|Year : 2015 | Volume
| Issue : 1 | Page : 6-12
Role of gamma knife radiosurgery in the management of functioning pituitary adenomas
Mohammad F Elshirbiny MSc. , Raef F. A. Hafez, Nabil Ali, Ashraf A Ezzeldien, Mohammad A Kassem
Department of Neurosurgery, Mansoura Faculty of Medicine and International Medical Center, Mansoura, Egypt
|Date of Submission||07-May-2015|
|Date of Acceptance||24-May-2015|
|Date of Web Publication||26-Nov-2015|
Mohammad F Elshirbiny
Department of Neurosurgery, Faculty of Medicine, Mansoura University, Mansoura
Source of Support: None, Conflict of Interest: None
Historically, the treatment armamentarium for secretory pituitary adenomas included neurosurgery, medical management, fractionated radiotherapy, and, recently, gamma knife surgery (GKS). The objective of this study was to evaluate the efficacy, safety, and role of GKS in the treatment of secretory pituitary adenomas as regards hormonal and adenoma size control. Between January 2010 and January 2014, a prospective analysis of 40 consecutive patients who underwent GKS for secretory pituitary adenomas at the International Medical Center, Cairo, Egypt, was carried out. Eight patients had adrenocorticotropic hormone-secreting adenoma, 16 patients had prolactin-secreting adenoma, and 16 had growth hormone-secreting adenoma. In 19 patients, GKS was the secondary treatment to a prior surgery with failure of hormonal control along with medical treatment. In the remaining 21 patients, the secretory pituitary adenomas were not controlled with medical treatment alone. The follow-up period ranged between 12 and 60 months. Hormonal control was achieved with either normalization or a marked decline in abnormal hormone level of more 50%. Radiological tumor size control was carried out with either tumor size stabilization or reduction. Among the 40 patients, 21 had microadenoma of 1 cm 3 volume or less. Overall, 24 patients (60%) had hormonal control and 38 patients (95%) had tumor size control after GKS. There was a direct correlation between tumor size, prescription radiation dose, and hormonal and size control after GKS. Twenty out of the treated 21 microadenoma cases showed both hormonal and size control. In conclusion, GKS is a safe and effective treatment method for secretory pituitary adenomas that have failed to respond to medical treatment alone or have postsurgical residual tumor, or recurrence, especially microadenomas.
Keywords: gamma knife surgery (gks), pituitary adenomas, pituitary hormones, radiosurgery, prolactinoma
|How to cite this article:|
Elshirbiny MF, Hafez RF, Ali N, Ezzeldien AA, Kassem MA. Role of gamma knife radiosurgery in the management of functioning pituitary adenomas. Benha Med J 2015;32:6-12
|How to cite this URL:|
Elshirbiny MF, Hafez RF, Ali N, Ezzeldien AA, Kassem MA. Role of gamma knife radiosurgery in the management of functioning pituitary adenomas. Benha Med J [serial online] 2015 [cited 2017 Jun 25];32:6-12. Available from: http://www.bmfj.eg.net/text.asp?2015/32/1/6/170551
| Introduction|| |
Pituitary adenomas are common lesions and represent 20% of all primary brain tumors ,, . Pituitary adenomas are classified into two groups. The first is the secretory pituitary adenomas that produce excess of normal pituitary hormones; usually they are microadenomas. Such functioning adenomas include those with Cushing's disease [high adrenocorticotropic hormone (ACTH)], acromegaly [high growth hormone (GH)], prolactinomas with high prolactin (PRL) hormone, and rarely adenoma, which can overproduce more than one hormone. Occasionally, some secretory microadenomas may produce pressure symptoms relating to compression of the optic pathway or invasion of the cavernous sinus. The second is nonsecretory pituitary adenomas that represent ~30% of pituitary adenomas. They are usually macroadenomas that enlarge and can extend beyond the confines of the sella turcica into the cavernous sinus, suprasellar region, infrasellar region, and even invade the clivus  .
Surgery, fractionated radiotherapy, and medication are the three key elements of the treatment strategy for secretory pituitary adenoma. Transsphenoidal microsurgery has remained the primary treatment method for most patients with functioning adenomas causing acromegaly or Cushing's disease. Most prolactinomas can be controlled successfully with medical treatment, and transsphenoidal microsurgery is the second treatment step  .
The persistence or recurrence of secretory pituitary diseases due to tumor invasion into surrounding structures, or incomplete tumor resection, is quite common, and long-term tumor control rates after transsphenoidal excision alone vary from 50 to 80%  . For residual or recurrent tumors, fractionated radiation therapy has been the traditional treatment. However, it has a prolonged latency for its effects and is associated with more frequent side effects such as hypopituitarism and visual damage ,, .
In 1968, Leksell treated the first pituitary adenoma patient with the Gamma knife technique. Since that time, stereotactic radiosurgery has become an important tool in the neurosurgical treatment of patients with pituitary adenomas  . Recently, gamma knife surgery (GKS) has gained acceptance as a primary minimally invasive treatment option for secreting pituitary microadenomas, or as a complementary treatment option in combination with microsurgery for secreting macroadenomas. 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 of the surrounding normal brain structures , .
| Materials and methods|| |
Forty consecutive patients with secretory pituitary adenoma were treated with Leksell GKS at the International Medical Center, Gamma Knife Center, Cairo, Egypt, between January 2010 and January 2014. GKS was utilized in our study as an adjuvant treatment in all studied 40 cases, after being resistant to medical therapies or intolerant to its side effects, with or without previous pituitary surgery. In 19 patients, some form of prior surgery such as transsphenoidal resection or craniotomy had been performed with the presence of residual, especially involving the cavernous sinus, or recurrence tumors. The median follow-up period was 20 months (12-60 months). The remaining 21 patients had a history of medical treatment failure without any surgical intervention Twenty-one patients had microadenomas of diameter 10 mm or less, who were referred directly by an endocrinologist.
In all treated cases, optic apparatus was at least 2-3 mm distance from the treated adenoma. Radiological (MRI and sometimes CT scan), endocrinological, ophthalmological, and neuroradiological examinations were conducted. The initial diagnosis was made based on MRI findings, endocrinological findings, pathological findings (available for postoperative cases), and clinical history. In all patients, initial pre-GKS levels of ACTH, cortisol and urinary free cortisol, GH and insulin-like growth factor I, PRL, LH, FSH, testosterone or estradiol, TSH, and free T 3 and T 4 were obtained. Cessation of the antisecretory agents 1-2 months before GKS is advised in most of the treated patients.
The results were classified as follows: 24 patients showed clinical improvement, tumor size control, and hormonal control (hormonal normalization or marked decline >50% compared with that before GKS) after gamma knife antisecretory medical treatment; nine patients showed some hormonal decline of less than 50% with little improvement or stable clinical condition that was achieved with antisecretory drugs; and seven patients showed failure to achieve any hormonal control or decline with persistent clinical condition that sometimes worsened.
Gamma knife procedure and neuroimaging
Application of the stereotactic frame was performed under local anesthesia on the morning of the procedure. Stereotactic MRI was then performed to determine the pathology. The gamma knife procedure was performed using Leksell gamma knife model 4C - APS version. The stereotactic MRI sequences were performed on a 1.5-T magnetic resonance machine. The stereotactic MRI sequences included T1 coronal cuts without contrast first and then T1 coronal immediately after contrast injection, followed by axial T1 and sagittal T1. MRI slice thickness was 1.5 mm without any gap on zero angle. T2-coronal sequence may be obtained, especially in postsurgical cases, to optimize visualization of optic apparatus. The fat suppression techniques in MRI sequence can prove useful for differentiating tumor from surgical fat grafts. CT is generally reserved for patients who cannot undergo an MRI (e.g. a patient with a pacemaker).
The stereotactic MRI sequences were then transmitted to Leksell gamma plan, when treatment plan was carried out. Thereafter, the treatment protocol was passed to the Leksell gamma knife control unit where treatment was applied automatically with APS. Either the 4 or the 8 mm collimator helmet was utilized, especially in microadenoma, to achieve conformity and to avoid radiation neural injuries. In some cases, plugging was applied to avoid optic structure injuries. Occasionally, the 72° gamma angle of radiation beams was utilized so that the radiation beams were delivered parallel to the optic nerve avoiding intersection and injuries to optic apparatus. Nevertheless, in many treated microadenomas 90° gamma angle fulfilled the same purpose.
Follow-up was carried out regularly every 6 months in the first year after GKS and then yearly follow-up was carried out. The median follow-up period was 20 months (12-60 months). Follow-up criteria included MRI with contrast and endocrinological and ophthalmological assessments.
| Results|| |
This study was conducted on 40 patients with secretory pituitary adenoma treated with GKS at the international medical center between January 2010 and January 2014, with a median follow-up period of 20 months (12-60 months). There were 16 female and 24 male patients, and their ages ranged between 17 and 63 years (mean = 34.2 years). In all 40 cases there was failure to control high hormonal level. In 19 cases, either postsurgical residual tumor or recurrences were observed. In 21 cases, after failure of medical treatment alone, or intolerance to drugs, side effects without any previous surgery was observed. Twenty-one cases had adenoma of 1 cm 3 volume or less. The clinical characteristics of the treated patients are summarized in [Table 1]. There were 16 patients with acromegaly (high GH), eight patients with Cushing's disease (high ACTH and urinary free cortisol), and 16 patients with prolactinoma (high PRL).
|Table 1 The clinical characteristics of the 40 patients treated for secretory pituitary adenoma|
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The peripheral prescription dose varied depending on tumor size, type of hormonal secretion, and proximity to optic apparatus. For acromegaly the dose ranged between 20 and 25 Gy, for prolactinomas it ranged between 18 and 22 Gy, and for Cushing's disease it is usually between 25 and 30 Gy. The isodose curve ranged between 35 and 60%, and adenoma radiation coverage ranged between 93 and 100%.
Optic apparatus in all cases received less than 8 Gy. Third cranial nerve in those with cavernous sinus invasion received less than 21 Gy and pituitary gland and stalk received less than 15 Gy. The secretory pituitary adenoma volumes treated in this study ranged between 0.036 and 3.7 cm 3 , with a peripheral dose of 20-22 Gy, and seven of them had an adenoma size of 1 cm 3 volume or less. Five patients had hormonal decline of less than 50% and the remaining two patients showed failure of hormonal control; they had an adenoma volume of 2.6 and 3.2 cm 3 , respectively. Both were treated with peripheral prescription dose limited to 18 Gy because of adenoma sizes and proximity to optic apparatus ([Figure 1] and [Figure 2]). Their distribution was as follows: 3-3.84 cm 3 in two patients, 2-2.85 cm 3 in 10 patients, 1.2-1.98 cm 3 in seven patients, and 1 cm 3 volume or less in 21 patients.
|Figure 1 Gamma plan for postoperative residual prolactinoma of 1.9 cm3 volume. The prescription dose was 22 Gy to the 35% isodose curve.|
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|Figure 2 Follow-up MRI for the same postoperative residual prolactinoma patients 4 years after gamma knife surgery showing marked adenoma reduction.|
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The overall results of GKS for the 40 patients ([Table 2]) were as follows: 24 patients (60%) showed clinical improvement, tumor size control, and hormonal control (hormonal normalization was seen in 14 patients or a marked decline >50% in 10 patients compared with that before GKS); nine patients (22.5%) showed some hormonal decline of less than 50% with little improvement or stable clinical condition; and seven patients (17.5%) showed failure to achieve any hormonal control with persistent clinical condition or even worsened. Hormonal control in our study occurred within 12-36 months, although clinical improvement sometimes happened before that.
|Table 2 Hormonal and adenoma size control in the 40 patients treated for secretory pituitary adenoma|
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As regards adenoma sizes determined with MRI at follow-up after GKS, 38 (95%) out of the 40 studied cases showed tumor size control. In 33 of them the adenomas were of stable size (local control), and in five cases the adenomas reduced in size; such reduction started usually after 12-24 months and sometimes continued.
Among the 16 prolactinoma patients who were treated, nine patients (56%) had hormonal control after at least two successive serum PRL depending on age and sex. Most of them responded after 12 months and up to 3 years.
Among the 16 acromeagalic patients who were treated, 10 patients (62%) showed hormonal control (GH <2, 5 μg/l), which usually happened after 12-24 months after GKS. Nine of them had adenoma volume of 1 cm 3 or less and all were treated with a marginal dose of 22-25 Gy. Three patients had hormonal decline of less than 50%, and the remaining three patients had failure of hormonal control. The treated adenomas measured 2.6, 2.8, and 3.7 cm 3 , respectively. All these cases were treated with a peripheral dose of 22 Gy or less because of tumor size and proximity to optic apparatus ([Figure 3] and [Figure 4]). Among the eight patients with Cushing's disease who were treated, five patients (62%) had hormonal control with 24-h free urinary cortisol in the normal range.
|Figure 3 Gamma plan for acromegalic patient pituitary adenoma of 1.8 cm 3 volume. The prescription dose was 25 Gy to 50% isodose curve.|
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|Figure 4 Follow-up MRI for the same acromegalic patient 5 years after gamma knife surgery with continue reduction of tumor size.|
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The peripheral prescription dose was 25-30 Gy, and all patients had microadenoma of 1 cm 3 volume or less. One patient had hormonal decline of less than 50% with a tumor measuring 2 cm 3 , and in the remaining two cases there was failure of hormonal control; the adenoma volumes in these patients were 2.88 and 2.82 cm 3 , and the prescription dose was less than 25 Gy ([Figure 5] and [Figure 6]).
|Figure 5 Gamma plan for Cushing's disease with pituitary microadenoma of 0.249 cm 3 volume. The prescription dose was 25 Gy to 50% isodose curve.|
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|Figure 6 Follow-up MRI for the same Cushing's disease with pituitary microadenoma at 18 months' follow-up, with tumor size reduction, being concave in coronal MRI sequence.|
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Overall, among the 24 patients who showed hormonal control in our study, there were 20 with microadenomas of 1 cm 3 volume or less, taking into consideration that the total number of microadenomas treated in our study was 21.
One patient treated for prolactinoma developed third nerve palsy after GKS. The patient had a large prolactinoma residual with intracavernous sinus extension. He improved gradually with time.
Two patients in this study presented with anterior pituitary hormone deficiency (gonadotrophic deficiency in one patient with Cushing's disease and thyrotrophic hormone deficiency in one prolactinoma patient), which was detected after 36 months of follow-up. Hormonal replacement was essential for these patients. None of our studied patients showed panhypopituitarism during the follow-up period. No additional visual complications occurred in all treated cases compared with pre-GKS condition.
| Discussion|| |
There are multiple treatment modalities for secretory pituitary adenomas. Radiosurgery is an effective, noninvasive method for treating patients with functioning pituitary adenoma as a complement to the surgery. Pituitary adenoma that compresses the optic pathway should be removed with microsurgery. Residual tumors, especially in the cavernous sinus, recurrence and/or resistant to medical treatment are good indicators for radiosurgery  . In the treatment of pituitary adenomas, radiotherapy 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, especially macroadenomas  .
In our study, the goal of GKS, in the treatment of secretory pituitary adenomas, is to control tumor growth and control high hormonal secretion. GKS was utilized as an adjuvant treatment in all 40 cases after being resistant to medical therapies, or intolerant to drug side effects, with or without previous pituitary surgery. In 19 of them a prior pituitary surgery had been performed, with the presence of residual tumor or recurrence. The remaining 21 patients had a history of medical treatment failure without pituitary surgery. These 21 patients had functioning microadenomas of 10 mm or less and were usually referred by endocrinologist directly.
Secretory adenomas require a higher radiation dose compared with nonfunctioning pituitary adenomas  . Laws and Vance  estimated that a higher percentage of control of hyperfunctioning syndromes could be achieved with a higher margin dose. Ganz suggested that the effective dose for secretory adenomas should be higher than 25 Gy  .
The volumes of the secretory adenomas in 40 patients ranged between 3.7 and 0.036 cm 3 , of whom 21 had microadenomas. The peripheral prescription dose varied depending on tumor size, type of hormonal secretion, and proximity to optic apparatus. For acromegaly adenomas it ranged between 20 and 25 Gy, for prolactinomas it ranged between 18 and 22 Gy, and for Cushing's disease adenomas it is usually between 25 and 30 Gy. The isodose curve ranged between 35 and 60% and the adenoma coverage ranged between 93 and 100%.
Hayashi et al.  reported that tumor growth control rate for pituitary adenoma after GKS was between 93 and 94%, and that tumor shrinkage rate ranged from 46 to 56.7%. Many studies have reported tumor growth control rate greater than 95%, with follow-up varying from months to years , . Izawa et al.  , after a mean follow-up of 24 months in 79 secretory pituitary adenoma patients treated with GKS, reported local tumor control in 93.6% of patients, with reduction in 24.1% of patients. They prescribed a mean marginal dose of 22.5 Gy  .
Sheehan and colleagues in their extensively reviewed studies involving 1621 patients with secretory pituitary adenomas treated with radiosurgery showed a mean tumor control rate of 96%, considering only the series with a mean or median follow-up of 4 years or more , .
As regards adenoma sizes determined at follow-up on MRI after GKS in our study, 38 patients (95%) showed tumor size control, 33 adenomas were stable in size (local tumor control) and five patients showed adenomas reduced in size. The reduction in sizes happened usually after 18-24 months of 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.
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 with acromegaly, and 44% of patients with prolactinoma.
Petrovich et al.  reported a median time to normalization of hormonal after radiosurgery of 22, 18, and 24 months for patients with tumors that produce ACTH, GH, and PRL, respectively.
Sheehan et al.  in their study on 418 pituitary adenomas treated with GKS found a relation between marginal dose and endocrine remission. The tumor margin radiation dose was inversely correlated with time to endocrine remission. Smaller adenoma volume correlated with improved endocrine remission in those with secretory adenomas. Thus, they concluded that smaller adenoma volume improves the probability of endocrine remission and lowers the risk of new pituitary hormone deficiency with GKS. A higher margin dose offers a greater chance of endocrine remission and control of tumor growth.
The overall results of GKS for the 40 treated cases in this study were as follows: 24 patients (60%) showed clinical improvement, tumor size control, and hormonal control (hormonal normalization in 14 patients and marked decline >50% in 10 patients); nine patients (22.5%) showed some hormonal decline of less than 50% with little improvement or stable clinical condition; and seven patients (17.5%) showed failure to achieve any hormonal control. Among the 16 patients treated for prolactinoma in this work, nine patients (56%) had hormonal control. In most of them it was found after 12 months and up to 3 years. All were treated with a peripheral dose of 20-22 Gy, of whom seven had microadenomas. Among the 16 patients treated for acromegaly, 10 (62%) had hormonal control, which usually occurred 12-24 months after GKS and in nine of them the adenoma volume was 1 cm 3 or less and they were treated with a marginal dose of 22-25 Gy. Among the eight patients treated for Cushing's disease, five patients (62%) had hormonal control with a peripheral prescription dose of 25-30 Gy; all of them had an adenoma volume of less than 1 cm 3 (microadenomas).
Overall, among the 24 patients who achieved hormonal control in our study, there were 20 patients with microadenomas of 1 cm 3 volume or less, taking into consideration that the total number of microadenoma patients treated was 21. This indicates that secretory pituitary adenoma volume has a great impact on results of GKS in controlling the high abnormal hormonal level and in controlling adenoma growth, giving chance to apply high prescription marginal and maximum dose and better radiation conformity without injuries of critical neural structures.
The incidence of hypopituitarism after radiosurgery reported in the literature is quite variable. Older studies that included patients treated in the precomputed tomography reported higher incidence  .
Most studies suggest a maximum dose to optic apparatus of 8 Gy or less to keep the risk of optic neuropathy close to zero and a minimum 2-5 mm between the tumor and optical apparatus , . However, in patients with functioning adenomas when the dose increase may be related to an increase in hormonal control, some authors accept the maximum dose of 10 Gy, as restricted to a small volume of the optical apparatus  .
In the 40 patients in our study, optic apparatus received less than 8 Gy, third cranial nerve in those with cavernous sinus invasion received less than 21 Gy, and pituitary gland and stalk received less than 15 Gy. Two patients in this study developed anterior pituitary hormone deficiency (gonadotrophic deficiency in one patient with Cushing's disease and thyrotrophic hormone deficiency in one prolactinoma patient), which was detected after 36 months of follow-up; hormonal replacement was essential for these patients. One prolactinoma patient developed third nerve palsy after GKS. He had large prolactinoma residual with intracavernous sinus extension.
None of our cases showed panhypopituitarism during the follow-up period. No additional visual complications occurred in all treated cases compared with pre-GKS visual status.
| Conclusion|| |
Although not usually an initial treatment for patients with secretory pituitary adenomas, especially macroadenoma, GKS is a safe and highly effective treatment method for secretory pituitary adenoma patients who show failure to achieve hormonal control after medical treatment alone, intolerant to its side effects or postoperative residual functioning adenoma or recurrence. GKS is a safe and effective method for controlling secretory pituitary adenoma growth and inducing hormonal control, especially in microadenomas with low morbidity, and could be a primary minimal invasive option. The hormonal and tumor growth control in the treatment of secretory pituitary adenoma with GKS are correlated to adenoma size and prescription radiation dose; smaller pituitary permits high marginal dose, giving high chance for rapid hormonal and growth control and low risk for pituitary function disturbance or visual apparatus injuries.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]