Radiosurgery of growth hormone–producing pituitary adenomas: factors associated with biochemical remission

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Object

The authors reviewed outcomes after stereotactic radiosurgery for patients with acromegaly and analyzed factors associated with biochemical remission.

Methods

Retrospective analysis was performed for 46 consecutive cases of growth hormone (GH)–producing pituitary adenomas treated by radiosurgery between 1991 and 2004. Biochemical remission was defined as a fasting GH less than 2 ng/ml and a normal age- and sex-adjusted insulin-like growth factor–I (IGF-I) level while patients were not receiving any pituitary suppressive medications. The median follow up after radiosurgery was 63 months (range 22–168 months).

Twenty-three patients (50%) had biochemical remission documented at a median of 36 months (range 6–63 months) after one radiosurgical procedure. The actuarial rates of biochemical remission at 2 and 5 years after radiosurgery were 11 and 60%, respectively. Multivariate analysis showed that IGF-I levels less than 2.25 times the upper limit of normal (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.2–6.9, p = 0.02) and the absence of pituitary suppressive medications at the time of radiosurgery (HR 4.2, 95% CI 1.4–13.2, p = 0.01) correlated with biochemical remission. The incidence of new anterior pituitary deficits was 10% at 2 years and 33% at 5 years.

Conclusions

Discontinuation of pituitary suppressive medications at least 1 month before radiosurgery significantly improved endocrine outcomes for patients with acromegaly. Patients with GH–producing pituitary adenomas should not undergo further radiation therapy or surgery for at least 5 years after radiosurgery because GH and IGF-I levels continue to normalize over that interval.

Abbreviations used in this paper:CI = confidence interval; GH = growth hormone; HR = hazard ratio; IGF-I = insulin-like growth factor–I; MR = magnetic resonance.

Growth hormone–producing pituitary adenomas account for approximately 20% of all pituitary neoplasms. Untreated acromegaly is a morbid condition associated with disfigurement and an increased mortality rate, primarily due to heart disease.5 Treatment options include drug therapy,10 resection,1,11,15,26 radiation therapy,4,8,24 stereotactic radiosurgery,3,6,15–17,23,25 or a combination of these approaches. The goals of treatment are to achieve normal levels of GH and IGF-I to reverse the metabolic imbalance and to improve symptoms related to tumor mass effect.12,14,20 Transsphenoidal surgery is generally considered the first line of treatment for patients with acromegaly. Resection leads to rapid normalization of hormone levels in the majority of patients (55–91%).1,11,15,26 Biochemical remission is achieved less frequently in patients with macroadenomas or in patients whose tumors extend into the cavernous sinus.

Radiation therapy has long been regarded as a conventional adjuvant to surgical treatment or as primary treatment for inoperable tumors. Despite tumor control rates greater than 90% after radiation therapy of GH–producing tumors, the rate of biochemical remission is much lower when contemporary criteria of cure are used,30 and biochemical remission can take several years to achieve.4,8 In addition, like surgery, radiotherapy can cause hypothalamopituitary dysfunction and cognitive decline, and it also carries a small risk of radiation-induced neoplasms.2,7,27 Stereotactic radiosurgery has emerged as an effective alternative or adjunct to resection and radiation therapy for patients with pituitary adenomas.25 Radiosurgery allows focused radiation to be delivered to the tumor in a single session with little radiation exposure to the surrounding normal structures.

Previously, we reviewed our experience with stereotactic radiosurgery in patients with a variety of hormone-producing pituitary adenomas.23 In this report, we examine our now larger experience of using radiosurgery to manage GH-producing pituitary adenomas and analyze factors associated with biochemical remission after radiosurgery.

Clinical Material and Methods

Patient Population

The clinical, radiological, and endocrinological information on 48 consecutive patients who underwent radiosurgery for the treatment of GH-producing pituitary adenomas at the Mayo Clinic in Rochester, Minnesota, between October 1991 and April 2004 was retrieved from a prospective, longitudinally maintained computer database. Two patients did not have adequate follow-up information and were excluded from this study. The median age of the remaining 46 patients was 45 years (range 12–75 years). There were 22 men and 24 women. Forty-three patients (93%) had undergone previous surgery (range one–three surgeries). Six patients (13%) had undergone prior radiation therapy (median dose 47.5 Gy). Thirty-nine patients (85%) had tumors with cavernous sinus extension.

The median preradiosurgery GH level was 8.4 ng/ml (range 0.5–82 ng/ml). Over the 15-year study interval, a variety of assays were used to determine IGF-I levels. For purposes of comparison, we converted all IGF-I levels to the multiple of the upper limit of the age- and sex-based reference range.13 Specifically, the measured IGF-I level was divided by the upper limit of normal for the assay used. The median IGF-I level was 2.25 times the upper limit of normal (range 1.05–7.0). Pituitary suppressive medications were given before radiosurgery at the discretion of each patient's endocrinologist. Twenty-seven patients (59%) had not received any pituitary suppressive medications for at least 1 month before radiosurgery, whereas 19 patients (41%) were receiving pituitary suppressive medications at the time of radiosurgery. Medical therapy included octreotide (11 patients [24%]), dopamine-agonist therapy (six patients [13%]), or both (two patients [4%]). Eleven of the 13 patients who were being treated with somatostatin agonists at the time of radiosurgery were receiving immediate-release octreotide acetate, and two patients were receiving Sandostatin LAR Depot (Novartis Pharmaceuticals Corporation). Anterior pituitary function was normal in 30 patients (65%) before radiosurgery, whereas nine patients (20%) had partial anterior pituitary function. Seven patients (15%) had panhypopituitarism before radiosurgery.

Radiosurgery Dosimetry

Radiosurgery was performed using the Leksell Gamma Knife (Elekta Instruments). Target localization was based on stereotactic MR imaging. A median of seven isocenters of radiation (range one–18 isocenters) was used to cover a median tumor volume of 3.3 cm3 (range 0.5–18.0 cm3). The median tumor margin dose was 20 Gy (range 14.4–30 Gy), and the median maximum radiation dose was 43.5 Gy (range 30–60 Gy). The median maximum radiation dose to the anterior visual pathways was 9.5 Gy (range 5.2–13.0 Gy). Of note, 36 patients (78%) received a radiation dose to the optic apparatus greater than 8 Gy.

Follow Up

Follow-up examinations consisting of MR imaging, visual field and ophthalmological examination, and endocrinological testing were performed at 6-month intervals for the first 2 years, then yearly thereafter. Patients receiving suppressive medications at the time of radiosurgery or who began taking these medications after the procedure usually continued their medical regimen until their symptoms improved and biochemical remission was demonstrated. The medications were then discontinued; hormone assays were repeated after patients had not received any medication for at least 3 months. Biochemical remission was defined as a fasting GH level less than 2 ng/ml and normal age- and sex-adjusted IGF-I levels without any pituitary suppressive medications. Patients with normal (30 patients) or partial (nine patients) anterior pituitary function before radiosurgery also underwent assessment of morning cortisol, free thyroxine, thyroid-stimulating hormone, and gonadotropin/sex hormone levels to evaluate for new hormone deficits. The median duration of follow up after radiosurgery was 63 months (range 22–168 months).

Statistical Analysis

The dependent variable for all statistical analyses was time to biochemical remission after one radiosurgical procedure. The actuarial rate of biochemical remission was determined using the Kaplan–Meier method, and univariate analyses were performed using the log-rank test. Factors associated with biochemical remission at a significance level of 0.10 or less on univariate analysis were entered into a Cox proportional hazards model.

Results

Tumor Growth

No patient had tumor growth after radiosurgery. Tumor size remained unchanged in 14 patients (30%) and decreased in 32 patients (70%).

Biochemical Remission

Biochemical remission was documented in 23 patients (50%) at a median of 36 months (range 6–63 months) after one radiosurgical procedure. Eighteen (78%) of these 23 patients underwent further endocrine testing confirming biochemical remission 1 year or more after the initial documentation of hormone normalization. The actuarial rates of biochemical remission at 2 and 5 years after radiosurgery were 11 and 60%, respectively (Fig. 1).

Fig. 1.
Fig. 1.

Graph showing the biochemical remission rate after radiosurgery for 46 patients with GH-producing pituitary adenomas.

Univariate analysis showed that a normalized IGF-I level less than 2.25 times the upper limit of normal (p = 0.008) and the absence of pituitary suppressive medications at the time of radiosurgery (p = 0.003) were associated with biochemical remission (Table 1). Correlation with maximum radiation dose approached but did not reach statistical significance (p = 0.07). Multivariate analysis showed that IGF-I levels less than 2.25 times the upper limit of normal (HR 2.9, 95% CI 1.2–6.9, p = 0.02; Fig. 2) and the absence of pituitary suppressive medications at the time of radiosurgery (HR 4.2, 95% CI 1.4–13.2, p = 0.01; Fig. 3) correlated with biochemical remission.

TABLE 1

Univariate analysis of factors associated with biochemical remission

FactorPositive Predictorp Value
sexM0.38
age (yrs)<450.76
prior surgeryno1.00
cavernous sinus extensionno1.00
GH before radiosurgery (ng/ml)<8.40.20
normalized IGF-I before radiosurgery<2.250.008
volume (cm3)<3.30.57
tumor margin dose (Gy)≥200.76
maximum radiation dose (Gy)≥400.07
pituitary suppressive medications at radiosurgeryno0.003
Fig. 2.
Fig. 2.

Graph depicting a comparison of the biochemical remission rates for patients with IGF-I levels less than 2.25 times the upper limit of normal (24 patients) and patients with IGF-I levels greater than 2.25 times the upper limit of normal (22 patients). Squares indicate the group of patients who had lower initial IGF-I levels; triangles indicate those who had higher levels (HR 2.9, 95% CI 1.2–6.9, p = 0.02).

Fig. 3.
Fig. 3.

Graph depicting a comparison of the biochemical remission rates for patients not receiving pituitary suppressive medications at the time of radiosurgery (27 patients) and patients receiving pituitary suppressive medications at the time of radiosurgery (19 patients). Squares indicate the group of patients who were not receiving medication; triangles indicate those who were (HR 4.2, 95% CI 1.4–13.2, p = 0.01).

Complications and Additional Treatment

Fifteen patients (33%) had a radiation-related complication after radiosurgery. The most frequent complication, new anterior pituitary deficits, occurred in 13 (33%) of 39 patients who had normal or partial pituitary function before radiosurgery. The median time to the appearance of new deficits was 32 months (range 12–120 months). The deficits included hypoadrenalism (in one patient); hypogonadism (in two patients); hypothyroidism (in three patients); hypothyroidism and hypoadrenalism (in one patient); and hypothyroidism, hypoadrenalism, and hypogonadism (in six patients). Two patients had undetectable GH levels after radiosurgery; neither one underwent GH stimulation testing or received GH replacement therapy. Of the six patients (15%) who developed panhypopituitarism after radiosurgery, three had normal anterior pituitary function before radiosurgery whereas three had partial pituitary insufficiency. The incidence of new anterior pituitary deficits was 10% at 2 years and 33% at 5 years (Fig. 4). No analyzed factor correlated with new hormone deficits after radiosurgery. No patient developed diabetes insipidus. No patient had a decline in either visual acuity or visual fields after radiosurgery.

Fig. 4.
Fig. 4.

Graph illustrating the incidence of new anterior pituitary deficits after radiosurgery in 39 patients with acromegaly.

One patient developed an asymptomatic stenosis of the internal carotid artery. Another patient had an enlarging cyst in the adjacent temporal lobe that was resected 12 years after radiosurgery. Histopathological examination showed radiation necrosis. Both of these patients had received conventional radiation therapy (45 Gy) prior to radiosurgery. Two patients underwent additional tumor-directed treatment because of persistent GH overproduction. One patient underwent a craniotomy 13 months after radiosurgery followed by repeated radiosurgery 17 months after the first radiosurgical procedure. He had diplopia after the resection secondary to damage of the oculomotor nerve. Biochemical remission was documented 56 months after the first radiosurgery. A second patient underwent repeated radiosurgery 22 months after the first procedure. She continues to have elevated GH and IGF-I levels 102 months after her first radiosurgery.

Discussion

In patients with GH-producing pituitary adenomas, mortality rates are significantly higher than in age- and sex-matched control populations.5,20 Medical therapy with somatostatin agonists (octreotide) and, more recently, GH receptor agonists (pegvisomant) is often initiated to minimize the metabolic consequences of GH oversecretion.10,14,20 Nevertheless, many patients present with large tumors and compression of the optic nerves and chiasm, so resection through the transsphenoidal approach is frequently performed to relieve mass effect rapidly and normalize GH and IGF-I levels. In addition, for most of the patients whose tumors do not extend into the cavernous sinus, surgery provides a biochemical remission and eliminates the life-long expenses and potential side effects related to ongoing medical treatment. Consequently, transsphenoidal surgery performed by an experienced pituitary surgeon is generally considered the treatment of choice for appropriately selected patients. Yet many cases cannot be adequately managed with resection alone; in these cases radiation therapy has been performed to control tumor growth and correct hormone overproduction. Despite the high rate of tumor growth control, radiotherapy using conventional dosing regimens is associated with documented biochemical remission rates ranging from 5 to 16% when normalization of IGF-I levels is used as the criterion for biochemical remission.4,8

Stereotactic radiosurgery has emerged as an effective alternative to medical therapy, repeated resection, or radiation therapy for patients with acromegaly. Unfortunately, studies of these modalities are frequently difficult to compare because of advances in the procedure, such as the introduction of stereotactic MR imaging for tumor localization and improved dose-planning software. Also, few published studies include adequate endocrine evaluations after radiosurgery or apply standardized criteria for biochemical remission (growth hormone suppression during an oral glucose tolerance test and normal age- and sex-adjusted IGF-I levels).12 Other methodological factors that limit our understanding of the efficacy and safety of radiosurgery for GH-producing pituitary adenomas include small patient numbers, short follow-up intervals, and limited statistical analyses of factors related to biochemical remission.15–17,23 For all these reasons, our ability to counsel patients with acromegaly about radiosurgery is rather limited.

In the present study we attempted to address these shortcomings and compare our results to those reported in other recently published articles. First, the number of patients with acromegaly who were included in our study population has increased from 26 in our earlier review to 46 in the current report.23 Second, the median follow-up interval nearly doubled from 36 to 63 months. Third, our criteria for biochemical remission were quite similar to those recommended by the endocrinological community. It is recognized that GH secretion is pulsatile and can vary significantly throughout the day, so by itself, it is a poor indicator of disease status. The joint consensus statement from the Growth Hormone Research Society and Pituitary Society recommended documentation of GH suppression during a properly administered oral glucose tolerance test in addition to normal age- and sex-adjusted IGF-I levels. Because the routine administration of an oral glucose tolerance test is not practical in our practice, we defined biochemical remission as a fasting GH level less than 2 ng/ml and a normal age- and sex-adjusted IGF-I level obtained while patients are not receiving any pituitary suppressive medications. Fourth, we used life table methods to more accurately depict endocrine outcomes that clearly change based on the length of follow up. Last, we performed both univariate and multivariate analyses for a number of patient variables that could affect biochemical remission after radiosurgery.

By 5 years after surgery biochemical remission had been achieved in 60% of our patients. Factors related to biochemical remission were lower IGF-I levels before radiosurgery and the absence of pituitary suppressive medications at the time of the procedure. Biochemical remission rates exceeded 80% for patients with lower IGF-I levels before radiosurgery (less than 2.25 times the upper limit of normal) and for those not taking pituitary suppressive medications at the time of radiosurgery. Another important observation was that biochemical remission continued over the first 5 years after radiosurgery. This finding emphasizes the need for longer follow up in patients with acromegaly, and suggests that further tumor-directed therapies before 5 years have passed are probably not indicated. Complications were primarily limited to new anterior pituitary deficits, which occurred in one third of our patients within 5 years after radiosurgery. Radiation necrosis of the temporal lobe requiring surgery (one patient) and internal carotid artery stenosis (one patient) were also noted in our series as in earlier studies.19,25 The patients who experienced these two complications had both undergone radiation therapy prior to radiosurgery. Notably, no patient developed visual deficits despite the majority (78%) receiving more than 8 Gy of radiation to the anterior visual pathways.

The observation that treatment with pituitary suppressive medications at the time of radiosurgery is a negative predictor of endocrine normalization supports the theory of Landolt et al.,16 who found that octreotide treatment reduced the likelihood of a biochemical remission from 60 to 11% in patients with acromegaly undergoing radiosurgery. They hypothesized that octreotide played a radioprotective role as a result of reducing the metabolic activity in the adenoma cells. Another possible mechanism may involve the chemical structure of these agents. Octreotide contains disulfide bonds, which in the cell may be reduced to expose free thiols. Free thiols may act as scavengers of oxygen free radicals induced by ionizing radiation, thereby reducing their ability to cause DNA damage. Nevertheless, two recent studies found no difference in the endocrine outcome between patients who received somatostatin agonists at the time of radiosurgery and those who did not.3,6 One possible explanation is that authors have used different criteria to define biochemical remission or endocrine cure. For example, Castinetti and colleagues6 defined remission as a mean GH level of less than 2 ng/ml and normal age-adjusted IGF-I while patients were not being treated with somatostatin agonists, whereas Landolt and coauthors16 considered a cure to be achieved if patients had GH levels less than 5 ng/ml and IGF-I levels below the age-related limit while patients were not receiving medication. Our criteria of biochemical remission were the same as those of Castinetti et al., and we did note a significant negative effect on biochemical remission for patients receiving pituitary suppressive medications. No doubt, part of this discrepancy relates to the duration of follow up after radiosurgery. The actuarial curve of biochemical remission was quite steep between 1 and 5 years after radiosurgery in our series. In the series of Castenetti and colleagues, the mean follow up was 50 months, with 44% of their patients having a final off-treatment evaluation less than 36 months after radiosurgery. Reevaluation of these same patients at a later date is likely to increase the number of patients considered cured after radiosurgery.

A second explanation for the difference in observed cure rates may relate to the completeness of tumor coverage during the radiosurgical procedure. In both the series of Attanasio et al.3 and that of Castinetti et al.,6 the dose of radiation to the optic apparatus was deliberately limited to less than 8 Gy. The median dose to the anterior visual pathways in our series was 9.5 Gy. In addition, our median prescribed isodose volume was 3.3 cm3 compared with 1.4 cm3 reported in the paper by Attanasio and colleagues. In an attempt to reduce the radiation exposure of the optic pathways, it is possible that the tumor coverage was subtotal, contributing to the lower biochemical remission rates noted in these papers (17–30%) compared with our series (50%). Of course, irradiating a greater volume of the sellar region is also associated with a higher rate of new pituitary deficits. Thirty-three percent of our patients developed new anterior pituitary deficits compared with 7 and 17% reported in the other papers. Therefore, our rate of new pituitary insufficiency was comparable to studies on radiosurgery of nonfunctioning pituitary adenomas, which are typically larger at the time of radiosurgery.9,22,31 Conversely, we did not detect any increase in visual morbidity related to our radiosurgical technique. Thus, we believe that strict adherence to the dose prescription guidelines developed in the early 1990s, which recommend limiting the optic nerve and chiasm dose to less than 8 Gy,29 may result in subtotal tumor coverage, thereby contributing to persistently elevated hormone levels after radiosurgery. Our results (no patient having a new visual deficit after radiosurgery) in conjunction with those of other authors,18,21,28 who have documented minimal risk with the anterior visual pathways receiving 10 to 12 Gy, support the concept that larger radiation volumes and tumor margin doses can be safely used during pituitary adenoma radiosurgery.

Like Castinetti and colleagues,6 we noted that biochemical remission was more common in patients who had lower IGF-I levels before radiosurgery than in those who had higher preradiosurgical levels. Castinetti et al. noted that the initial GH and IGF-I levels for patients who were in remission after radiosurgery (7.1 ng/ml and 495 ng/ml, respectively) were significantly lower when compared with the levels of patients whose condition remained uncured after radiosurgery (25.3 ng/ml and 673 ng/ml, respectively).6 On the basis of their results, they emphasized the importance of preradiosurgical hormone levels in predicting the endocrine success of radiosurgery. In our multivariate analysis, we found that biochemical remission was almost three times more likely in patients who had initial IGF-I levels less than 2.25 times the upper limit of normal compared with patients who had initial IGF-I levels more than 2.25 times the upper limit of normal. Therefore, we agree that as a general indicator of disease severity, the initial level of hypersecretion of GH and IGF-I in patients with acromegaly may predict the chance of endocrine normalization after radiosurgery. Further study is needed to determine more precisely the levels of hormone oversecretion that are unlikely to be corrected by radiosurgery.

Conclusions

Although transsphenoidal microsurgery should be considered the best option for properly selected patients with acromegaly, hormone normalization is possible at low morbidity after radiosurgery for many patients with persistent GH oversecretion following resection. Discontinuation of pituitary suppressive medications at least 1 month before radiosurgery significantly improved endocrine outcomes for patients with acromegaly. Patients with GH-producing pituitary adenomas should not undergo further radiation or surgery for at least 5 years after radiosurgery because we found that GH and IGF-I levels continued to normalize over that interval. Future studies on pituitary adenoma radiosurgery must define biochemical remission according to accepted criteria to better facilitate comparisons between different treatment options.

References

  • 1

    Abosch ATyrrell JBLamborn KRHannegan LTApplebury CBWilson CB: Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 83:341134181998

  • 2

    Alexander MJDeSalles AATomiyasu U: Multiple radiation-induced intracranial lesions after treatment for pituitary adenoma. Case report. J Neurosurg 88:1111151998

  • 3

    Attanasio REpaminonda PMotti EGiugni EVentrella LCozzi R: Gamma-knife radiosurgery in acromegaly: a 4-year follow-up study. J Clin Endocrinol Metab 88:310531122003

  • 4

    Barkan ALHalasz IDornfeld KJJaffe CAFriberg RDChandler WF: Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab 82:318731911997

  • 5

    Bengtsson BAEden SErnest IOden ASjogren B: Epidemiology and long-term survival in acromegaly. A study of 166 cases diagnosed between 1955 and 1984. Acta Med Scand 223:3273351988

  • 6

    Castinetti FTaieb DKuhn JMChanson PTamura MJaquet P: Outcome of gamma knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. J Clin Endocrinol Metab 90:448344882005

  • 7

    Constine LSWoolf PDCann DMick GMcCormick KRaubertas RF: Hypothalamicpituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87941993

  • 8

    Cozzi RBarausse MAsnaghi DDallabonzana DLodrini SAttanasio R: Failure of radiotherapy in acromegaly. Eur J Endocrinol 145:7177262001

  • 9

    Feigel GCBonelli CMBerghold AMokry M: Effects of gamma knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 97:5 Suppl4154212002

  • 10

    Freda PUKatznelson Lvan der Lely AJReyes CMZhao SRabinowitz RD: Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. J Clin Endocrinol Metab 90:46544732005

  • 11

    Freda PUWardlaw SLPost KD: Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. J Neurosurg 89:3533581998

  • 12

    : Biochemical assessment and long-term monitoring in patients with acromegaly: statement from a joint consensus conference of the Growth Hormone Research Society and the Pituitary Society. J Clin Endocrinol Metab 89:309931022004

  • 13

    Gutt BWowra BAlexandrov RUhl ESchaaf LStalla GK: Gamma-knife surgery is effective in normalising plasma insulin-like growth factor I in patients with acromegaly. Exp Clin Endocrinol Diabetes 113:2192242005

  • 14

    Holdaway IM: Treatment of acromegaly. Horm Res 62:3 Suppl79922004

  • 15

    Ikeda HJokura HYoshimoto T: Transsphenoidal surgery and adjuvant gamma knife treatment for growth hormone-secreting pituitary adenoma. J Neurosurg 95:2852912001

  • 16

    Landolt AMHaller DLomax NScheib SSchubiger OSiegfried J: Octreotide may act as a radioprotective agent in acromegaly. J Clin Endocrinol Metab 85:128712892000

  • 17

    Landolt AMHaller DLomax NScheib SSchubiger OSiegfried J: Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy. J Neurosurg 88:100210081998

  • 18

    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

  • 19

    Lim YLLeem WKim TSRhee BAKim GK: Four years' experiences in the treatment of pituitary adenomas with gamma knife radiosurgery. Stereotact Funct Neurosurg 70:1 Suppl951091998

  • 20

    Melmed SVance MLBarkan ALBengtsson BAKleinberg DKlibanski A: Current status and future opportunities for controlling acromegaly. Pituitary 5:1851962002

  • 21

    Ove RKelman SAmin PPChin LS: Preservation of visual fields after perisellar gamma-knife radiosurgery. Int J Cancer 90:3433502000

  • 22

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

  • 23

    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

  • 24

    Powell JSWardlaw SLPost KDFreda PU: Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure. J Clin Endocrinol Metab 85:206820712000

  • 25

    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

  • 26

    Shimon ICohen ZRRam ZHadani M: Transsphenoidal surgery for acromegaly: endocrinological follow-up of 98 patients. Neurosurgery 48:123912452001

  • 27

    Simmons NELaws ER Jr: Glioma occurrence after sellar irradiation: case report and review. Neurosurgery 42:1721781998

  • 28

    Stafford SLPollock BELeavitt JAFoote RLBrown PDGorman DA: A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 55:117711812003

  • 29

    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

  • 30

    van Lindert EHey OBoecher-Schwarz HPerneczky A: Treatment results of acromegaly as analyzed by different criteria. Acta Neurochir (Wien) 139:9059131997

  • 31

    Vladyka VLiscak RNovotny J JrMarek JJezkova J: Radiation tolerance of functioning pituitary tissue in gamma knife surgery for pituitary adenomas. Neurosurgery 52:3093172003

Article Information

Address reprint requests to: Bruce E. Pollock, M.D., Department of Neurological Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. email: pollock.bruce@mayo.edu.

© AANS, except where prohibited by US copyright law."

Headings

Figures

  • View in gallery

    Graph showing the biochemical remission rate after radiosurgery for 46 patients with GH-producing pituitary adenomas.

  • View in gallery

    Graph depicting a comparison of the biochemical remission rates for patients with IGF-I levels less than 2.25 times the upper limit of normal (24 patients) and patients with IGF-I levels greater than 2.25 times the upper limit of normal (22 patients). Squares indicate the group of patients who had lower initial IGF-I levels; triangles indicate those who had higher levels (HR 2.9, 95% CI 1.2–6.9, p = 0.02).

  • View in gallery

    Graph depicting a comparison of the biochemical remission rates for patients not receiving pituitary suppressive medications at the time of radiosurgery (27 patients) and patients receiving pituitary suppressive medications at the time of radiosurgery (19 patients). Squares indicate the group of patients who were not receiving medication; triangles indicate those who were (HR 4.2, 95% CI 1.4–13.2, p = 0.01).

  • View in gallery

    Graph illustrating the incidence of new anterior pituitary deficits after radiosurgery in 39 patients with acromegaly.

References

1

Abosch ATyrrell JBLamborn KRHannegan LTApplebury CBWilson CB: Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 83:341134181998

2

Alexander MJDeSalles AATomiyasu U: Multiple radiation-induced intracranial lesions after treatment for pituitary adenoma. Case report. J Neurosurg 88:1111151998

3

Attanasio REpaminonda PMotti EGiugni EVentrella LCozzi R: Gamma-knife radiosurgery in acromegaly: a 4-year follow-up study. J Clin Endocrinol Metab 88:310531122003

4

Barkan ALHalasz IDornfeld KJJaffe CAFriberg RDChandler WF: Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab 82:318731911997

5

Bengtsson BAEden SErnest IOden ASjogren B: Epidemiology and long-term survival in acromegaly. A study of 166 cases diagnosed between 1955 and 1984. Acta Med Scand 223:3273351988

6

Castinetti FTaieb DKuhn JMChanson PTamura MJaquet P: Outcome of gamma knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. J Clin Endocrinol Metab 90:448344882005

7

Constine LSWoolf PDCann DMick GMcCormick KRaubertas RF: Hypothalamicpituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87941993

8

Cozzi RBarausse MAsnaghi DDallabonzana DLodrini SAttanasio R: Failure of radiotherapy in acromegaly. Eur J Endocrinol 145:7177262001

9

Feigel GCBonelli CMBerghold AMokry M: Effects of gamma knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 97:5 Suppl4154212002

10

Freda PUKatznelson Lvan der Lely AJReyes CMZhao SRabinowitz RD: Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. J Clin Endocrinol Metab 90:46544732005

11

Freda PUWardlaw SLPost KD: Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. J Neurosurg 89:3533581998

12

: Biochemical assessment and long-term monitoring in patients with acromegaly: statement from a joint consensus conference of the Growth Hormone Research Society and the Pituitary Society. J Clin Endocrinol Metab 89:309931022004

13

Gutt BWowra BAlexandrov RUhl ESchaaf LStalla GK: Gamma-knife surgery is effective in normalising plasma insulin-like growth factor I in patients with acromegaly. Exp Clin Endocrinol Diabetes 113:2192242005

14

Holdaway IM: Treatment of acromegaly. Horm Res 62:3 Suppl79922004

15

Ikeda HJokura HYoshimoto T: Transsphenoidal surgery and adjuvant gamma knife treatment for growth hormone-secreting pituitary adenoma. J Neurosurg 95:2852912001

16

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