s disease with SRS or HSRT. Study outcomes included biochemical control, time to biochemical control, local control, and late complications. Binary logistic regression and Cox proportional hazards regression evaluated predictors of outcomes.


Patients treated with SRS (n = 9) and HSRT (n = 9) were enrolled with median follow-up of 3.4 years. Clinicopathologic details were balanced between the cohorts. Local control was 100% in both cohorts. Time to biochemical control was 6.6. and 9.5 months in the SRS and HSRT cohorts, respectively (p = 0.6258). Two patients in each cohort required salvage bilateral adrenalectomy. Late complications including secondary malignancy, radionecrosis, cranial nerve neuropathy, and optic pathway injury were minimal for either cohort.


HSRT is an appropriate treatment approach for refractory Cushing’s disease, particularly for patients with large tumors abutting the optic apparatus. Prospective studies are needed to validate these findings and identify factors suggesting optimal fractionation approaches.


Cushing’s disease Fractionation Radiosurgery Pituitary adenoma Biochemical control Hypofractionated stereotactic radiotherapy 



This work was supported by CTSA Award No. UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.


There was no funding associated with this study.

Compliance with ethical standards

Conflict of interest

Alexander Sherry declares that he has no conflicts of interest. Mohamed H. Khattab receives research funding support from Varian Medical Systems and Brainlab, Inc. Mark Xu declares that he has no conflicts of interest. Patrick Kelly declares that he has no conflicts of interest. Joshua Anderson declares that he has no conflicts of interest. Guozhen Luo declares that she has no conflicts of interest. Andrea Utz declares that she has no conflicts of interest. Lola Chambless declares that she has no conflicts of interest. Anthony Cmelak declares that he has no conflicts of interest. Albert Attia receives funding from Brainlab, AstraZeneca, and Novocure.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was waived by the IRB due to the determination of minimal risk of the study.


  1. 1.
    Cushing H (1932) The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 50:137–195Google Scholar
  2. 2.
    Cushing H (1932) Further notes on pituitary basophilism. JAMA 99:281–284CrossRefGoogle Scholar
  3. 3.
    Buliman A, Tataranu L, Paun D et al (2016) Cushing’s disease: a multidisciplinary overview of the clinical features, diagnosis, and treatment. J Med Life 9:12–18PubMedPubMedCentralGoogle Scholar
  4. 4.
    Broder MS, Neary MP, Chang E et al (2015) Incidence of Cushing’s syndrome and Cushing’s disease in commercially-insured patients %3c65 years old in the United States. Pituitary 18:283–289. CrossRefPubMedGoogle Scholar
  5. 5.
    Dahia PLM, Grossman AB (1999) The molecular pathogenesis of corticotroph tumors. Endocr Rev 20:136–155. CrossRefPubMedGoogle Scholar
  6. 6.
    Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. Lancet 367:1605–1617. CrossRefPubMedGoogle Scholar
  7. 7.
    Pivonello R, De Leo M, Cozzolino A, Colao A (2015) The treatment of cushing’s disease. Endocr Rev 36:385–486. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Pivonello R, De Martino M, De Leo M et al (2008) Cushing’s syndrome. Endocrinol Metab Clin North Am 37:135–149. CrossRefPubMedGoogle Scholar
  9. 9.
    Feelders RA, Pulgar SJ, Kempel A, Pereira AM (2012) The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 167:311–326. CrossRefPubMedGoogle Scholar
  10. 10.
    Graversen D, Vestergaard P, Stochholm K et al (2012) Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med 23:278–282. CrossRefPubMedGoogle Scholar
  11. 11.
    Clayton RN (2010) Mortality in Cushing’s disease. Neuroendocrinology 92(Suppl 1):71–76. CrossRefPubMedGoogle Scholar
  12. 12.
    Miller JW, Crapo L (1993) The medical treatment of cushing’s syndrome. Endocr Rev 14:443–458. CrossRefPubMedGoogle Scholar
  13. 13.
    Juszczak A, Ertorer ME, Grossman A (2013) The therapy of cushing’s disease in adults and children: an update. Horm Metab Res 45:109–117. CrossRefPubMedGoogle Scholar
  14. 14.
    Mehta GU, Lonser RR, Oldfield EH (2012) The history of pituitary surgery for Cushing disease. J Neurosurg 116:261–268. CrossRefPubMedGoogle Scholar
  15. 15.
    Loeffler JS, Shih HA (2011) Radiation therapy in the management of pituitary adenomas [Review]. J Clin Endocrinol Metab 96:1992–2003. CrossRefGoogle Scholar
  16. 16.
    Kong DS, Il Lee J, Do HL et al (2007) The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: long-term results of 125 consecutive patients treated in a single institution. Cancer 110:854–860. CrossRefPubMedGoogle Scholar
  17. 17.
    Mitsumori M, Shrieve DC, Alexander E et al (1998) Initial clinical results of linac-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas. Int J Radiat Oncol Biol Phys 42:573–580. CrossRefPubMedGoogle Scholar
  18. 18.
    Fowler JF (2010) 21 Years of biologically effective dose. Br J Radiol 83:554–568. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pham CJ, Chang SD, Gibbs IC et al (2004) Preliminary visual field preservation after staged CyberKnife radiosurgery for perioptic lesions. Neurosurgery 54:799–810. CrossRefPubMedGoogle Scholar
  20. 20.
    Adler JR, Gibbs IC, Puataweepong P, Chang SD (2006) Visual field preservation after multisession CyberKnife radiosurgery for perioptic lesions. Neurosurgery 59:2442–2454. CrossRefGoogle Scholar
  21. 21.
    Liao HI, Wang CC, Wei KC et al (2014) Fractionated stereotactic radiosurgery using the Novalis system for the management of pituitary adenomas close to the optic apparatus. J Clin Neurosci 21:111–115. CrossRefPubMedGoogle Scholar
  22. 22.
    Niranjan A, Flickinger JC (2008) Radiobiology, principle and technique of radiosurgery. Prog Neurol Surg 21:32–42. CrossRefPubMedGoogle Scholar
  23. 23.
    Kondziolka D, Shin SM, Brunswick A et al (2015) The biology of radiosurgery and its clinical applications for brain tumors. Neuro Oncol 17:29–44. CrossRefPubMedGoogle Scholar
  24. 24.
    Hall EJ, Brenner DJ (1993) The radiobiology of radiosurgery: rationale for different treatment regimes for AVMs and malignancies. Int J Radiat Oncol Biol Phys 25:381–385. CrossRefPubMedGoogle Scholar
  25. 25.
    Harris PA, Taylor R, Thielke R et al (2009) Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf 42:377–381. CrossRefGoogle Scholar
  26. 26.
    Cahan W, Woodard H (1948) Sarcoma arising in irradiated bone; report of 11 cases. Cancer 1:3–29CrossRefGoogle Scholar
  27. 27.
    Sonino N, Zielezny M, Fava GA et al (1996) Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. J Clin Endocrinol Metab 81:2647–2652. CrossRefPubMedGoogle Scholar
  28. 28.
    Howlett T, Plowman P, Wass J et al (1989) Megavoltage pituitary irradiation in the management of Cushing’s disease and Nelson’s syndrome: long-term follow-up. Clin Endocrinol 31:309–323CrossRefGoogle Scholar
  29. 29.
    Vicente A, Estrada J, de la Cuerda C et al (2009) Results of external pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. Acta Endocrinol (Copenh) 125:470–474. CrossRefGoogle Scholar
  30. 30.
    Tran LM, Blount L, Horton D et al (1991) Radiation therapy of pituitary tumors: results in 95 cases. Am J Clin Oncol 14:25–29. CrossRefPubMedGoogle Scholar
  31. 31.
    Zierhut D, Flentje M, Adolph J et al (1995) External radiotherapy of pituitary adenomas. Int J Radiat Oncol Biol Phys 33:307–314. CrossRefPubMedGoogle Scholar
  32. 32.
    Estrada J, Boronat M, Mielgo M et al (1997) The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in cushing’s disease. N Engl J Med 336:172–177. CrossRefPubMedGoogle Scholar
  33. 33.
    Minniti G, Osti M, Jaffrain-Rea ML et al (2007) Long-term follow-up results of postoperative radiation therapy for Cushing’s disease. J Neurooncol 84:79–84. CrossRefPubMedGoogle Scholar
  34. 34.
    Voges J, Kocher M, Runge M et al (2006) Linear accelerator radiosurgery for pituitary macroadenomas: a 7-year follow-up study. Cancer 107:1355–1364. CrossRefPubMedGoogle Scholar
  35. 35.
    Sheehan JP, Pouratian N, Steiner L et al (2011) Gamma knife surgery for pituitary adenomas: factors related to radiological and endocrine outcomes. J Neurosurg 114:303–309. CrossRefPubMedGoogle Scholar
  36. 36.
    Castinetti F, Nagai M, Morange I et al (2009) Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 94:3400–3407. CrossRefPubMedGoogle Scholar
  37. 37.
    Devin JK, Allen GS, Cmelak AJ et al (2004) The efficacy of linear accelerator radiosurgery in the management of patients with Cushing’s disease. Stereotact Funct Neurosurg 82:254–262. CrossRefPubMedGoogle Scholar
  38. 38.
    Jagannathan J, Sheehan J, Pouratian N et al (2007) Gamma knife surgery for Cushing’s disease. J Neurosurg 106:980–987. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Alexander D. Sherry
    • 1
  • Mohamed H. Khattab
    • 2
    Email author
  • Mark C. Xu
    • 1
  • Patrick Kelly
    • 3
  • Joshua L. Anderson
    • 1
  • Guozhen Luo
    • 2
  • Andrea L. Utz
    • 3
    • 4
    • 5
  • Lola B. Chambless
    • 3
  • Anthony J. Cmelak
    • 2
  • Albert Attia
    • 2
    • 3
  1. 1.Vanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of Radiation Oncology, Vanderbilt-Ingram Cancer CenterVanderbilt University Medical CenterNashvilleUSA
  3. 3.Department of Neurological SurgeryVanderbilt University Medical CenterNashvilleUSA
  4. 4.Division of Diabetes, Endocrinology & Metabolism, Department of MedicineVanderbilt University Medical CenterNashvilleUSA
  5. 5.Vanderbilt Pituitary CenterNashvilleUSA

Personalised recommendations