Gamma Knife radiosurgery for the management of nonfunctioning pituitary adenomas: a multicenter study

Clinical article

Restricted access


Pituitary adenomas are fairly common intracranial neoplasms, and nonfunctioning ones constitute a large subgroup of these adenomas. Complete resection is often difficult and may pose undue risk to neurological and endocrine function. Stereotactic radiosurgery has come to play an important role in the management of patients with nonfunctioning pituitary adenomas. This study examines the outcomes after radiosurgery in a large, multicenter patient population.


Under the auspices of the North American Gamma Knife Consortium, 9 Gamma Knife surgery (GKS) centers retrospectively combined their outcome data obtained in 512 patients with nonfunctional pituitary adenomas. Prior resection was performed in 479 patients (93.6%) and prior fractionated external-beam radiotherapy was performed in 34 patients (6.6%). The median age at the time of radiosurgery was 53 years. Fifty-eight percent of patients had some degree of hypopituitarism prior to radiosurgery. Patients received a median dose of 16 Gy to the tumor margin. The median follow-up was 36 months (range 1–223 months).


Overall tumor control was achieved in 93.4% of patients at last follow-up; actuarial tumor control was 98%, 95%, 91%, and 85% at 3, 5, 8, and 10 years postradiosurgery, respectively. Smaller adenoma volume (OR 1.08 [95% CI 1.02–1.13], p = 0.006) and absence of suprasellar extension (OR 2.10 [95% CI 0.96–4.61], p = 0.064) were associated with progression-free tumor survival. New or worsened hypopituitarism after radiosurgery was noted in 21% of patients, with thyroid and cortisol deficiencies reported as the most common postradiosurgery endocrinopathies. History of prior radiation therapy and greater tumor margin doses were predictive of new or worsening endocrinopathy after GKS. New or progressive cranial nerve deficits were noted in 9% of patients; 6.6% had worsening or new onset optic nerve dysfunction. In multivariate analysis, decreasing age, increasing volume, history of prior radiation therapy, and history of prior pituitary axis deficiency were predictive of new or worsening cranial nerve dysfunction. No patient died as a result of tumor progression. Favorable outcomes of tumor control and neurological preservation were reflected in a 4-point radiosurgical pituitary score.


Gamma Knife surgery is an effective and well-tolerated management strategy for the vast majority of patients with recurrent or residual nonfunctional pituitary adenomas. Delayed hypopituitarism is the most common complication after radiosurgery. Neurological and cranial nerve function were preserved in more than 90% of patients after radiosurgery. The radiosurgical pituitary score may predict outcomes for future patients who undergo GKS for a nonfunctioning adenoma.

Abbreviations used in this paper:CN = cranial nerve; EBRT = external-beam radiation therapy; GKS = Gamma Knife surgery; NAGKC = North American Gamma Knife Consortium; RPS = radiosurgical pituitary score; SRS = stereotactic radiosurgery.

Article Information

Address correspondence to: Jason Sheehan, M.D., Ph.D., Department of Neurological Surgery, University of Virginia Health System, Box 800212, Charlottesville, Virginia 22908. email:

Please include this information when citing this paper: published online April 26, 2013; DOI: 10.3171/2013.3.JNS12766.

© AANS, except where prohibited by US copyright law.



  • View in gallery

    Progression-free survival after GKS for a cohort of 512 patients with nonfunctioning pituitary adenomas.

  • View in gallery

    Progression-free survival after GKS for those undergoing upfront compared with salvage radiosurgery.

  • View in gallery

    Progression-free survival after GKS as a function of adenoma volume.

  • View in gallery

    Progression-free survival after GKS as a function of presence or absence of suprasellar extension of the pituitary adenoma. HR = hazard ratio.

  • View in gallery

    Progression-free survival after radiosurgery as a function of margin dose ≥ 16 Gy or < 16 Gy.

  • View in gallery

    Progression-free survival after radiosurgery as a function of margin dose < 12 Gy, 12 to 20 Gy, and > 20 Gy.

  • View in gallery

    Radiosurgical pituitary score. The score is as follows: age: 1 point for > 50 years old, 0 points for ≤ 50 years old; tumor volume: 1 point for tumor volume < 5 cm3, 0 points for tumor volume ≥ 5 cm3; and prior radiation: 2 points for no previous radiation, 0 points for prior radiation. A higher score represents a more favorable outcome, and numbers on the y axis refer to percentage of favorable outcomes.


  • 1

    Adler JR JrGibbs ICPuataweepong PChang SD: Visual field preservation after multisession cyberknife radiosurgery for perioptic lesions. Neurosurgery 59:2442542006

  • 2

    Altman DG: Practical Statistics for Medical Research Boca Raton, FLChapman & Hall/CRC1999

  • 3

    Arbous MSMeursing AEvan Kleef JWde Lange JJSpoormans HHTouw P: Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology 102:2572682005

  • 4

    Brada MAshley SFord DTraish DBurchell LRajan B: Cerebrovascular mortality in patients with pituitary adenoma. Clin Endocrinol (Oxf) 57:7137172002

  • 5

    Brada MJankowska P: Radiotherapy for pituitary adenomas. Endocrinol Metab Clin North Am 37:2632752008

  • 6

    Brochier SGalland FKujas MParker FGaillard SRaftopoulos C: Factors predicting relapse of nonfunctioning pituitary macroadenomas after neurosurgery: a study of 142 patients. Eur J Endocrinol 163:1932002010

  • 7

    Cahan WGWoodard HQHiginbotham NLStewart FWColey BL: Sarcoma arising in irradiated bone: report of eleven cases. 1948. Cancer 82:8341998

  • 8

    Castinetti FNagai MMorange IDufour HCaron PChanson P: Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 94:340034072009

  • 9

    Chandler WFSchteingart DELloyd RVMcKeever PEIbarra-Perez G: Surgical treatment of Cushing's disease. J Neurosurg 66:2042121987

  • 10

    Daly AFRixhon MAdam CDempegioti ATichomirowa MABeckers A: High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 91:476947752006

  • 11

    Dekkers OMPereira AMRoelfsema FVoormolen JHNeelis KJSchroijen MA: Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 91:179618012006

  • 12

    Dekkers OMPereira AMRomijn JA: Treatment and follow-up of clinically nonfunctioning pituitary macroadenomas. J Clin Endocrinol Metab 93:371737262008

  • 13

    Ezzat SAsa SLCouldwell WTBarr CEDodge WEVance ML: The prevalence of pituitary adenomas: a systematic review. Cancer 101:6136192004

  • 14

    Feigl GCPistracher KBerghold AMokry M: Pituitary insufficiency as a side effect after radiosurgery for pituitary adenomas: the role of the hypothalamus. Clinical article. J Neurosurg 113:Suppl1531592010

  • 15

    Fernández-Balsells MMMurad MHBarwise AGallegos-Orozco JFPaul ALane MA: Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis. J Clin Endocrinol Metab 96:9059122011

  • 16

    Gopalan RSchlesinger DVance MLLaws ESheehan J: Long-term outcomes after Gamma Knife radiosurgery for patients with a nonfunctioning pituitary adenoma. Neurosurgery 69:2842932011

  • 17

    Greenman YStern N: How should a nonfunctioning pituitary macroadenoma be monitored after debulking surgery?. Clin Endocrinol (Oxf) 70:8298322009

  • 18

    Hasegawa TKobayashi TKida Y: Tolerance of the optic apparatus in single-fraction irradiation using stereotactic radiosurgery: evaluation in 100 patients with craniopharyngioma. Neurosurgery 66:6886952010

  • 19

    Höybye CGrenbäck ERähn TDegerblad MThorén MHulting AL: Adrenocorticotropic hormone-producing pituitary tumors: 12- to 22-year follow-up after treatment with stereotactic radiosurgery. Neurosurgery 49:2842922001

  • 20

    Iwata HSato KTatewaki KYokota NInoue MBaba Y: Hypofractionated stereotactic radiotherapy with CyberKnife for nonfunctioning pituitary adenoma: high local control with low toxicity. Neuro Oncol 13:9169222011

  • 21

    Jane JA JrVance MLWoodburn CJLaws ER Jr: Stereotactic radiosurgery for hypersecreting pituitary tumors: part of a multimodality approach. Neurosurg Focus 14:5e122003

  • 22

    Kuo JSChen JCYu CZelman VGiannotta SLPetrovich Z: Gamma knife radiosurgery for benign cavernous sinus tumors: quantitative analysis of treatment outcomes. Neurosurgery 54:138513942004

  • 23

    Lagasse RS: Anesthesia safety: model or myth? A review of the published literature and analysis of current original data. Anesthesiology 97:160916172002

  • 24

    Laws EREbersold MJPiepgras DGThe results of transsphenoidal surgery in specific clinical entities. Laws ERRandall RVKern EB: Management of Pituitary Adenomas and Related Lesions with Emphasis on Transsphenoidal Microsurgery New YorkAppleton-Century-Crofts1982. 277305

  • 25

    Laws ER JrVance ML: Radiosurgery for pituitary tumors and craniopharyngiomas. Neurosurg Clin N Am 10:3273361999

  • 26

    Leber KABerglöff JPendl G: Dose-response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg 88:43501998

  • 27

    Leksell L: Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry 46:7978031983

  • 28

    Levy RPFabrikant JIFrankel KAPhillips MHLyman JTLawrence JH: Heavy-charged-particle radiosurgery of the pituitary gland: clinical results of 840 patients. Stereotact Funct Neurosurg 57:22351991

  • 29

    Lim YLLeem WKim TSRhee BAKim GK: Four years' experiences in the treatment of pituitary adenomas with gamma knife radiosurgery. Stereotact Funct Neurosurg 70:Suppl 1951091998

  • 30

    Loeffler JSNiemierko AChapman PH: Second tumors after radiosurgery: tip of the iceberg or a bump in the road?. Neurosurgery 52:143614422003

  • 31

    Loeffler JSShih HA: Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 96:199220032011

  • 32

    Mayo CMartel MKMarks LBFlickinger JNam JKirkpatrick J: Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 76:3 SupplS28S352010

  • 33

    Meij BPLopes MBEllegala DBAlden TDLaws ER Jr: The long-term significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. J Neurosurg 96:1952082002

  • 34

    Mingione VYen CPVance MLSteiner MSheehan JLaws ER: Gamma surgery in the treatment of nonsecretory pituitary macroadenoma. J Neurosurg 104:8768832006

  • 35

    Minniti GTraish DAshley SGonsalves ABrada M: Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J Clin Endocrinol Metab 90:8008042005

  • 36

    Muramatsu JYoshida MShioura HKawamura YIto HTakeuchi H: [Clinical results of LINAC-based stereotactic radiosurgery for pituitary adenoma.]. Nippon Igaku Hoshasen Gakkai Zasshi 63:2252302003. (Jpn)

  • 37

    Noh TWJeong HJLee MKKim TSKim SHLee EJ: Predicting recurrence of nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 94:440644132009

  • 38

    O'Sullivan EPWoods CGlynn NBehan LACrowley RO'Kelly P: The natural history of surgically treated but radiotherapy-naïve nonfunctioning pituitary adenomas. Clin Endocrinol (Oxf) 71:7097142009

  • 39

    Park KJKano HParry PVNiranjan AFlickinger JCLunsford LD: Long-term outcomes after gamma knife stereotactic radiosurgery for nonfunctional pituitary adenomas. Neurosurgery 69:118811992011

  • 40

    Park PChandler WFBarkan ALOrrego JJCowan JAGriffith KA: The role of radiation therapy after surgical resection of nonfunctional pituitary macroadenomas. Neurosurgery 55:1001072004

  • 41

    Patil CGLad SPHarsh GRLaws ER JrBoakye M: National trends, complications, and outcomes following transsphenoidal surgery for Cushing's disease from 1993 to 2002. Neurosurg Focus 23:3E72007

  • 42

    Pollock BECarpenter PC: Stereotactic radiosurgery as an alternative to fractionated radiotherapy for patients with recurrent or residual nonfunctioning pituitary adenomas. Neurosurgery 53:108610942003

  • 43

    Pollock BENippoldt TBStafford SLFoote RLAbboud CF: Results of stereotactic radiosurgery in patients with hormone-producing pituitary adenomas: factors associated with endocrine normalization. J Neurosurg 97:5255302002

  • 44

    Sayer FTSherman JHYen CPSchlesinger DJKersh RSheehan JP: Initial experience with the eXtend System: a relocatable frame system for multiple-session gamma knife radiosurgery. World Neurosurg 75:6656722011

  • 45

    Sheehan J: Radiosurgical induced neoplasia: a seldom seen complication. World Neurosurg 73:6446452010

  • 46

    Sheehan JMVance MLSheehan JPEllegala DBLaws ER Jr: Radiosurgery for Cushing's disease after failed transsphenoidal surgery. J Neurosurg 93:7387422000

  • 47

    Sheehan JPKondziolka DFlickinger JLunsford LD: Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma. J Neurosurg 97:5 Suppl4084142002

  • 48

    Sheehan JPNiranjan ASheehan JMJane JA JrLaws ERKondziolka D: Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 102:6786912005

  • 49

    Sheehan JPPouratian NSteiner LLaws ERVance ML: Gamma Knife surgery for pituitary adenomas: factors related to radiological and endocrine outcomes. Clinical article. J Neurosurg 114:3033092011

  • 50

    Shin MKurita HSasaki TTago MMorita AUeki K: Stereotactic radiosurgery for pituitary adenoma invading the cavernous sinus. J Neurosurg 93:Suppl 3252000

  • 51

    Spiegelmann RNissim OMenhel JAlezra DPfeffer MR: Linear accelerator radiosurgery for meningiomas in and around the cavernous sinus. Neurosurgery 51:137313802002

  • 52

    Taussky PKalra RCoppens JMohebali JJensen RCouldwell WT: Endocrinological outcome after pituitary transposition (hypophysopexy) and adjuvant radiotherapy for tumors involving the cavernous sinus. Clinical article. J Neurosurg 115:55622011

  • 53

    Tishler RBLoeffler JSLunsford LDDuma CAlexander E IIIKooy HM: Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 27:2152211993

  • 54

    van den Bergh ACvan den Berg GSchoorl MASluiter WJvan der Vliet AMHoving EW: Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy. Int J Radiat Oncol Biol Phys 67:8638692007

  • 55

    Vance ML: Pituitary adenoma: a clinician's perspective. Endocr Pract 14:7577632008

  • 56

    Vladyka VLiscák RNovotný J JrMarek JJezková J: Radiation tolerance of functioning pituitary tissue in gamma knife surgery for pituitary adenomas. Neurosurgery 52:3093172003


Cited By



All Time Past Year Past 30 Days
Abstract Views 266 266 40
Full Text Views 456 456 16
PDF Downloads 107 107 12
EPUB Downloads 0 0 0


Google Scholar