GAMMA KNIFE EFFECT ON PATIENTS WITH PITUITARY ADENOMA Evaluation of Gamma Knife Effect on Patients with Pituitary Adenoma

INTRODUCTION: Pituitary adenomas are usually benign tumors that can be either secreting (growth hormone in acromegaly, adrenocorticotropin hormone in Cushing disease and prolactin in prolactinoma) or non-secreting adenomas . Pituitary tumors account for approximately 15% of all primary brain tumors and almost 25% of benign primary brain tumors. According to these measures, pituitary tumors are the third most


GAMMA KNIFE EFFECT ON PATIENTS WITH PITUITARY ADENOMA
microsurgery for both secreting macroadenomas and mass producing non secretory macroadenoma. GKS can provide adenoma growth control and long-term endocrine control that is superior to that of repeat surgery and the long latency of the radiation response. Moreover, GKS limits radiation exposure to the surrounding normal brain structures [5] ; or to optic nerve and optic chiasm.

THE AIM OF STUDY:
This study aimed to evaluate the effectiveness and safety of gamma knife in the treatment of pituitary adenomas with their associated complications.

PATIENTS AND METHODS:
This clinical study was conducted at the Neuroscience Teaching Hospital during the period from January 2017 to June 2018, Gamma Knife Department on 132 patients who were clinically, radiologically and endocrinologically proven to have pituitary adenoma. The study population composed of 54 men (40.9%) and 78 women (59.1%) whose age ranged from 13 to 85 years (mean 45.6). The patients had history ranged from 7 months to 14 years (mean 3.4 years) and Gamma knife radiosurgery served as the primary treatment modality. The diagnosis was made on the basis of magnetic resonance imaging (MRI) findings, endocrinological labroatory findings, the clinical history of patients, ophthalmological examination of the optic field study as well as routine investigations.
All patients were examined (3 weeks, 2 months, and 6 months) post Gamma knife to assess the complications; or to assess improvement in symptoms especially visual field and ophthalmological symptoms. At 6 months visit, they were asked to perform new MRI to observe the changes (some cases had longer follow up which reached to 1 year and others were followed up after 1.5 year). Patients were asked to stay in hospital for few hours and then discharged.

Procedure:
Under local anesthesia with lidocaine 2%, Leksell Frame were applied to patients heads, the frame was calibrated with special helmet, then patients were asked to obtain new MRI (3 tesla MRI) with Leksell frame (or to do CT scan instead of MRI when MRI is contra-indicated). The stereotactic MRI sequences were then transmitted to Leksell gamma plan, and tumor was localized by a software and then tumor was targeted. The doses were applied according to a schedule and at the surgeon's preference. Thereafter, the treatment protocol was passed to the Leksell Gamma knife control unit where treatment was applied automatically, and radiation emission to patients was performed. Either the 4 or the 8 mm collimator helmet was utilized, especially in microadenoma in order to achieve conformity and to avoid radiation neural injuries.

RESULTS:
The number of patients in this study were 132 patient; 78(59.1%) of them were females and 54 (40.9%) were males as shown in "figure 1".

GAMMA KNIFE EFFECT ON PATIENTS WITH PITUITARY ADENOMA
The ages of patients ranged from 13-85. Our results revealed that 2 of the patients were in the teenage group, 21 in twenties, 27 in thirties, 33 in fourties, 26 in fifties, 9 in sixties, 8 in seventies and 6 in eighteens, with a mean age of 45.6 years. As illustrated in "figure 2". Types of pituitary adenomas included in this study 67(50.75%) prolactinoma, 10(7.57%) somatotroph adenoma (2 of them were jigantism and 8 were acromegaly), ACTH releasing adenoma or Cushing disease were 22(16.66%) and non-functioning adenoma were 33(25.02%) patients as shown in "figure 3". Regarding the size of adenoma, 1cm and below were categorized as microadenoma, while those sizes above 1cm were categorized as macroadenoma [4] . Prolactinoma patients consisted of 47 microadenoma (6 males & 41 females) (size 0.2-1cm), while macroadenoma for prolactinoma were 20 patients (15 males & 5 post-menopausal women) (size 1.1-5.5 cm). Cushing disease group consisted of 8 microadenoma patients (3 males and 5 females) (size 0.3-1cm), while macroadenoma cases in Cushing disease were 14 patients (7 males and 7 females) (tumor size 1.1-2.9cm). GH secreting microadenoma consisted of 3 patients (2 males and 1 female) (size 0.5-1 cm), while GH secreting macroadenoma were 7 patients (2 males and 5 females) (size 1.1-4.8cm). Non-secretory adenomas included only 33 patients with macroadenoma (19 males and 14 females) (tumor size 1.8-6.7 cm) with no microadenoma as shown in "table 1".  The total number of cases in this study was 132 who were categorized into 3 groups according to the duration of their follow up period (6 months (50) patients, 1 year (45) patients and 1.5 year (37) patients). Results of non-specific signs and symptoms in "table 3" showed that:-All patients with macroadenoma (secretory and non-secretory) presented with headache, while only 3 patients with microadenoma (2 prolactinoma and 1 acromegaly) had headache. After Gamma knife usage, headache was subsided within 6 months except for 1 case with non-secretory macroadenoma who died within 6 months of follow up.

GAMMA KNIFE EFFECT ON PATIENTS WITH PITUITARY ADENOMA
Vomiting occurred only in 5 cases (1 Cushing disease with macroadenoma, 2 prolactinoma macroadenoma and 2 non-secretory macroadenoma patients); vomiting was very mild (occurring once or twice every 3 months). After Gamma knife, all cases with vomiting were relieved within 6 months of follow up. Vision problems appeared only in cases of macroadenoma, which ranged from unilateral upper quadrantinopia (19), bilateral upper quadrantinopia (15), unilateral temporal hemianopia (17), bitemporal hemianopia (9), blurred vision in one eye (10) and one eye blindness with blurred vision in the other eye (4) cases [depending on the size of macroadenoma]. After Gamma knife, vision problems relieved totally or at least partially (61 cases got better within 6 months and 4 only within 1 year), except 9 cases as there was no relief (5 prolactinoma, 1 Cushing and 3 non-secretory cases). Abducent nerve palsy with oculomotor nerve palsy occurred only in 3 patient (2 non-secretory and 1 prolactinoma), which didn't got relieved by Gamma knife. Attacks of fit occurred only in 1 case of nonsecreting adenoma with a big size tumor (6.7 cm). The specific signs and symptoms showed that:-A-Prolactinoma:-All female patients (premenopausal 41 microadenoma patients) had lactating breasts before Gamma knife application, and they stopped lactation 6 months after doing Gamma knife, with the use of cabrigoline. Among all the 41 premenopausal female microadenoma patients, 34 were shown to have menstrual abnormality and 7 had no menses at all. However, after Gamma knife use, the menses of 22 patients of the irregular menses group became regular within 6 months, 7 became regular within 1 year and 3 patients became regular within 1.5 year, while 2 patients menses remained irregular. Regarding those 7 women who were having no menses at all, 1 patient showed a regular menses within 1 year, 5 patients had irregular menses (1 within 6 months, 3 within 1 year and 1 within 1.5 year) after doing gamma knife, while only 1 patient of them still remained without menses; as shown in "table 3". All female patients (premenopause 41 microadenoma patients) were infertile (either have no children or they are not married or at least they become infertile during the start of disease), however, after Gamma knife, 1 patient became pregnant 1.5 year post Gamma knife treatment. The 5 female postmenopausal patients with macroadenoma who presented with pressure symptoms on optic nerve showed partially better vision after Gamma knife application (2 within 6 months and 1 within 1 year) except for 2 cases which didn't get relieved. Among the 21 male patients with prolactinoma, 11 were having increase in the size of their breasts (5 microadenoma and 6 macroadenoma). After Gamma knife treatment, 8 of them had the sense of breast size relief (3 within 6 months, 4 within 1 year and 1 within 1.5 year), while the remaining 3 cases (1 microadenoma and 2 macroadenoma) didn't feel better. All male patients (21 patients) were having loss of libido, no erection and no desire to do sex; after Gamma knife, 12 of them returned their sexual desire (fully or at least partially) (3 within 6 months, 2 within 1 year and 7 within 1.5 years), and the wives of 2 of them became pregnant after 1.5 year. However, the other 9 cases didn't get relieved. All the 15 male patients with macroadenoma had pressure effect on optic nerve, which after Gamma knife got partially or totally relieved (7 within 6 months and 5 within 1 year) except for 3 patients who didn't get relieved. B-ACTH secreting adenoma (Cushing disease): All patients (22 cases) had increase in their body weight, moon face, buffalo hump (found only in 2 cases) and Cushing syndrome. After Gamma knife treatment, these sings were relieved in 19 cases (17 within 6 months and 2 within 1 year), while the rest did not get relieved. Out of the 22 patients, 10 patients had hypertension (3 cases with the start of the disease, while the rest had chronic hypertension); after Gamma knife, the newly onset hypertension (3 cases) got relieved within 6 months. Out of the 22 patients, 15 patients had Diabetes mellitus (4 cases occured with the start of the disease and 11 cases had chronic diabetes); after Gamma knife, 3 cases of the newly onset D.M. have relieved within 6 months and only 1 did not get relieved. C-GH secreting adenoma: Acromegaly: Coarse head features, increase in head, hands and feet size occured in 8 patients

GAMMA KNIFE EFFECT ON PATIENTS WITH PITUITARY ADENOMA
from 10 with increase in GH secretion (all of those 8 patients were above 20 years), their sings & symptoms began to relieve partially (3 within 1 year and the other 5 after 1.5 year). Gigantism: Very tall patients occured only in 2 patients (1 was 13 years and the other was 15 years old). Visual problems: All patients with GH adenoma with macroadenoma (7 cases) had visual problems (1 gigantism and 6 acromegaly cases); after performing Gamma knife, 5 of those patients got better partially or totally within 6 months and 2 of them within 1 year. D-Non secretory adenoma: Pressure effect of non-secretory adenoma on normal pituitary causing pressure on normal neurohypophesis and their transport of vasopressin hormone causing Diabetes insipidus, which occurred only in 1 case within 6 months (who then died), and not relieve by Gamma knife. Pan hypopituitarism: which occurred only in 1 case within 6 months after doing Gamma knife (who then died). Hydrocephalus: occurred only in 1 case before doing Gamma knife and the patient treated by ventriculoperitoneal (V.P) shunt. Transformation of non-secretory adenoma to adenocarcinoma: which occurred in 1 case within 1 year of doing Gamma knife (the female patient had both abducent and occulomotor nerve palsies]; then she underwent 2 surgical operations (open craniotomy) after Gamma knife treatment. Pressure symptoms on optic nerve (all the 33 cases) which after Gamma knife g partially or totally (21 within 6 months, 8 within 1 year and 1 within 1.5 year) except for 3 cases which were didn't get relieve. According to death rate: only 1 case with non secretory adenoma died within 6 months of doing Gamma knife from all the 132 cases (patient had Diabetes insipidus prior to Gamma knife treatment, but after Gamma knife he developed panhypopituitarism followed by fits, then he died) as shown in "table 3".

Results of normalization of hormonal levels:
According to normalization of hormonal levels of pituitary adenoma in "table 4":prolactinoma patients, 55 patients (82.08%) showed returning of prolactin level to normal after doing Gamma knife (49 returned to normal level within 6 months, 5 within 1 year and 1 within 1.5 year, while the remaining 12 patients didn't return to normal). Those 55 patients were on continuous consumption of cabrigoline (one tab. per week). Out of the 22 patients with Cushing disease, 18 (81.81%) ACTH and cortisol levels returned t normal after performing the Gamma knife treatment as follows: 17 within 6 months and 1 within 1 year. Out of the 10 patients with GH secreting adenoma, 9 (90%) patients showed a return of GH hormone levels to normal as follows: 5 within 6 months, 3 within 1 year and 1 within 1.5 years, while all of them were taking sandastatine ampoules (1 amp. Per month). Pressure symptoms on optic nerve (all the 33 cases) which after Gamma knife got relieved partially or totally (21 within 6 months, 8 within 1 year and 1 within 1.5 year) except for 3 cases According to death rate: only 1 case with nonsecretory adenoma died within 6 months of l the 132 cases (patient had Diabetes insipidus prior to Gamma knife treatment, but after Gamma knife he developed panhypopituitarism followed by fits,

Results of normalization of hormonal levels:
ation of hormonal levels out of 67 prolactinoma patients, 55 patients (82.08%) showed returning of prolactin level to normal after doing Gamma knife (49 returned to normal level within 6 months, 5 within 1 year and 1 hin 1.5 year, while the remaining 12 patients didn't return to normal). Those 55 patients were on continuous consumption of cabrigoline (one Out of the 22 patients with Cushing disease, 18 (81.81%) ACTH and cortisol levels returned to performing the Gamma knife treatment as follows: 17 within 6 months and 1 Out of the 10 patients with GH secreting adenoma, 9 (90%) patients showed a return of GH hormone levels to normal as follows: 5 in 1 year and 1 within 1.5 years, while all of them were taking sandastatine

DISCUSSION:
In the treatment of pituitary adenoma (especially macroadenomas), radiosurgery is classically indicated in cases of incomplete resection or recurrent tumors, in functioning tumors that cannot be controlled with medical therapy and in patients inoperable or who refuse surgery [6] . In case of secretory pituitary adenomas, Gamma knife is used for tumor growth control and for endocrinological hypersecretion normalization [7] . In this study, Gamma knife was utilized as an adjuvant treatment in all 132 cases after being resistant to medical therapies, or intolerant to drug side effects, with or without a previous pituitary surgical interference. In accordance with his details, Ganz proposed that the effective dose for secretory adenomas must be greater than 25 Gy [8] . While Pollock's reported regarding functioning adenomas demonstrated no relationship between the dose of radiation and endocrinological outcome [9] . In the current study, the lowest effective radiation dose was 16 Gy delivered to the tumor margin with a mean marginal dose of 20 Gy. The dose of radiation prescribed in this study for pituitary adenoma differs from one type to other, for prolactinoma, it ranges from 20 Gy to 25 Gy, for GH secreting adenoma it ranges from 20 Gy to 22 Gy, for Cushing disease, it ranges from 18 Gy to 22 Gy, for non-secretory adenoma, the dose ranges from 16 Gy to 20 Gy. While the coverage area for the dose of Gamma rays radiation ranges from 95% to 100% in microadenoma, and from 86% to 95% in macroadenoma. A correlation between the endocrine remission and marginal dose was found in the study conducted by Sheehan et al. on (418) pituitary adenoma patients who were treated with Gamma knife. There was an inverse relationship between endocrine remission time and dose of tumor margin radiation dose. In patients with secretory adenomas, smaller adenoma volume was found

GAMMA KNIFE EFFECT ON PATIENTS WITH PITUITARY ADENOMA
to be associated with improved endocrine remission. Thus, they concluded that smaller adenoma volume improves the probability of endocrine remission and lowers the risk of new pituitary hormone deficiency with Gamma knife. The greater opportunity for endocrine remission and tumor growth control can be offered by the higher margin doses [10] . Stereotactic radiosurgery provided excellent control of tumor growth in almost all published studies. In a study done by Hayashi, it was revealed that tumor control rate for pituitary adenoma following Gamma knife use was between (93% -94%), and the range of tumor shrinkage rate was between (46%-56.7%) [11] . However, greater than (95%) of tumor size control was reported by several studies with follow-up varying from months to years [12] . Local control of tumor in (93.6%) of patients, with reduction in (24.1%) of patients was observed by Izawa et al. after (24) months follow-up among (79) patients with secretory pituitary adenomas who were treated with Gamma knife, with a mean marginal dose prescription of 22.5 Gy [13] . In this study, the control rate of growth with necrosis for pituitary adenoma ranged from 88.05% in prolactinoma, 86.36% in cushings, 90% in GH secreting adenoma and 93.93% in non-secretory adenoma, in a follow up period of 6 months and 1 year; while tumor size reduction ranged from 20.89% in prolactinoma, 22.72% in Cushing disease, 20% in GH adenoma and 21.21% in non-secretory adenoma in a follow up period of 1 year and 1.5 years. In cases of tumor shrinkage, some studies have even revealed visual function improvement after radiosurgery. There is a tendency of the majority of pituitary adenomas to be slow growing lesions. As such, it may be misleading to assess patients with a relatively short follow-up [7] . In patients who suffer from dopamineregic drug intolerance or who have tumor extended to cavernous sinuses, the Gamma knife is considered as an appropriate alternative. Pan et al mentioned the largest series of adenomas which can be treated by Gamma knife. Normal levels of serum prolactin for gender was used as a cure criteria by Pan et al, and 15% of endocrinological remission rates were recorded in (128) patients with a (33) months median follow-up. Some studies utilize relatively similar criteria and 'Cure' rates varied from (20-84%) [14] .
In this study, normalization of serum prolactin level occurs in 82.08%. Cushing disease is a severe catabolic disease requiring a rapid cortisol hypersecretion normalization, making pituitary microsurgery is the primary treatment for Cushing disease. However, Gamma knife surgery can be utilized in case of open surgery contraindication or refusal, or utilized as a secondary treatment in case of open surgery failure or tumor extention into the cavernous sinuses. Several series of studies used the (24) hour urine cortisol collection as part of endocrinological assessment criteria, with a endocrinological 'cure' rate ranging from (17-83%) [15] . In a recent study, Laws and Vance observed a remission in approximately (60%) of Cushing's disease patients after more than (6) months of follow-up with a mean remission time of approximately one year when gamma knife surgery was used as a complement to open surgery [16] . In this study, normalization of serum cortisol level occurs in 81.81% of cases in a follow up period of 6 months, 1year, & 1.5 year. To control acromegaly, there is still no consistent applied criteria. The most widely accepted guidelines for a remission in acromegaly consist of a GH level less than 1ng/ml in response to a glucose challenge and a normal serum IGF-1 when gender and age are to be matched. Gamma knife results are explained in details for acromegaly patients in some studies with such criteria. In such series, the range of mean radiosurgery margin doses was (15-34) Gy. After radiosurgery, the variation of 'Cure' rates was from (0-100%). The range of endocrinological remission rates was from (20-96%) in these series of at least (16) patients and (2) years median follow-up [17] . The current study showed that the serum GH level normalization happened in (90%) of cases in a period of (6) months follow up. Sheehan et al. in their extensively reviewed studies reported that the hormonal normalization ranged between 17 and 83% in patients with Cushing's disease, between 20 and 96% in patients with acromegaly, and between 0-84% in patients with prolactinoma [5] . Castro et al. in their study on 28 cases with functioning pituitary adenomas treated with radiosurgery reported hormone control in 67% of patients with Cushing's disease, 40% of patients