Long-term recurrence and mortality after surgery and adjuvant radiotherapy for nonfunctional pituitary adenomas

Restricted access


Long-term outcomes following surgery for nonfunctional pituitary adenomas (NFPAs) are unclear. The role of adjuvant radiation therapy is therefore controversial because it is associated with higher tumor control but also carries known long-term morbidity. The authors' aim was to determine predictors of recurrence and overall survival and to define patient subgroups that may benefit from radiotherapy.


The authors performed a retrospective cohort analysis of 663 patients who underwent surgery between 1975 and 1995 for treatment of primary NFPAs. The main outcome measures were disease progression after surgery, defined by clinical and/or imaging criteria, and all-cause mortality.


Over a median clinical follow-up of 8.4 years, there were 64 (9.7%) recurrences after treatment, with a median time to recurrence of 5.6 years. The 5-, 10-, and 15-year recurrence-free probabilities were 0.93, 0.87, and 0.81, respectively. Multivariate Cox proportional hazard regression analysis identified the following predictors as associated with increased recurrence: cavernous sinus invasion (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.5–6.4; p < 0.001) and subtotal resection (STR) without radiotherapy (HR 3.6, 95% CI 1.4–14; p = 0.01). Using time-to-event estimates to adjust for differences in follow-up between groups, radiotherapy was found to reduce tumor recurrence in only those patients who received an STR (p < 0.001, log-rank test) but not gross-total resection (GTR; p = 0.63, log-rank test). Median follow-up for overall survival was 14.0 years. The 5-, 10-, 15- and 20-year overall survival estimates were 0.91, 0.81, 0.69, and 0.55, respectively. Within the study cohort and in age- and sex-adjusted comparison with the general US population, increased relative mortality was observed in patients who underwent radiotherapy or STR.


Cavernous sinus invasion is an important prognostic variable for long-term control of NFPAs. Radiotherapy results in long-term tumor control for patients who undergo STR but does not affect recurrence rates and may increase the risk of death after GTR. Given the risks associated with radiotherapy, there is no role for its routine application in patients who have undergone GTR of their NFPA. In all patients, long-term monitoring is required.

Abbreviations used in this paper: ACTH = adrenocorticotropic hormone; CI = confidence interval; CT = computed tomography; GH = growth hormone; GTR = gross-total resection; HR = hazard ratio; MR = magnetic resonance; NDI = National Death Index; NFPA = nonfunctional pituitary adenoma; OR = odds ratio; SSDI = Social Security Death Index; STR = subtotal resection.

Article Information

Address correspondence to: Edward F. Chang, M.D., Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, M779 Campus Box 0122, San Francisco, California 94143. email: echang@itsa.ucsf.edu.

© AANS, except where prohibited by US copyright law.



  • View in gallery

    Kaplan–Meier plot of recurrence-free survival after resection in 663 patients with NFPAs. Patients who underwent an STR without radiotherapy had far shorter time to recurrence than all other groups (p < 0.005, log-rank test). No statistical difference was observed between patients who underwent GTR with and without radiotherapy (p = 0.43, log-rank test).

  • View in gallery

    Kaplan–Meier plots of overall survival after resection of NFPA. A: Total population (663 patients). B. Subset of patients who survived > 10 years after surgery (484 patients). Patients who underwent GTR without radiotherapy appeared to have improved overall survival compared with all other groups (*p < 0.05, log-rank test).


  • 1

    Arafah BMKailani SHNekl KEGold RSSelman WR: Immediate recovery of pituitary function after transsphenoidal resection of pituitary macroadenomas. J Clin Endocrinol Metab 79:3483541994

  • 2

    Barker FG IIKlibanski ASwearingen B: Transsphenoidal surgery for pituitary tumors in the United States, 1996-2000: mortality, morbidity, and the effects of hospital and surgeon volume. J Clin Endocrinol Metab 88:470947192003

  • 3

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

  • 4

    Brada MFord DAshley SBliss JMCrowley SMason M: Risk of second brain tumour after conservative surgery and radio-therapy for pituitary adenoma. BMJ 304:134313461992

  • 5

    Brada MRajan BTraish DAshley SHolmes-Sellors PJNussey S: The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Clin Endocrinol (Oxf) 38:5715781993

  • 6

    Bradley KJWass JATurner HE: Non-functioning pituitary adenomas with positive immunoreactivity for ACTH behave more aggressively than ACTH immunonegative tumours but do not recur more frequently. Clin Endocrinol (Oxf) 58:59642003

  • 7

    Bradley KMAdams CBPotter CPWheeler DWAnslow PJBurke CW: An audit of selected patients with non-functioning pituitary adenoma treated by transsphenoidal surgery without irradiation. Clin Endocrinol (Oxf) 41:6556591994

  • 8

    Cappabianca PCavallo LMde Divitiis E: Endoscopic endonasal transsphenoidal surgery. Neurosurgery 55:9339412004

  • 9

    Ciric IRagin ABaumgartner CPierce D: Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 40:2252271997

  • 10

    Comtois RBeauregard HSomma MSerri OAris-Jilwan NHardy J: The clinical and endocrine outcome to trans-sphenoidal microsurgery of nonsecreting pituitary adenomas. Cancer 68:8608661991

  • 11

    Cowper DCKubal JDMaynard CHynes DM: A primer and comparative review of major US mortality databases. Ann Epidemiol 12:4624682002

  • 12

    Erfurth EMBulow BSvahn-Tapper GNorrving BOdh KMikoczy Z: Risk factors for cerebrovascular deaths in patients operated and irradiated for pituitary tumors. J Clin Endocrinol Metab 87:489248992002

  • 13

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

  • 14

    Fisher BJGaspar LENoone B: Radiation therapy of pituitary adenoma: delayed sequelae. Radiology 187:8438461993

  • 15

    Flickinger JCNelson PBMartinez AJDeutsch MTaylor F: Radiotherapy of nonfunctional adenomas of the pituitary gland. Results with long-term follow-up. Cancer 63:240924141989

  • 16

    Gittoes NJ: Radiotherapy for non-functioning pituitary tumors—when and under what circumstances?. Pituitary 6:1031082003

  • 17

    Gittoes NJBates ASTse WBullivant BSheppard MCClayton RN: Radiotherapy for non-function pituitary tumours. Clin Endocrinol (Oxf) 48:3313371998

  • 18

    Greenman YOuaknine GVeshchev IReider G IISegev YStern N: Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and re-growth. Clin Endocrinol (Oxf) 58:7637692003

  • 19

    Hall WALuciano MGDoppman JLPatronas NJOldfield EH: Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 120:8178201994

  • 20

    Hardy JTranssphenoidal surgery of hypersecreting pituitary tumors. Kohler PORoss GT: Diagnosis and Treatment of Pituitary Tumors. International Congress Series Vol 303:AmsterdamExcerpta Medica1973. 179198

  • 21

    Kobayashi TMori YUchiyama YKida YFujitani S: Long-term results of gamma knife surgery for growth hormone-producing pituitary adenoma: is the disease difficult to cure?. J Neurosurg 102:Suppl1191232005

  • 22

    Lillehei KOKirschman DLKleinschmidt-DeMasters BKRidg-way EC: Reassessment of the role of radiation therapy in the treatment of endocrine-inactive pituitary macroadenomas. Neurosurgery 43:4324391998

  • 23

    Lindholm JNielsen EHBjerre PChristiansen JSHagen CJuul S: Hypopituitarism and mortality in pituitary adenoma. Clin Endocrinol (Oxf) 65:51582006

  • 24

    Losa MValle MMortini PFranzin Ada Passano CFCenzato M: Gamma knife surgery for treatment of residual nonfunctioning pituitary adenomas after surgical debulking. J Neurosurg 100:4384442004

  • 25

    McCollough WMMarcus RB JrRhoton AL JrBallinger WEMillion RR: Long-term follow-up of radiotherapy for pituitary adenoma: the absence of late recurrence after greater than or equal to 4500 cGy. Int J Radiat Oncol Biol Phys 21:6076141991

  • 26

    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

  • 27

    Nammour GMYbarra JNaheedy MHRomeo JHAron DC: Incidental pituitary macroadenoma: a population-based study. Am J Med Sci 314:2872911997

  • 28

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

  • 29

    Peace KAOrme SMSebastian JPThompson ARBarnes SEllis A: The effect of treatment variables on mood and social adjustment in adult patients with pituitary disease. Clin Endocrinol (Oxf) 46:4454501997

  • 30

    Picozzi PLosa MMortini PValle MAFranzin AAttuati L: Radiosurgery and the prevention of regrowth of incompletely removed nonfunctioning pituitary adenomas. J Neurosurg 102:Suppl71742005

  • 31

    Scheithauer BWJaap AJHorvath EKovacs KLloyd RVMeyer FB: Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery 47:7237302000

  • 32

    Schisterman EFWhitcomb BW: Use of the Social Security Administration Death Master File for ascertainment of mortality status. Popul Health Metr 2:22004

  • 33

    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

  • 34

    Snyder PJFowble BFSchatz NJSavino PJGennarelli TA: Hypopituitarism following radiation therapy of pituitary adenomas. Am J Med 81:4574621986

  • 35

    Tomlinson JWHolden NHills RKWheatley KClayton RNBates AS: Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357:4254312001

  • 36

    Turner HEStratton IMByrne JVAdams CBWass JA: Audit of selected patients with nonfunctioning pituitary adenomas treated without irradiation—a follow-up study. Clin Endocrinol (Oxf) 51:2812841999

  • 37

    Wilson CGNeurosurgical management of large and invasive pituitary tumors. Tindall GTCollins WF: Clinical Management of Pituitary Disorders New YorkRaven Press1979. 335342

  • 38

    Zada GKelly DFCohan PWang CSwerdloff R: Endonasal transsphenoidal approach for pituitary adenomas and other sellar lesions: an assessment of efficacy, safety, and patient impressions. J Neurosurg 98:3503582003




All Time Past Year Past 30 Days
Abstract Views 175 175 33
Full Text Views 221 221 4
PDF Downloads 104 104 3
EPUB Downloads 0 0 0


Google Scholar