Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.287674
Source of Support: None, Conflict of Interest: None
Keywords: Pituitary adenoma, Stereotactic radiosurgery, Gamma KnifeKey Message: The aim of stereotactic radiosurgery for pituitary adenomas is to stop tumor growth, normalize hormonal hypersecretion, preserve pituitary function and important surrounding structures. Stereotactic radiosurgery is a safe treatment option for residual or recurrent pituitary adenomas.
Pituitary adenomas account for 10-20% of primary brain tumors and are the third commonest intracranial tumors. From the radiosurgery point of view, pituitary tumors can be classified in two ways. The first classification is based on the size of the tumor – adenomas less than 1 cm are known as microadenomas and those more than 1 cm are known as macroadenomas. The other classification is based on hormonal activity of the adenoma i.e., functional or non-functional pituitary adenomas. Functional pituitary adenomas are the tumors that secrete excess of hormones and present with various clinical syndromes. Prolactinomas, the pituitary adenomas which secrete prolactin, are the most common secretory adenomas and are associated with amenorrhea-galactorrhea syndrome (infertility in women, and impotence and infertility in men). Pituitary adenomas secreting growth-hormone (GH) results in acromegaly in adults and gigantism in children. Lastly, pituitary tumors secreting adrenocorticotropic hormone (ACTH) cause Cushing's disease, which is far more common in females than in males.
Non-functional pituitary adenomas are the ones which do not secrete any excess amount of hormone and account for approximately 30% of all pituitary adenomas. However, it has been shown that about 70-80% of these non-functional pituitary adenomas produce gonadotropins or their subunits and are actually gonadotroph adenomas. Some of the adenomas stain for GH, PRL, ACTH or thyrotropin, but there are no clinical symptoms of hormonal excess as the serum levels of these hormones are not elevated enough to cause the clinical syndromes. Hence these adenomas are also named as 'clinically non-functional adenomas. As there is no hormonal hypersecretion, these tumors come into clinical attention once they have grown large enough to cause pressure over visual apparatus or other structures. They can grow even bigger and may result in raised intracranial pressure. Hypopituitarism can also be seen in these patients due to compromise of the function of the normal pituitary by the adenoma. However, an increasing number of non-functional pituitary adenomas are getting detected at the stage of microadenomas due to imaging studies done for an unrelated problem like evaluation of headache or following head injury. These asymptomatic adenomas are known as pituitary incidentalomas. Incidental lesions of pituitary have been found in up to 22.5% of patients in various magnetic resonance imaging (MRI) and computed tomography studies, with 78% of these being adenomas. These patients with incidentalomas pose a clinical situation where the guidelines are not clear. Many of these patients are considered for gamma knife radiosurgery, it being a relatively less invasive treatment modality. Before we discuss the role of gamma knife radiosurgery in the management of pituitary adenomas, it will be prudent to discuss about some of the technical aspects of gamma knife radiosurgery which are pertinent in the radiosurgical management of pituitary adenomas.
Intracranial radiosurgery was first practiced by Lars Leksell, a practicing functional neurosurgeon at Karolinska University in Stockholm, Sweden. He attached an X-ray tube to his stereotactic arc centered frame and targeted trigeminal ganglion in a patient with trigeminal neuralgia. He thus integrated stereotactic precision with the penetrating capability and the tissue effect of the photon beam. However, the lack of good imaging modalities limited the expansion of intracranial radiosurgery techniques for the next few decades. The only available imaging modalities at that time were ventriculography, cisternography and angiography. Application of radiosurgery was limited to the structures/pathologies visible on these modalities.
The first Gamma Knife unit came into clinical practice in 1969 and ever since has become the modality of choice for intracranial radiosurgery. It is considered the gold standard for radiosurgery due to its higher precision and quality control. The current model of Leksell Gamma Knife consists of 192 cobalt-60 sources, which are arranged in conical configuration and deliver gamma rays simultaneously directed to a single focus precisely, estimated to be 0.3-mm, though it depends on various factors. There are many mechanisms in gamma knife which enable the generation of a highly conformal plan for intracranial targets and sparing the adjacent critical structures at the same time. One of the ways to achieve conformality is its ability to combine three different collimator size options (4, 8, and 16 mm) simultaneously in a single shot to get a 'composite shot'. Another important mechanism to achieve this is 'dynamic shaping', in which the gamma rays coming from a particular part of the gantry can be blocked in order to spare the organ at risk. Another advancement which is of particular interest for radiosurgery of pituitary tumors is the option of 'EXTEND' system in the Gamma knife Perfexion and mask-based radiosurgery in the new 'ICON' model. These allow hypofractionation without the need of frame application.
Gamma rays act by breaking of the DNA strands both by direct action of radiation and indirect action by the free radicals which are products of radiation effect on other molecules, especially water molecules. Progressive vascular obliteration play an important role apart from the direct cytotoxic effect.
The treatment of choice for all symptomatic pituitary adenomas (except prolactinomas) is surgical resection, and transsphenoidal route is the favoured approach. Radiotherapy has traditionally been used in adenomas which are residual or recurrent. The role of radiotherapy was palliative only as the conventional radiotherapy was associated with a multitude of side effects due to its inability to spare the adjacent normal structures, which include but are not limited to visual diminution secondary to radiation induced optic neuropathy, impairment of neurocognitive function, and risk of secondary malignancy. Moreover, the incidence of post-radiotherapy hypopituitarism (50-80%) was very high and the time of hormonal normalization in functional adenomas was quite long (5-15 years) and unpredictable.,, However, the scenario has changed after the advent and popularization of gamma knife radiosurgery. The gamma knife enables one to deliver a very high dose of radiation to the tumor with the ability to shield the optic apparatus and giving minimal dose to the surrounding brain and all that in a single sitting (most of the times). The aim of stereotactic radiosurgery for pituitary adenomas is to stop tumor growth, normalize hormonal hypersecretion, preserve pituitary function and important surrounding structures.
Role of Gamma knife RS in non-functional pituitary tumors
The aim of gamma knife radiosurgery in cases of non-functional pituitary adenoma is to stop tumor growth while preserving adjacent structures like optic apparatus and normal pituitary. Surgery is the treatment modality of choice in the management of non-functional pituitary adenomas and gamma knife radiosurgery is restricted for residual or recurrent lesions only. Sometimes, when there is a giant pituitary adenoma or a macroadenoma with cavernous sinus invasion, the part of the tumor extending into the cavernous sinus is left behind to be later subjected to gamma knife radiosurgery while the rest of the tumor is removed [Figure 1] and [Figure 2]. This is a safe approach.
The reported tumor control rates in non-functional pituitary adenomas with gamma knife vary from 94-100% and 76-87% at 5 year and 10 years of follow-up, respectively, with a minimum marginal dose ranging from 14-16.6.,,,,, Some centres use higher dose, as high as 20 Gy even for non-functional pituitary adenomas. However, 12 Gy is the minimum single-session antiproliferative dose to the adenoma and a dose less than 10 Gy has been demonstrated to be associated with high chances of treatment failure., However, one must remember to reduce the dose in patients who have previously received radiotherapy.
Tumor control was achieved in all patients in one study, which included 79 patients of non-functional pituitary adenoma. They reported average tumor volume reduction of 60% of pre-treatment volume in 89% of patients at a median follow up of 5 years. The marginal dose ranged between 12 and 35 Gy, with the median of 20 Gy. The study period of this study was 1993 to 2003 and this might be the reason of use of high dose in this series as the recommended dose is not so high these days. They observed that the shrinkage of tumor started as soon as 2 years after gamma knife treatment. There was no perimeter vision impairment after radiosurgery even with this high dose, while 4 out of 52 patients with abnormal perimeter vision at the time of radiosurgery treatment reported improvement in their study. They observed impairment of hypophysis function in only 2 patients.
Mingione V et al. described their experience of treating 100 patients with non-functional pituitary adenoma, 92 patients had residual or recurrent macroadenoma following one or more surgical procedures, while 8 patients had gamma knife radiosurgery as the primary treatment. Peripheral doses between 5 and 25 Gy (mean 18.5 Gy) were administered. Mean imaging follow-up in 90 patients was 44.9 months (range - 6 to 142 months). Out of these 90 patients, tumor volume decreased in 59 patients (65.6%), remained unchanged in 24 (26.7%), and increased in seven (7.8%) patients. They concluded that minimal effective peripheral dose was 12 Gy; peripheral doses greater than 20 Gy did not seem to provide additional benefit. Twenty percent patients suffered new hormone deficits out of the 61 patients with a partially or fully functioning pituitary gland. In patients with endocrinological follow-up data that had been collected over more than 2 years, the rate of new deficits was 25%.
In a recent meta-analysis by Kotecha et al., 2671 patients treated with either single fraction SRS or hypofractionated stereotactic radiotherapy (HSRT) between 1971-2017 were included. SRS was used in 27 studies (median dose: 15 Gy, Range: 5-35 Gy) and HSRT in 8 studies (median total dose: 21 Gy, range: 12-25 Gy, delivered in 3-5 fractions). The 5-year random effects local control estimate after SRS was 94% (95% CI: 93-96%) and 97.0% (95% CI: 93-98%) after HSRT. The 10-year local control random effects estimate after SRS was 83.0% (95% CI, 77-88%). Post-SRS hypopituitarism was the most common treatment-related toxicity observed, with a random effects estimate of 21.0% (95% CI: 15-27%), whereas visual dysfunction or other cranial nerve injuries were uncommon (range: 0-7%).
Role of Gamma knife RS in functional pituitary adenoma
The aim of gamma knife radiosurgery in cases of functional pituitary adenoma is to stop tumor growth and excess hormone secretion, i.e., both biochemical and radiological tumor control. Biochemical remission, i.e., hormonal control is most of the times associated with radiological control, while the vice versa is not always true. Medical therapy is the treatment modality of choice in case of prolactinomas, while surgery is the preferred modality in case of acromegaly and Cushing's disease. Surgery is again the preferred modality in case of residual and recurrent Cushing's disease and acromegaly. Gamma knife radiosurgery is preferred in candidates where surgical attempts have failed to achieve complete hormonal remission or in some special circumstances which we will discuss [Figure 3].
A recently published multi institutional study including data of patients with acromegaly who underwent SRS with endocrine follow-up of ≥6 months was published recently. This study included 371 patients with a mean endocrine follow-up of 79 months. The mean SRS treatment volume was 3.0 cm3 and the mean marginal dose was 24.2 Gy. The actuarial rates of initial and durable endocrine remission at 10 year were 69% and 59%, respectively. The mean time to durable remission after SRS was 38 months. Biochemical relapse after initial remission occurred in 9% with a mean time to recurrence of 17 months. It was observed that cessation of IGF-1 lowering medication prior to SRS was the only significant independent predictor of durable remission. Adverse radiation effects included the development of ≥1 new endocrinopathy in 26% and ≥1 cranial neuropathy in 4%.
Other studies have reported endocrine remission rates ranging from 17-58% at 5 years after radiosurgery. This large variation might be due to the different criteria of endocrine remission criteria used in different studies.
It is not always feasible to give high dose of radiation to the functioning pituitary adenomas (>25 Gy) due to proximity of the optic apparatus. Pai et al. evaluated the efficacy and safety of low-dose (<25 Gy) GKRS in the treatment of patients with acromegaly. They concluded that reasonable remission rates comparable to those with standard GKRS margin doses can be achieved with a lower dose.
The first line of treatment in Cushing disease (CD) is surgical excision. Remission rates for CD patients with macroadenomas or invasive microadenomas are much lower. Gamma knife is used where there is residual disease not amenable to surgical resection. Cushing disease is a less common indication for GKRS as compared to acromegaly in our practice and literature is also sparse on the same topic.
A retrospective series involving describing the results of SRS alone or SRS along with bilateral adrenalectomy in patients who had undergone prior transsphenoidal resection was published recently. A favourable outcome, defined as biochemical remission and tumor growth control, was achieved in 72% of patients in patients who received SRS alone. Five patients (28%) required additional treatment due to persistent hypercortisolemia (n = 4) or hypercortisolemia and tumor growth (n = 1). They also compared these patients who received SRS alone with the patients who underwent bilateral adrenalectomy along with SRS. They found that favourable outcomes were more frequent in the adrenalectomy and SRS group at 1 year and 3 years, but no difference was noted at 5 years. They also concluded that patients with mild to moderate Cushing disease can be safely managed with SRS alone, while patients with severe Cushing disease should be considered for bilateral adrenalectomy along with SRS.
A recent study involving 242 patients tried to compare the difference in the response rates of matched cohorts of Cushing disease and acromegaly to SRS. They found that patients with ACTH-secreting tumours achieved endocrine remission sooner than those with GH-secreting tumors after radiosurgery. Other factors found to be associated with an increased time to endocrine remission on multivariate analysis included patient age and cavernous sinus invasion. The incidence of new hypopituitarism developing after stereotactic radiosurgery was same in both the adenoma types.
It has been found that the administration of somatostatin analogues or dopaminergic agonists at the time of radiosurgery decreased the success of the radiosurgical treatment, may be because of some radioprotective effect of these drugs, although it has not been proved. It is recommended to discontinue these agents at least 2 weeks prior to radiosurgical treatment.
Irradiation of whole pituitary gland
Sometimes it is difficult to define a functional adenoma, especially after multiple surgical interventions. Whole of the sella needs to be irradiated in these situations especially in functional adenomas to achieve desired hormonal control.
A recent study addressed the question if whole sella SRS is as effective as targeted SRS. Data was collected retrospectively from 10 centres from 1990 to 2016, and 128 patients were included in the analysis. It was seen that the whole sella patients had a higher pre-SRS random serum growth hormone, larger treatment volume, and higher maximum point dose to the optic apparatus. The rates of initial/durable endocrine remission, new loss of pituitary function, and new cranial neuropathy were similar between groups. Mortality and new visual deficit were higher in the whole sella cohort but the difference was not statistically significant.
Primary GKRS for the acromegaly and Cushing disease
Few patients cannot undergo surgical excision of the adenoma due to the associated co-morbidities in Cushing disease and acromegaly. Upfront GKS has been tried in these patients. In a series of 46 patients, Gupta et al. found that upfront radiosurgery offered good tumor control as well as a low rate of adverse radiation effects. Endocrine remission was achieved in 51% of their entire cohort, with 28% remission in acromegaly and 81% remission for those with Cushing's disease at the 5-year intervals. We had a patient of acromegaly in whom surgical tumor excision could not be done due to kissing carotids. The patient had to undergo gamma knife radiosurgery.
In a series of 46 paediatric patients who received radiosurgery for acromegaly or cushings disease, endocrine remission rates for CD and acromegaly were 80% and 42%, respectively, at the last follow-up (median - 63.7 months, range, 7-246 months).
GKRS can be repeated if biochemical control is not achieved after the first dose. In a series of 21 patients of acromegaly who received repeat SRS, tumor control rate of 83.3% and endocrine remission rate of 42.9% was described by Alonso et al. Median time from initial SRS to repeat SRS was 5 years in their series. New deficits developed in 19% of patients. They concluded that repeat radiosurgery for persistent acromegaly offers a reasonable benefit to risk profile for this challenging patient cohort.
A multi-centric study involving 20 patients studied the feasibility and effect of repeat SRS in Cushing disease. Median margin dose of 20 Gy was given in these patients 1.3 years to 9.7 years after initial SRS. Median endocrine follow-up was 6.6 years (1.4-19.1 years). Endocrine remission after second SRS was achieved in 60% of patients at a median time of 6 months (range 2-64 months) after repeat SRS. Overall, the cumulative rates of durable endocrine remission at 5 and 10 years were 47% and 53%, respectively. The adverse events included transient visual loss and permanent diplopia. They concluded that repeat SRS achieves lasting biochemical remission in approximately half of patients with Cushing disease refractory to both prior microsurgery and SRS.
At AIIMS New Delhi, till now we have treated 856 patients of pituitary adenoma out of which 320 (37%) patients had functional adenoma. Majority of functional adenomas were GH secreting adenomas. Majority of the pituitary adenomas received secondary gamma knife radiosurgery (residual adenomas following surgical excision) which included both functional and non-functional adenomas. Primary gamma knife radiosurgery was offered to patients harbouring smaller adenomas away from visual apparatus, medically unfit patients or not deemed suitable for surgical excision for various reasons.
For non-functional adenomas, 12 Gy marginal dose (50% isodose) is the standard dose with caution that any part of visual apparatus remains outside 8 Gy isodose line. There were very few patients who did not respond to this treatment protocol and needed a second dose of gamma knife radiosurgery. For functional adenomas, the marginal dose of 24 Gy (50% isodose) is used. It always remains a challenge to keep the visual apparatus outside 8 Gy line while delivering high dose of 24 Gy to functional adenomas. Many times, we need to reduce the dose to 22 Gy or 20 Gy. At times when we are not able to deliver the minimum 18 Gy marginal dose to the functional adenoma, we prefer to dose fractionate. Around 13 Gy to 14 Gy marginal dose is delivered in the first fraction and second fraction of 10 Gy usually is delivered after 4 weeks. With this protocol, we have never encountered any visual decline and have achieved hormonal control rate more than 70% after 2-3 years on an average. A similar approach is used in larger non-functional adenomas where 12 Gy marginal dose cannot be delivered in single fraction without compromising visual apparatus. Dose fractionation is done here as well. First dose of 8 Gy followed by 6 Gy after 4 weeks is used with very good results.
The majority of our patients had residual adenomas in cavernous sinus which included both functioning and non-functional tumors. Using even the higher dose of 24 Gy in functional adenomas, we have never come across radiation induced neuropathies of extraocular nerves. Till now, we have encountered only one case of non-debilitating stroke due to internal carotid artery occlusion in a case of acromegaly. This patient had residual functional adenoma in the cavernous sinus which had already undergone external beam conventional radiation therapy in the past. Gamma knife radiosurgery was used to treat the persisting functional adenoma in the cavernous sinus. The patient responded to the treatment, but developed internal carotid artery occlusion in due course of time with stroke, which was mild and the patient made good recovery.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]