Stereotactic radiosurgery in pituitary adenomas: long-term single institution experience and role of the hypothalamic-pituitary axis

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1 Jour. of Radiosurgery and BRT, Vol. 0, pp. 1 8 Reprints available directly from the publisher Photocopying permitted by license only 2011 Old City Publishing, Inc. Published by license under the OCP Science imprint, a member of the Old City Publishing Group. Clinical Investigation Stereotactic radiosurgery in pituitary adenomas: long-term single institution experience and role of the hypothalamic-pituitary axis Kita Sallabanda, M.D., Ph.D. 1, Sergey Usychkin, M.D. 2, Fernando Puebla, M.D., Ph.D. 2, José C. Bustos, M.D., Ph.D. 1, José A. Gutiérrez, M.D., Ph.D. 1, Carmen Peraza, Ph.D. 3, César Beltrán, M.D. 2, Hugo Marsiglia, M.D. 2,4 and José Samblás, M.D. 1 1 Instituto Madrileño de Oncología, Grupo IMO, Department of Neurosurgery, 7 Plaza Republica Argentina, 28002, Madrid, Spain 2 Instituto Madrileño de Oncología, Grupo IMO, Department of Radiotherapy, 7 Plaza Republica Argentina, 28002, Madrid, Spain 3 Instituto Madrileño de Oncología, Grupo IMO, Department of Medical Physics, 7 Plaza Republica Argentina, 28002, Madrid, Spain 4 Institut de Cancerologie Gustave Roussy, Breast Cancer Unit, 39 Rue Camille Desmoulins, 94805, Ville Juif, Paris, France. Correspondance to: Kita Sallabanda, M.D., Ph.D., Instituto Madrileño de Oncología, Grupo IMO, Department of Neurosurgery, 7 Plaza Republica Argentina, 28002, Madrid, Spain Phone: (34) ; Fax: (34) ; ksallabanda@grupoimo.com (Received June 8, 2011; accepted July 7, 2011) Stereotactic radiosurgery (SRS) is an effective treatment for incompletely resected or recurrent pituitary adenomas characterized by high rates of local control and endocrinological remission. The SRS-associated morbidity is usually considered minimal, but could not be neglected. It is mainly related to new pituitary hormone deficit, and seemingly caused by un-intentional inclusion of the hypothalamus, pituitary stalk and gland in the high-dose irradiation area. We report long-term clinical outcomes of 30 pituitary adenoma patients who received SRS in our institution. Dose was generally prescribed to the 90% isodose line and ranged from 10 to 16 Gy (mean and median 14 Gy). Selection of prescription dose was based on a tumor location and proximity to adjacent radiationsensitive structures and previous radiotherapy. The length of follow-up varied from 15 to 230 months (mean months, median 90 months). Overall, in 28 patients (93%) control of tumor growth was observed during the followup. In 19 patients (63%) tumor size was considered stable after SRS, in 9 patients (30%) tumor reduced in size and in 2 patients (7%) tumor progression was observed. Among 26 patients with functioning pituitary adenomas 17 patients (65,4%) had normalization and 4 patients (15,3%) had improvement of endocrinological function. Persistent hypersecretion was observed in 5 patients (19,3%) with functioning pituitary adenomas. New hypopituitarism after SRS treatment was observed in 4 patients (13.3%). The median maximum dose to hypothalamus, pituitary stalk and pituitary gland was 2.33 Gy (range Gy), Gy (range Gy) and Gy (range Gy), respectively. SRS allows to effectively control tumor growth in % of patients and in the great part of patients a relatively rapid endocrinological remission is observed. Doses to the structures of hypothalamicpituitary axis might have influence on the development of radiation-induced hypopituitarism. Every effort should be made to spare these structures as much as possible. Key words Stereotactic radiosurgery, pituitary adenoma, long-term outcome, radiation-induced hypopituitarism, role of hypothalamic-pituitary axis INTRODUCTION Pituitary adenomas are the third most common intracranial tumors following gliomas and meningiomas with the incidence exceeding 20% in the general population [1]. These neoplasms are fairly common and Journal of Radiosurgery and SBRT Vol RSBRT 128 (Usychkin).indd 1 10/23/2011 5:08:57 PM

2 K. Sallabanda et al. represent between 10 and 20% of all primary intracranial tumors [2]. Microsurgical resection is a first line treatment for most of pituitary adenomas, except prolactinomas. Reported long-term tumor growth control rate after microsurgery alone range from 50 to 80% [2,3,4,5]. Reasons of treatment failure in pituitary adenomas include incomplete tumor resection or recurrence due to tumor invasion into surrounding structures (for example, cavernous sinus) or presence of microscopical tumor rests. Persistence of hypersecretory postsurgical adenoma results in adverse clinical symptoms. In patients with residual persistent or recurrent pituitary adenoma second-line treatment options include repeat resection, fractionated radiotherapy, stereotactic radiosurgery, and medical treatment. Favorable results in terms of growth control and endocrinological remission of pituitary adenoma after radiosurgical treatment mostly with Gamma Knife technique have been reported [6,7,8,9,10]. The SRSassociated morbidity is usually considered minimal, but could not be neglected. It is mainly related to new pituitary hormone deficit, and seemingly caused by un-intentional inclusion of the hypothalamus, pituitary stalk and gland in the high-dose irradiation area [10]. We report long-term clinical outcomes of patients with pituitary adenomas treated with linac-based stereotactic radiosurgery technique. Furthermore results of retrospective correlation study of hypothalamus-pituitary gland axis and endocrinological outcomes in these patients are reported. MATERIALS AND METHODS From Febrary 1992 to Febrary 2010, 87 patients with resistant and recurrent pituitary adenomas received SRS in the Radiosurgery Department of Madrid Institute of Oncology (Grupo IMO) in Madrid, Spain. For the purpose of present analysis 30 patients with a minimal follow-up of 12 months and available serial neuro-imaging and endocrinological studies data were selected. Other 57 patients were not analysed due to the lack of complete follow-up data concerning neuroimaging and endocrinological testing. The reason was that the patients came from different parts of Spain and different hospitals, in many cases it was impossible to have an adequate follow-up. The study is statistically correct. There were 18 women and 12 men. Age varied from 23 to 85 years (mean 47,5 year). Detailed patients characteristics are presented in Table 1. Majority of patients (n=26, 87%) underwent initial microsurgical endoscopeassisted tumor removal via mainly endonasal transsphenoidal approach. In these patients the diagnosis of pituitary adenoma was established histopathologically. Nine patients received second microsurgical resection for tumor recurrence before they were referred to radiosurgery treatment. In eight patients pituitary adenoma extended to the cavernous sinus. Six patients with recurrent pituitary adenomas received postoperative fractionated radiotherapy treatment of 50,4 Gy prior SRS. Eleven patients received medical treatment prior SRS, among them four patients treated with dopamine agonists and eight patients treated with peri-operative glucocorticoid replacement therapy. The median time elapsed between surgical resection and SRS was 18.3 months (range from 2.7 to months). Before radiosurgical procedure all patients underwent neurological examination, campimetry assessment and hormonal testing. GH, IGF-1, ACTH, cortisol, PRL, TSH, free T3, T4, FSH and LH hormones levels in plasma were evaluated. In a patients with acromegaly oral glucose test was not performed routinely. Stereotactic radiosurgery technique All SRS procedures were performed using a linear accelerator with a high-precision positioning system and mechanical fixation of the tertiary collimator (SRS 200; University of Florida, USA), with 6-MeV photons. On the day of procedure Brown-Roberts-Wells stereotactic frame was fixed on the patient s head under local anesthesia in such a way as to make it parallel to the optic pathways. Axial thin CT slices with contrat enhancement were obtained and fused with MR images acquired in a day of procedure or several days before it. All radiological data were transferred to BrainScan planning workstation (BrainLAB). Fusion of images was performed using mutual information matching algorithm of a planning workstation. The visible contrast-enhanced tumor and adjacent anatomical structures-at-risk (optic pathways and brainstem) were delineated during the initial treatment planning. For the purpose of present analysis hypothalamus, pituitary stalk and pituitary gland were delineated retrospectively in 19 patients treated (for whom it was possible to recover dosimetrical plans) in order to calculate the dose to these structures (Figure 1). Dose was generally prescribed to the 90% isodose line and ranged from 10 to 16 Gy (mean and median 14 Gy). 14 Gy was prescribed in 63.3% of patients and 15 Gy in 20% of patients. In most cases one isocenter (80%) and one collimator (67%) was enough to completely cover target volume with prescription isodose. Median maximum dose in target volume was 15.7 Gy (range Gy). Conformity and homogeneity indexes were calculated according to the ICRU62 criteria [11]. Selection of prescription dose was based on 2 Journal of Radiosurgery and SBRT Vol RSBRT 128 (Usychkin).indd 2 10/23/2011 5:08:58 PM

3 Stereotactic radiosurgery in pituitary adenomas Table 1. Clinical and treatment characteristics of patients with pituitary adenoma Characteristics No of patients % Total number of patients Sex Male Female Type of pituitary adenoma Functioning Non-functioning Tumor size at diagnosis Macroadenoma Microadenoma Type of functioning adenoma Somatotropic adenoma Adrenocorticotropic adenoma Prolactinoma Mixed-type adenoma Symptoms Acromegaly Cushing s disease Diabetes mellitus Obesity Arterial hypertension Menstrual cycle disorder Visual disorder Pituitary insufficiency prior SRS Cavernous sinus extension No of microsurgical resection of tumor Radiation therapy prior SRS a tumor location and proximity to adjacent radiationsensitive structures and previous radiotherapy. Maximal acceptable dose to optic pathways was limited to 8 Gy and no more than 0.5 cm 3 of brainstem could receive dose greater than 10 Gy. This prescription policy necessitated at least 3-5 mm clearance between tumor margin and optic pathways. After SRS a prophylactic treatment with dexamethasone was administered to all patients during the stay in a hospital for 24 hours to prevent any early complications of radiosurgical treatment. Follow-up All patients included in the present analysis were followed by treating neurosurgeon with regular neurological examination, including evaluation of visual Journal of Radiosurgery and SBRT Vol RSBRT 128 (Usychkin).indd 3 10/23/2011 5:08:58 PM

4 K. Sallabanda et al. percentages were used for categorical variables. Exploration of factors associated with radiation-induced hypopituitarim was performed by the Mann-Whitney U-test. Median time to endocrinological outcome among patients with different types of functioning pituitary adenomas was calculated by the Kaplan-Meier method and compared by log-rank test. Two-tailed tests were always used and p values inferior to 0.05 were considered as statistically significant. All statistical analyses were performed using the SPSS version 17.0 software. RESULTS Control of tumor growth Figure 1 Delineated structures of hypothalamuspituitary axis function and regular MR neuroimaging which were carried out at 6 and 12 months after radiosurgical procedure and yearly thereafter. The length of follow-up varied from 15 to 230 months (mean months, median 90 months). Control of tumor growth was defined on the serial follow-up neuroimaging studies as either stable tumor or shrinkage of tumor 2 mm while tumor progression was defined as growth in size 2 mm. During the follow-up period the same battery of endocrinological tests was used to evaluate control of hormone hypersecretion. The endocrinological outcomes were defined as follows: improvement or normalization of endocrinological function if the hormone level reduced significantly or normalized after treatment and as refractory hypersecretion if the elevated hormone level remained stable during the follow-up period. Futhermore, radiosurgical treatment-related hypopituitarism was defined as a new deficit in at least one of hormone levels which was normal prior to radiosurgery. Statistical methods Measures of central tendency and dispersion were used for numerical variables; simple frequencies and Overall, in 28 patients (93%) control of tumor growth was observed during the follow-up. In 19 patients (63%) tumor size was considered stable after SRS, in 9 patients (30%) tumor reduced in size and in 2 patients (7%) tumor progression was observed. Concerning the type of pituitary adenoma, all patients with GH-secreting and ACTH-secreting tumors have achieved control of tumor growth. There were 2 patients with progressive growth of tumor. The first patient, a 72 year old woman with non-functioning pituitary macroadenoma extended to cavernous sinus which was partially resected and treated with 14 Gy of SRS. 4,5 years after SRS treatment a tumor growth was diagnosed based on follow-up MR-imaging studies. She received second SRS treatment of 13 Gy. The second patient, a 85 year old man with mixed type functioning pituitary adenoma (GH and PRL-secreting tumor) who received only medical treatment before SRS (cabergoline and somatostatin) and was treated with 14 Gy of SRS. Endocrinological outcomes Overall, among 26 patients with functioning pituitary adenomas 17 patients (65,4%) had normalization and 4 patients (15,3%) had improvement of endocrinological function. Median time to normalization or improvement of endocrinological function was 12.3, 61.8 and months for GH, ACTH-secreting and other types of functioning pituitary adenoma (PRL, TSH, LH-secreting), respectively (Figure 2). Persistent hypersecretion was observed in 5 patients (19,3%) with functioning pituitary adenomas. There were one patient with GH-secreting tumor, two patients with ACTH-secreting tumors, one patient with PRL-secreting tumor and one patient with mixed-type GH and PRL-secreting tumor. Among these patients with persistent hormone hypersecretion three 4 Journal of Radiosurgery and SBRT Vol RSBRT 128 (Usychkin).indd 4 10/23/2011 5:08:59 PM

5 Stereotactic radiosurgery in pituitary adenomas extension of tumor to the cavernous sinus in these three patients. No statistically significant differences in mean of maximum dose to hypothalamus, pituitary stalk, target volume and conformity index were found among patients with or without new radiation-induced hypopituitarism (Table 3). DISCUSSION Figure 2 Kaplan-Meier analysis of time to normalization or improvement of endocrinological function patients with GH-secreting, ACTH-secreting and GH, PRL-secreting tumors received 14 Gy, one patient with PRL-secreting tumor received 15 Gy and one patient with ACTH-secreting tumor received 16 Gy. New hypopituitarism after SRS treatment was observed in 4 patients (13.3%). Two of these patients developed panhypopituitarism and two other patients developed new deficit of LH and TSH hormones, respectively. In one of the patients with new panhypopituitarism 14 Gy was prescribed to 50% isodose line and the maximal dose in the tumor was 28 Gy. Three other patients received Gy prescribed to 90% isodose line and the maximal dose in the tumor varied from 15,5 to 16,8 Gy. Dose to hypothalamic-pituitary axis Due to the rapid dose fall-off characteristic for stereotactic radiosurgery technique structures of hypothalamic-pituitary axis, such as hypothalamus, pituitary stalk and rest of pituitary gland receive relatively low doses during radiosurgical procedure. In present analysis we analyzed dose to hypothalamic-pituitary axis in 19 patients (63.3%) and found that the median maximum dose was 2.33 Gy (range Gy), Gy (range Gy) and Gy (range Gy) to hypothalamus, pituitary stalk and the rests of pituitary gland, respectively. Among four patients with new hypopituitarism after SRS it was possible to analyze a dose to hypothalamicpituitary axis in three of them. Dose to hypothalamus was 0,93, 1,67 and 1,87 Gy, dose to pituitary stalk was 11.97, and Gy in these three patients. None of these patients received radiotherapy treatment prior SRS. At the time of SRS treatment tumor volume was 0.07, 0.52 and 1.48 cm 3. There was no extrasellar Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy are two therapeutic modalities widely used in the treatment of recurrent or persistent pituitary adenomas. Goals of radiation treatment differ depending on the type of pituitary adenoma. In case of non-functioning pituitary adenoma the goal is to control tumor growth whereas for functioning pituitary adenomas the normalization of hypothalamic-pituitary axis function is also major goal of treatment. The choice of therapeutic modality is based upon tumor size, location and proximity to the nearby dose-limiting structures, first of all optic pathways. SRS is indicated in tumors less than 3 cm in diameter, with clearly demarcated margins and a 3 5 clearance between tumor margin and optic pathways. SRS was proved to be highly effective in the control of tumor growth. In many published studies the rate of tumor growth control defined as no further tumor growth after SRS is from 90 to 100% [10,12,13,14,15,16,17,1 8,19,20]. At the same time the rate of tumor shrinkage varies significantly (from 13 to 100%) and probably depend on the proportion of hormone-secreting tumors, marginal dose applied and diagnostic criteria used [10,12,13,14,15,16,17,18,19,20]. In a recently published article of Poon et al tumors < 1 cm 3 and those without evidence of cavernous sinus extension were statistically significantly related to a good response in tumor size reduction [21]. In our series of pituitary adenoma treated with SRS a 93% rate of tumor growth control has been reported while tumor size reduction was observed in 30% of patients. Only in 2 patients (7%) single SRS procedure has failed to achive tumor growth control. Both patients received second SRS treatment. A substantial variation of endocrinological outcomes after SRS is observed in published series from different centres. Variable rate from 18 to 88% [10,12,13,14,15,16,17,18,19,20] of hormone hypersecretion normalization was seen, probably due to varying criteria of endocrinological remission used in different centres. The type of functioning pituitary adenoma (ACTH-secreting tumors were more sensitive to SRS in comparison with GH- and PRL-secreting tumors), tumor margin radiation dose (higher dose inversely correlated to the time to endocrine remission) and tumor Journal of Radiosurgery and SBRT Vol RSBRT 128 (Usychkin).indd 5 10/23/2011 5:09:00 PM

6 K. Sallabanda et al. Table 2. Tumor growth control and endocrinological outcomes Tumor growth control Endocrinological outcomes Type of pituitary adenoma Persistent Stable Reduction Progression Normalization Improvement hypersecretion Non-functioning (n = 4) GH-secreting (n = 11) ACTH-secreting (n = 9) Other functioning adenomas (PRL, TSH, LH) (n = 6) Total functioning adenomas (n = 26) All patients (n = 30) Table 3. Analysis of dose to hypothalamus-pituitary axis and new hypopituitarism after SRS* Structure Patients with new hypopituitarism after SRS Patients without new hypopituitarism after SRS p value Dmax in hypothalamus (Gy) 1.49 ± 0.49 ( ) 2.97 ± 1.50 ( ) Dmax in pituitary stalk (Gy) ± 1.78 ( ) 9.77 ± 3.74 ( ) Dmax target volume (Gy) ± 0.69 ( ) ± 2.79 ( ) Target volume (cm 3 ) 0.69 ± 0.72 ( ) 1.67 ± 1.58 ( ) Conformity index 3.46 ± 2.09 ( ) 2.20 ± 0.78 ( ) * Values are reported as mean ± SD (range) Mann-Whitney U-test size (smaller tumors had better response) have been reported as statistically significant prognostic factors of endocrine remission rate [22]. In out series of patients in 80.7% of patients either normalization (65,4%) or improvement (15,3%) of endocrinological function was observed. It should be noted that in our series doses are different to those reported in other published series of pituitary adenoma SRS. 83,3% of our patients received Gy prescribed generally to 90% isodose whereas in other published series patients were treated with Gy presecribed to 50% isodose [7, 8, 9, 10]. In spite of these relatively low doses administered in our patients, results of tumor growth control and endocrinological function normalization or improvement rate are quite similar to the outcomes published in the literature. Actually we have not found a minimal effective dose to control hormonal hyperproduction of functional pituitary adenoma in published studies. Radiation-induced hypopituitarism (RIH) is among the most common treatment-related side effects in patients treated with stereotactic radiosurgery and fractionated radiotherapy. Its incidence varies from 4 to 14% in published series of SRS in patients with pituitary adenomas [10,12,13,14,15,16,17,18,19,20] and from 30 to 60% in series of stereotactic fractionated radiotherapy [23]. It has been proposed that RIH could be caused by direct neuronal rather than vascular injury in the hypothalamic-pituitary axis [23]. Chieng et al reported that hypothalamic-occipital blood flow in patients with nasopharyngeal cancer who have been treated with conventional radiotherapy did not change between 6 months and 5 years after cranial irradiation, although progressive hypothalamic dysfunction was observed in these patients [24]. In other study in the follow-up MR scans of patients with nasopharyngeal carcinoma who received course of radical radiotherapy no visible hypothalamic-pituitary region abnormalities 6 Journal of Radiosurgery and SBRT Vol RSBRT 128 (Usychkin).indd 6 10/23/2011 5:09:00 PM

7 Stereotactic radiosurgery in pituitary adenomas were found despite all of them had radiation-induced hyperprolactinemia [25]. Feigle et al showed that patients who received a dose of > 5,5 Gy to the pituitary stalk had a higher rate of pituitary insufficiency after stereotactic radiosurgery [26]. Recently the same author has reported results of spot dosimetry in 108 patients with pituitary adenoma treated with Gamma Knife. In their analysis patients with a new endocrinopathy following radiosurgery received a statistically significant higher mean total dose to the entire hypothalamic-pituitary axis (12,9 ± 10,1 Gy) than patients who did not develop a new pituitary insufficiency (9,4 ± 8,8 Gy), however, mean total doses to the hypothalamus (1 ± 1,4 Gy) and median eminence (1,6 ± 1,2 Gy) played no statistically significant role in the development of pituitary dysfunction after radiosurgery. Nevertheless patients who received a higher mean point dose to the pituitary stalk (5,3 ± 3,6 Gy) or to the pituitary gland (11 ± 6,9 Gy) showed a higher rate of endocrinopathy after radiosurgery [27]. Very similar results have been reported by Sicignano et al who in a study of 367 patients with pituitary adenoma showed that more dosimetrical rather than clinical parameters were associated with a higher rate of new pituitary deficits. In a DVH-curve analysis they found that the best predicting cut-off value of new pituitary insufficiency after SRS was a mean dose to the pituitary stalk and residual normal pituitary gland > 7,3 Gy and > 17,1 Gy respectively [28]. In our series of pituitary adenomas treated with linear accelerator stereotactic radiosurgery technique median maximum doses to hypothalamus, pituitary stalk and rests of pituitary gland were 2.33, and Gy respectively. In three patients with new endocrine insufficiency doses to pituitary stalk were 11.97, and Gy, relatively higher to other patients. In the fourth patient with panhypopituitarism after SRS it was not possible to calculate the dose delivered to the hypothalamic-pituitary axis, nevertheless, it is known that this patient received 14 Gy prescribed to 50% isodose line and the maximal dose in the tumor was 28 Gy. That s why probably the dose in the pituitary stalk in this patient was > Gy. Furthermore, relatively high conformity indexes evidencing low conformity of dose distribution were observed in these patients. However statistically significant difference in mean values of maximum doses to hypothalamus, pituitary stalk, target volume and conformity indexes was not found in our study. Recently reported results of SRS along with our results obtained in a series of patients treated with linear accelerator-based SRS underline a probable role of pituitary stalk and residual pituitary gland in the development of radiation-induced hypopituitarism. Whenever possible an attempt should be made to lower the dose in these structures, employing radiation techniques with maximum precision and highly conformal dose distribution. CONCLUSIONS Linear accelerator-based stereotactic radiosurgery technique is a valuable treatment modality for pituitary adenomas. This technique allows to effectively control tumor growth in % of patients and in the great part of patients a relatively rapid endocrinological remission is observed. Rate of radiation-related adverse effects is low, but could not be neglected. 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