- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Correspondence Address:
Nader Pouratian
Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
DOI:10.4103/2152-7806.95419
Copyright: © 2012 Kim W. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Kim W, Clelland C, Yang I, Pouratian N. Comprehensive review of stereotactic radiosurgery for medically and surgically refractory pituitary adenomas. Surg Neurol Int 26-Apr-2012;3:
How to cite this URL: Kim W, Clelland C, Yang I, Pouratian N. Comprehensive review of stereotactic radiosurgery for medically and surgically refractory pituitary adenomas. Surg Neurol Int 26-Apr-2012;3:. Available from: http://sni.wpengine.com/surgicalint_articles/comprehensive-review-of-stereotactic-radiosurgery-for-medically-and-surgically-refractory-pituitary-adenomas/
Abstract
Despite advances in surgical techniques and medical therapies, a significant proportion of pituitary adenomas remain endocrinologically active, demonstrate persistent radiographic disease, or recur when followed for long periods of time. While surgical intervention remains the first-line therapy, stereotactic radiosurgery is increasingly recognized as a viable treatment option for these often challenging tumors. In this review, we comprehensively review the literature to evaluate both endocrinologic and radiographic outcomes of radiosurgical management of pituitary adenomas. The literature clearly supports the use of radiosurgery, with endocrinologic remission rates and time to remission varying by tumor type [prolactinoma: 20–30%, growth hormone secreting adenomas: ~50%, adrenocorticotrophic hormone (ACTH)-secreting adenomas: 40–65%] and radiographic control rates almost universally greater than 90% with long-term follow-up. We stratify the outcomes by tumor type, review the importance of prognostic factors (particularly, pre-treatment endocrinologic function and tumor size), and discuss the complications of treatment (with special attention to endocrinopathy and visual complications). We conclude that the literature supports the use of radiosurgery for treatment-refractory pituitary adenomas, providing the patient with a minimally invasive, safe, and effective treatment option for an otherwise resistant tumor. As such, we provide literature-based treatment considerations, including radiosurgical dose, endocrinologic, radiographic, and medical considerations for each adenoma type.
Keywords: Pituitary adenoma, radiosurgery, stereotactic
INTRODUCTION
Pituitary adenomas are relatively common tumors, comprising approximately 10–20% of all primary intracranial lesions, with a reported incidence of up to 20% within the general populace.[
For decades, radiation therapy has served as an adjuvant treatment for residual or recurrent adenomas, and even as a primary form of treatment for pituitary lesions in patients who are not candidates for surgery. Initially performed solely with conventional fractionated radiation, this form of radiotherapy has the longest available follow-up and has been demonstrated to aid in tumor control and endocrine normalization following initial surgical resection of nonfunctioning and functioning pituitary adenomas. However, moderate rates of recurrent tumor growth (up to 20%),[
Stereotactic radiosurgery (SRS) has recently received a great deal of attention in the secondary treatment of pituitary adenomas. SRS for pituitary tumors was first performed using the Leksell Gamma Knife in 1968.[
MATERIALS AND METHODS
A Pubmed search was conducted with the key words “pituitary adenoma,” “radiosurgery,” “stereotactic,” “Gamma Knife,” and “Cyberknife,” alone and in combination. Search results were reviewed for primary series of nonfunctioning and secretory adenomas treated with single-dose radiosurgery (or up to three fractions for hypofractionated radiosurgery) since the year 1999. Additional studies were obtained through secondary review of references from publications acquired from the initial search results. Studies that published results on a single subset of pituitary adenomas were prioritized for compilation into relevant tables. Other studies that reported combined results on multiple adenoma subtypes were included if they had significant sample sizes or had important contributions to the clinical understanding of adenoma response to radiosurgery.
RESULTS AND DISCUSSION
Nonfunctioning pituitary adenoma
Nonfunctioning pituitary adenomas (NFPAs), as the name suggests, do not secrete excess normal pituitary hormones unlike their functioning counterparts. As such, the resultant presenting symptoms are generally secondary to tumor mass effect on the optic apparatus and pituitary gland, namely visual disturbances and endocrine deficiencies. In line with the presenting problem, first-line therapy remains surgical extirpation with the goal of surgical decompression of the affected adjacent structures while preserving neurologic and endocrine function. Retrospective analyses indicate that with any radiographic evidence of tumor remnant, the progression of tumor growth in nonfunctioning adenomas is typically about 50% at 5–10 years, and that the factors most associated with risk of growth are invasion into parasellar structures such as the cavernous sinus and length of imaging follow-up.[
Numerous reports to date have assessed the long-term tumor control of SRS in patients with NFPAs [
Given the relative novelty of CK in the adjuvant treatment of pituitary adenomas, the literature regarding its use and associated follow-up periods is limited compared to that with Gamma Knife. The few reports regarding its use in NFPAs contain retrospective follow-up periods of approximately 30 months. Although the reported tumor control rate of over 92–93%[
Rates of new anterior pituitary deficits following SRS of nonfunctioning adenomas ranged from 0 to 38% [
PRL producing adenoma
The most common pituitary adenoma, prolactinomas, accounts for 45% of pituitary tumors.[
The peripheral radiation dose commonly used for prolactinoma treatment is approximately 25 Gy (median range 13–34 Gy), which is higher than doses used in both nonfunctioning and ACTH/GH secreting tumors. Complete endocrine normalization [when assessed off medical (dopamine agonist) therapy] has been reported to occur in 11–80% of patients with a mean time to normalization of 2–8 years, although most studies report a remission rate of 20–30% [
Microadenomas appear to be more responsive than macroadenomas, with remission rates of 70% versus 30%, respectively.[
Growth hormone producing adenoma (acromegaly)
The excess production of GH from pituitary adenomas results in acromegaly, an endocrine disorder characterized by progressive somatic disfigurement and increased mortality secondary to the systemic effects of chronically elevated GH and its primary mediator insulin-like growth factor-1 (IGF-1).[
Numerous studies have been published regarding the treatment of GH-producing pituitary adenomas with SRS [
The limited number of studies reporting CK treatment of GH-producing adenomas show a comparable tumor control rate of 92–100%.[
Despite the disparate study designs, radiation dosing, and criteria for endocrine remission, a few prognostic trends have emerged as predictors of endocrine response to SRS in acromegaly. Multiple groups have reported that lower baseline levels of GH[
Rates of complications including new anterior pituitary deficits (0–50%) and worsening of visual acuity or fields (0–4%) were comparable to other tumor types receiving SRS. Similar to NFPAs, the group reporting the greatest incidence of new pituitary dysfunction had the longest follow-up time.[
Adrenocorticotrophic hormone-producing adenoma (Cushing's disease)
Radiosurgery for Cushing's disease is often an adjuvant to surgical resection of ACTH-secreting adenomas. Failure to achieve remission or tumor recurrence occurs in up to 30% following initial successful transsphenoidal resection of ACTH-secreting tumors in Cushing's disease patients.[
SRS achieves normalization of ACTH levels in a median time of approximately 7.5–58 months [
Bilateral adrenalectomy for the treatment of Cushing's syndrome may lead to uncontrolled growth of any preexisting pituitary adenoma due to the lack of negative feedback from endogenous cortisol. Resulting tumors of Nelson's syndrome are often aggressive and difficult to control. SRS has been reported to be less effective in Nelson's syndrome than Cushing's disease, with cure rates in less than 36% of patients despite lower ACTH levels in approximately 70% of patients and tumor growth control in up to 90% of patients.[
Complications and follow-up
Despite the varying median margin doses, the rates of new anterior pituitary deficits following SRS are relatively comparable across all pituitary adenoma subtypes. Radiation dose to the normal pituitary gland,[
With the availability of long-term follow-up data following SRS for pituitary adenomas, it has become increasingly clear that the disease course is still uncertain even after years of clinical stability and that lifetime observation is required. Tumor progression, for example, has been noted to recur as far as 120 months following radiosurgery, even after a decade of radiographic tumor control.[
Recommendations
Despite advances in endoscopic techniques, intraoperative imaging, and surgical methods, there is still a moderate incidence of subtotal resection of pituitary adenomas on account of invasion into parasellar structures and difficulty appreciating smaller functional tumors radiographically and intraoperatively. Patients who have undergone maximal safe surgical resection with residual, recurrent, or progressive endocrinologic or radiographic disease should be considered for radiotherapy. Patients who choose not to have further surgical resection or are medically unfavorable surgical candidates should be considered for radiation treatment as well. However, not all patients with residual adenomas following extirpation are candidates for radiosurgery. Pituitary lesions greater than 4–4.5 cm3 should be evaluated for repeat surgical resection as these macroadenomas have been found to have higher rates of recurrence[
Dosing for nonfunctional adenomas should range from 18 to 20 Gy as tolerated and able. Dosing for functioning adenomas should range from 23 to 25 Gy as tolerated and able. In order to maximize treatment efficacy and minimize the risk of new anterior pituitary deficits following SRS, it is critical to be able to define the normal gland and infundibulum and minimize the dose delivered to these structures. Additionally, in the case of functioning adenomas, endocrine suppressive medications should be discontinued at least 2 months prior to radiosurgery if tolerated by the patient, as preliminary evidence suggests the rates of remission are greater with this treatment protocol. Importantly, long-term follow-up (at least 10 years) is crucial to assess for endocrine remission, new pituitary deficits, and tumor or endocrine recurrence.
CONCLUSION
SRS has been demonstrated to be a suitable adjuvant therapy in patients with pituitary adenomas should they have residual or recurrent tumor, persistent or recurrent hormone hypersecretion, or medical comorbidities that make them unsuitable surgical candidates. The single treatment dosing is far more convenient than previously performed fractionated radiotherapies, which require daily visits for multiple weeks. In addition, SRS has been shown to have lower rates of endocrinopathies and faster times to remission than conventional radiotherapy. Although outcomes are not perfect and future studies with longer follow-up are needed, SRS serves as an excellent treatment consideration in patients with pituitary adenomas.
Publication of this manuscript has been made possible by an educational grant from
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