Pollock BE,Department of Neurological Surgery, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. pollock.bruce@mayo.edu

OBJECT: The goal of this study was to determine factors associated with endocrine normalization after radiosurgery is performed in patients with hormone-producing pituitary adenomas. METHODS: Between 1990 and 1999, 43 patients with hormone-producing pituitary adenomas underwent radiosurgery: 26 patients with growth hormone (GH)-producing tumors, nine with adrenocorticotrophic hormone-producing tumors, seven with tumors that produced prolactin (PRL) alone, and one with a tumor that secreted both GH and PRL. The median patient age was 42 years. Thirty-seven patients (86%) had undergone surgery earlier and in 30 (70%) there was tumor extension into the cavernous sinus. The product-limit method was used to calculate endocrine normalization while patients were not receiving any hormone-suppressive medication. The median follow-up period after radiosurgery was 36 months (range 12-108 months). In 20 patients (47%) there was normalization of hormone secretion at a median of 14 months (range 2-44 months) after radiosurgery; no correlation was found between tumor type and cure. Actuarial cure rates were 20, 32, and 61% at 1, 2, and 4 years posttreatment. Multivariate analysis demonstrated that the absence of hormone-suppressive medications at the time of radiosurgery (relative risk 8.9, 95% confidence interval [CI] 1.2-68.7, p = 0.04) and maximum radiation doses greater than 40 Gy (relative risk 3.9, 95% CI 1.3-11.7, p = 0.02) correlated with an endocrine cure. A new anterior pituitary deficiency developed in seven patients (16%), temporal lobe necrosis was identified in two patients, an asymptomatic internal carotid artery stenosis was detected in two patients, and unilateral blindness occurred in one patient. CONCLUSIONS: Radiosurgery provides an endocrine cure for many patients with persistent or recurrent hormone-producing pituitary adenomas. Further study is needed to determine whether pituitary hormone-suppressive medications have a radioprotective effect.

The hypothalamus-pituitary function after pituitary stereotactic radiosurgery: evaluation of growth hormone deficiency.    J Intern Med. 2003 Apr;253(4):454-62.

Degerblad M, Brismar K, Rahn T, Thoren M.

Department of Endocrinology and Diabetology, Karolinska Hospital, Stockholm, Sweden. Marie.Degerblad@molmed.ki.se

OBJECTIVES: Radiation therapy to the pituitary gland means a considerable risk of developing hypopituitarism. The aim of the study was to investigate the growth hormone releasing hormone (GHRH)-growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis after treatment with stereotactic radiosurgery to the pituitary because of Cushing's disease. SETTING: Inpatient ward in university clinic. SUBJECTS: Eleven adult patients (eight women, three men), 20-65 years of age were studied 2.5-11.3 years after stereotactic radiosurgery (isocentre dose 50-100 Gy lesion-1) and compared with healthy controls. MAIN OUTCOME MEASURES: Spontaneous GH secretion was evaluated as 12-h night GH profiles. Stimulated GH responses were evaluated in seven of 11 patients using arginine-insulin and GHRH tests. Serum IGF-I levels were measured in fasting serum morning samples. RESULTS: All patients except one displayed blunted nocturnal GH profiles. Our patients with Cushing's disease evaluated several years after stereotactic radiosurgery as the primary and only treatment, demonstrated severely blunted spontaneous GH secretion and GH response to arginine-insulin. A disturbed regulation at the hypothalamic level was suggested as mechanism for this. Noteworthy is that serum IGF-I values correlated to the mean values of the 12-h GH profile.

Effects of gamma knife radiosurgery of pituitary adenomas on pituitary function.

Feigl GC, Bonelli CM, Berghold A, Mokry M.  J Neurosurg. 2002 Dec;97(5 Suppl):415-21.

International Neuroscience Institute, Hannover, Germany.

OBJECT: The authors undertook a retrospective analysis of the incidence and time course of pituitary insufficiency following gamma knife radiosurgery (GKS) for pituitary adenomas. METHODS: Pituitary adenomas in 92 patients were analyzed. There were 61 hormonally inactive tumors, 18 prolactinomas, and nine somatotropic and four adrenocorticotropic adenomas. The mean tumor volume was 3.8 cm3 (range 0.2-14.6 cm3). The mean prescription dose was 15 Gy. The mean prescription isodose was 50.7%. The mean follow-up time was 4.6 years (range 1.2-10 years). The following new or deteriorating insufficiencies that did not require treatment were recorded for the different pituitary axes: follicle-stimulating hormone (FSH)/ luteinizing hormone (LH) 19 (20.6%), thyroid-stimulating hormone (TSH) 32 (34.8%), adrenocorticotropic hormone (ACTH) 10 (10.9%), and growth hormone (GH) 26 (28.3%). For new insufficiencies or deterioration requiring replacement therapy, the figures were as follows: FSH/LH 20 (21.7%), TSH 22 (23.9%), ACTH eight (8.7%), and GH 12 (13%). Spot dosimetry was performed in 59 patients in the hypothalamic region, the pituitary gland, and pituitary stalk. The pituitary stalks in patients with deterioration of pituitary function received a statistically higher dosage of radiation, 7.7 +/- 3.7 Gy compared with 5.5 +/- 3 Gy (p = 0.03). CONCLUSIONS: The function of the residual normal pituitary gland is less affected following GKS of pituitary adenomas than after fractionated radiotherapy. Nonetheless, increased attention needs to be exercised to reduce the dose to the stalk and pituitary gland to minimize the incidence of these complications.

Radiotherapy and stereotactic radiosurgery for pituitary tumors.

Petrovich Z, Jozsef G, Yu C, Apuzzo ML.  Neurosurg Clin N Am. 2003 Jan;14(1):147-66.

Department of Radiation Oncology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, NOR G356, Los Angeles, CA 90033-0804, USA. zpetrovi@hsc.usc.edu

Based on a review of the literature and our medical center experience, we believe that transphenoidal surgery is the procedure of choice in most patients with pituitary adenomas. Conversely, SRS is a procedure of choice for those with cavernous sinus involvement. Patients with incomplete surgical excision should be considered either for a planned stereotactic treatment or for external beam radiotherapy. The same applies to patients with recurrent tumors. We favor stereotactic treatment in patients who have tumors that are less than 35 mm in diameter and at least 3 mm from the chiasm or optic nerves. Other patients should be considered for three-dimensional conformal radiotherapy. Radiotherapy provides a good treatment alternative in those patients who either refuse surgery or have contraindications to this therapy. Contemporary radiotherapy and SRS for pituitary adenomas is safe and effective treatment.

Gamma knife radiosurgery for pituitary adenoma: early results.

Petrovich Z, Yu C, Giannotta SL, Zee CS, Apuzzo ML.  Neurosurgery. 2003 Jul;53(1):51-9; discussion 59-61.

Department of Radiation Oncology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA. zpetrovi@hsc.usc.edu

OBJECTIVE: In recent years, gamma knife radiosurgery (GKRS) has emerged as an important treatment modality in the management of pituitary adenomas. Treatment results after performing GKRS and the complications of this procedure are reviewed. METHODS: Between 1994 and 2002, a total of 78 patients with pituitary adenomas underwent a total of 84 GKRS procedures in our medical center. This patient group comprised 46 men (59%) and 32 women (41%). All patients were treated for recurrent or residual disease after surgery or radiotherapy, with 83% presenting with extensive tumor involvement. The cavernous sinus was involved in 75 patients (96%), and 22 patients (28%) had hormone-secreting adenomas. This latter subset of patients included 12 prolactinomas (15%), 6 growth-hormone secreting tumors (8%), and 4 adrenocorticotropic hormone-secreting tumors (5%). The median tumor volume was 2.3 cm(3), and the median radiation dose was 15 Gy defined to the 50% isodose line. The mean and median follow-up periods were 41 and 36 months, respectively. RESULTS: GKRS was tolerated well in these patients; acute toxicity was uncommon and of no clinical significance. Late toxicity was noted in three patients (4%) and consisted of VIth cranial nerve palsy. In two patients, there was spontaneous resolution of this palsy, and in one patient, it persisted for the entire 3-year duration of follow-up. Of the 15 patients who presented with cranial nerve dysfunction, 8 (53%) experienced complete recovery and 3 (20%) showed major improvement within 12 months of therapy. Tumor volume reduction was slow, with 30% of patients showing decreased tumor volume more than 3 years after undergoing GKRS. None of the 56 patients with nonfunctioning tumors showed progression in the treated volume, and 4 (18%) of the 22 hormone-secreting tumors relapsed (P = 0.008). Of the four patients with adrenocorticotropic hormone-secreting adenomas, therapy failed in two of them. All six patients with growth hormone-producing tumors responded well to therapy. Of the 12 patients with prolactinomas 10 (83%) had normalization of hormone level and 2 patients experienced increasing prolactin level. Two patients with prolactinomas had three normal pregnancies after undergoing GKRS. CONCLUSION: GKRS is a safe and effective therapy in selected patients with pituitary adenomas. None of the patients in our study experienced injury to the optic apparatus. A radiation dose higher than 15 Gy is probably needed to improve control of hormone-secreting adenomas. Longer follow-up is required for a more complete assessment of late toxicity and treatment efficacy.

Stereotactic radiosurgery as an alternative to fractionated radiotherapy for patients with recurrent or residual nonfunctioning pituitary adenomas.

Pollock BE, Carpenter PC.   Neurosurgery. 2003 Nov;53(5):1086-94.

Department of Neurological Surgery and Division of Radiation Oncology, Mayo Clinic and Foundation, Rochester, Minnesota.

OBJECTIVE: To evaluate tumor control rates and complications after stereotactic radiosurgery for patients with nonfunctioning pituitary adenomas. METHODS: Between 1992 and 2000, 33 patients underwent radiosurgery for treatment of nonfunctioning pituitary adenomas. Thirty-two patients (97%) had undergone one or more previous tumor resections. Twenty-two patients (67%) had enlarging tumors before radiosurgery. The median tumor margin dose was 16 Gy (range, 12-20 Gy). The median follow-up period after radiosurgery was 43 months (range, 16-106 mo). RESULTS: Tumor size decreased for 16 patients, remained unchanged for 16 patients, and increased for 1 patient. The actuarial tumor growth control rates at 2 and 5 years after radiosurgery were 97%. No patient demonstrated any decline in visual function. Five of 18 patients (28%) with anterior pituitary function before radiosurgery developed new deficits, at a median of 24 months after radiosurgery. The actuarial risks of developing new anterior pituitary deficits were 18 and 41% at 2 and 5 years, respectively. No patient developed diabetes insipidus. CONCLUSION: Stereotactic radiosurgery safely provides a high tumor control rate for patients with recurrent or residual nonfunctioning pituitary adenomas. However, despite encouraging early results, more long-term information is needed to determine whether radiosurgery is associated with lower risks of new endocrine deficits and radiation-induced neoplasms, compared with fractionated radiotherapy.

Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma.

Sheehan JP, Kondziolka D, Flickinger J, Lunsford LD.   J Neurosurg. 2002 Dec;97(5 Suppl):408-14.

Department of Neurosurgery, The Center for Image-Guided Surgery, University of Pittsburgh Medical Center-Presbyterian, Pittsburgh, Pennsylvania, USA. jps2f@virginia.edu

OBJECT: Nonfunctioning pituitary adenomas comprise approximately 30% of all pituitary tumors. The purpose of this retrospective study is to evaluate the efficacy and role of gamma knife radiosurgery (GKS) in the management of residual or recurrent nonfunctioning pituitary adenomas. METHODS: A review was conducted of the data obtained in 42 patients who underwent adjuvant GKS at the University of Pittsburgh between 1987 and 2001. Prior treatments included transsphenoidal resection, craniotomy and resection, or conventional radiotherapy. Endocrinological, ophthalmological, and radiological responses were evaluated. The duration of follow-up review varied from 6 to 102 months (mean 31.2 months). Fifteen patients were observed for more than 40 months. The mean radiation dose to the tumor margin was 16 Gy. Conformal radiosurgery planning was used to restrict the dose to the optic nerve and chiasm. Tumor control after GKS was achieved in 100% of patients with microadenomas and 97% of patients with macroadenomas. Gamma knife radiosurgery was equally effective in controlling adenomas with cavernous sinus invasion and suprasellar extension. No patient developed a new endocrinological deficiency following GKS. One patient's tumor enlarged with an associated decline in visual function. Another patient experienced a deterioration of visual fields despite a decrease in tumor size. CONCLUSIONS: Gamma knife radiosurgery can achieve tumor control in virtually all residual or recurrent nonfunctioning pituitary adenomas. Dose sparing facilitates tumor management even when the adenoma is close to the optic apparatus or invades the cavernous sinus.

Gamma knife radiosurgery for pituitary adenoma.

Shin M.  Biomed Pharmacother. 2002;56 Suppl 1:178s-181s.

Department of Neurosurgery, The University of Tokyo Hospital, Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. shinmasa@ka2.so-net.ne.jp

For the treatment of pituitary adenomas, transsphenoidal surgery is established as a first choice of treatment. However, pituitary adenomas are often not curable with surgery alone, and further treatment including radiation therapy is required to control the disease. In this report, we review the literature of gamma knife radiosurgery for pituitary adenomas and discuss the efficacy of this modern technology. Radiosurgery achieved 85-100% of growth control rates with only mild and transient neurological complications in most cases. Endocrinological normalization was obtained in more than 65% of GH producing tumors. These hormonal control rates seemed to be slightly better in GH producing tumors compared to ACTH producing tumors. To normalize the excessive GH or ACTH levels, radiosurgery for functioning adenomas requires a relatively higher dose, ideally more than 35 Gy at tumor margin. However, the adjacent optic apparatus is less tolerable for irradiation, and the tumors have to be sufficiently separated from it to prevent the radiation-induced visual deficits. Therefore, the role of surgery should not be underevaluated, and even if radiosurgery alone may be able to achieve an excellent outcome in some cases, surgical resection will remain the primary treatment for pituitary adenomas. For high-risk patients or patients with residual tumors after transsphenoidal surgery, gamma knife radiosurgery can be a first choice of treatment, achieving both growth control and hormonal remission with minimum neurological complications, which is equivalent to conventional radiation therapy but with much less risk of radiation injury to the surrounding structures.

A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery.

Stafford SL, Pollock BE, Leavitt JA, Foote RL, Brown PD, Link MJ, Gorman DA, Schomberg PJ.
Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1177-81.

Division of Radiation Oncology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. stafford.scott@mayo.edu

PURPOSE: To evaluate the risk of clinically significant radiation optic neuropathy (RON) for patients having stereotactic radiosurgery of benign tumors adjacent to the optic apparatus. METHODS AND MATERIALS: We reviewed the dose plans and clinical outcomes of 218 gamma knife procedures (215 patients) for tumors of the sellar and parasellar region (meningiomas, n = 122; pituitary adenomas, n = 89; craniopharyngiomas, n = 7 patients). Previous surgery or radiation therapy was performed in 156 (66%) and 24 (11%) patients, respectively. Median follow-up was 40 months (range 4-115). RESULTS: The median maximum radiation dose to the optic nerve was 10 Gy (range 0.4-16.0). Four patients (1.9%) developed RON at a median of 48 months after radiosurgery. All had prior surgery, and 3 of 4 had external beam radiotherapy (EBRT) in their management either before (n = 2) or adjuvantly (n = 1). The risk of developing a clinically significant RON was 1.1% for patients receiving 12 Gy or less. Patients receiving prior or concurrent EBRT had a greater risk of developing RON after radiosurgery (p = 0.004). CONCLUSION: RON occurred in less than 2% of our patients, despite the majority (73%) receiving more than 8 Gy to a short segment of the optic apparatus. Knowledge of the dose tolerance of these structures permits physicians to be more aggressive in treating patients with sellar or parasellar tumors, especially those with hormone-producing pituitary adenomas that appear to require higher doses to achieve biochemical remission.

Radiation tolerance of functioning pituitary tissue in gamma knife surgery for pituitary adenomas.

Vladyka V, Liscak R, Novotny J Jr, Marek J, Jezkova J.  Neurosurgery. 2003 Feb;52(2):309-16; discussion 316-7.

Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic. vilibald.vladyka@homolka.cz

OBJECTIVE: This study is intended to contribute to a determination of the sensitivity of preserved hypophyseal function to focal radiation in pituitary adenomas. METHODS: We compared two subgroups of patients followed up for a median of 5 years after gamma knife surgery (GKS). Subgroup 1 (n = 30) showed postirradiation hypopituitarism. Subgroup 2 (n = 33) was continually eupituitary. These subgroups were taken from a previously published study relating to a larger group of 163 patients with pituitary adenomas treated by GKS and evaluated after a median follow-up period of 2 years. A relatively high treatment dose was used in this larger group (median, 20 Gy to the tumor margin for growth control in nonfunctioning adenomas; median, 35 Gy for hypersecreting adenomas). Early results approached those of microsurgery, and there were only a few side effects. In the present study, we compared 16 different variables in the same two subgroups to discover the relationships that caused a delayed appearance of postirradiation hypopituitarism. The main pretreatment and treatment parameters were measured on reconstructed treatment plans. This database was used for statistical evaluation. RESULTS: The relationship between the mean dose and the volume of functioning hypophysis was stronger in terms of worsening of pituitary function than that of the spot dose to different intrasellar structures. We found that for our group of patients, the safe mean dose of radiation to the hypophysis was 15 Gy for gonadotropic and thyrotropic functions and 18 Gy for adrenocorticotropic function. The worsening of pituitary function was also significantly dependent on the dose to different anatomic levels of the infundibulum, but we did not succeed in fully characterizing this relationship. In addition, we discovered significant levels of dependency of postirradiation pituitary damage to different pretreatment and treatment variables. CONCLUSION: Knowledge of the radiation tolerance of functioning pituitary structures subjected to GKS can ensure better preservation of pituitary function after irradiation. This is valid for the group of patients we studied. Our study's findings can be used as a guideline for GKS treatment of new patients with pituitary adenomas, and it can serve for comparison with the experience of other gamma knife centers.

Efficacy of gamma knife radiosurgery for nonfunctioning pituitary adenomas: a quantitative follow up with magnetic resonance imaging-based volumetric analysis.

Wowra B, Stummer W.   J Neurosurg. 2002 Dec;97(5 Suppl):429-32.

Gamma Knife Praxis, Department of Neurosurgery, Ludwig-Maximilians-Universitat, Munchen, Germany. wowra@gammaknife.de

OBJECT: The authors assessed the efficacy of gamma knife radiosurgery (GKS) for nonfunctioning pituitary adenomas (NPAs) by sequential quantitative determinations of tumor volume and neurological and endocrinological follow-up examinations. METHODS: Through May of 2000, 45 patients with NPA were treated by GKS. Complete neurological and endocrinological follow-up information was obtained. In 30 patients (67%), follow-up examinations included stereotactic magnetic resonance imaging involving the GammaPlan software for sequential measurements of the NPA volume. These patients constitute the basis of this study. Sequential volume measurements after GKS were compared with initial tumor volumes at the date of GKS to quantify the therapeutic result. All data were stored prospectively in a computerized database. The median dose to the tumor margin was 16 Gy (range 11-20 Gy). The mean prescription isodose was 55% (range 45-75%). All except one patient (97%) underwent surgery for NPA before GKS. Fractionated radiotherapy was not administered. Median follow up after GKS was 55 months (range 28-86 months). The actuarial long-term recurrence-free survival was 93% with respect to a single GKS and 100% if a repeated GKS was included. Neurological side effects were not detected. The actuarial risk of radiosurgery-induced pituitary damage was calculated to be 14% after 6 years. The volumetric analysis revealed a temporary swelling of the NPA in four patients, followed by shrinkage of the lesion. This is the first time this has been observed in pituitary adenomas. CONCLUSIONS: Postoperative GKS for residual or recurrent small fragments of NPAs is effective and safe. With regard to the issues of radioprotection and therapeutic morbidity, it seems superior to fractionated radiotherapy. Quantification of tumor reduction is a valuable tool for documenting a therapeutic response and for identifying tumor recurrence. As part of a radiosurgical standard protocol, the follow-up examination for NPAs should include tumor volumetric analysis.