The role of stereotactic radiosurgery in the multimodal management of growth hormone–secreting pituitary adenomas

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Growth hormone (GH)–secreting pituitary adenomas represent a common source of GH excess in patients with acromegaly. Whereas surgical extirpation of the culprit lesion is considered first-line treatment, as many as 19% of patients develop recurrent symptoms due to regrowth of previously resected adenomatous tissue or to continued growth of the surgically inaccessible tumor. Although medical therapies that suppress GH production can be effective in the management of primary and recurrent acromegaly, these therapies are not curative, and lifelong treatment is required for hormonal control. Stereotactic radiosurgery has emerged as an effective adjunctive treatment modality, and is an appealing alternative to conventional fractionated radiation therapy. The authors reviewed the growing body of literature concerning the role of radiosurgical procedures in the treatment armamentarium of acromegaly, and identified more than 1350 patients across 45 case series. In this review, the authors report that radiosurgery offers true hormonal normalization in 17% to 82% of patients and tumor growth control in 37% to 100% of cases across all series, while minimizing adverse complications. As a result, stereotactic radiosurgery represents a safe and effective treatment option in the multimodal management of primary or recurrent acromegaly secondary to GH-secreting pituitary adenomas.

Abbreviations used in this paper: GH = growth hormone; GKS = Gamma Knife surgery; IGF = insulin-like growth factor; LINAC = linear accelerator; SRS = stereotactic radiosurgery.

Abstract

Growth hormone (GH)–secreting pituitary adenomas represent a common source of GH excess in patients with acromegaly. Whereas surgical extirpation of the culprit lesion is considered first-line treatment, as many as 19% of patients develop recurrent symptoms due to regrowth of previously resected adenomatous tissue or to continued growth of the surgically inaccessible tumor. Although medical therapies that suppress GH production can be effective in the management of primary and recurrent acromegaly, these therapies are not curative, and lifelong treatment is required for hormonal control. Stereotactic radiosurgery has emerged as an effective adjunctive treatment modality, and is an appealing alternative to conventional fractionated radiation therapy. The authors reviewed the growing body of literature concerning the role of radiosurgical procedures in the treatment armamentarium of acromegaly, and identified more than 1350 patients across 45 case series. In this review, the authors report that radiosurgery offers true hormonal normalization in 17% to 82% of patients and tumor growth control in 37% to 100% of cases across all series, while minimizing adverse complications. As a result, stereotactic radiosurgery represents a safe and effective treatment option in the multimodal management of primary or recurrent acromegaly secondary to GH-secreting pituitary adenomas.

Acromegaly consists of a constellation of clinical signs and symptoms caused by an excess production of GH. The onset of this disease can be quite insidious, and common clinical manifestations include acral overgrowth, soft tissue hypertrophy, metabolic derangements, and cardiovascular complications.37 While a host of pathological entities can cause GH overproduction, more than 90% of patients with acromegaly harbor a GH-secreting pituitary adenoma.49 Although these adenomas arise from the benign proliferation of somatotroph cells within the anterior pituitary gland, the pituitary's confined location within the sella turcica and close approximation to important neurovascular structures render masses in this region problematic. Therefore, aside from complications secondary to GH excess, patients may also experience headache, visual loss, cranial nerve deficits, and symptoms of additional pituitary hormone dysregulation.18

Surgical extirpation of the culprit lesion is considered first-line treatment and has the distinct advantage of instantaneously lowering GH levels by directly removing the source of hormone production.28 Recent studies estimate postoperative endocrinological remission rates to be 68% to 95%, irrespective of tumor volume.28,34 Despite this clinical efficacy, not only is surgery alone not curative in a select cohort of patients, but recurrent acromegaly following initial postoperative hormonal remission is reported to occur in as many as 19% of cases.28 Although regrowth of previously resected tumor has been documented,16 these recurrences most likely represent continued growth of nonresectable tumor tissue, either due to parasellar invasion or involvement of neighboring neurovascular structures.18,31,37 Stereotactic radiosurgery has emerged as a noninvasive adjuvant treatment modality for such recurrent or surgically inaccessible lesions. Unlike conventional fractionated radiotherapy, SRS delivers focused radiation to a precisely defined target in a single session and minimizes radiation exposure to adjacent normal structures.3,29,50 Over the past two decades, numerous case series have described the efficacy of SRS in patients harboring GH-secreting pituitary adenomas. In this report, we review the results from this robust body of literature, and highlight postradiosurgical rates of endocrinological remission and tumor growth control as well as assess the potential advantages and limitations of SRS in the multimodal management of acromegaly.

Methods

Data Acquisition

A PubMed search (National Library of Medicine) was performed to identify all articles pertaining to the use of SRS for the treatment of acromegaly. Surgical series describing endocrinological and radiographic outcomes were analyzed in detail and reference lists were reviewed for additional articles not identified in the original PubMed search. Pertinent clinical characteristics extracted from each report include the stereotactic radiosurgical unit; marginal radiation dose; rate of pituitary suppressive medication used during SRS; tumor size and prevalence of cavernous sinus invasion; rates of endocrinological remission and tumor growth control; and SRS-associated complications. Case series utilizing GKS, LINAC-based SRS, and CyberKnife radiosurgical systems are included in our analysis. Given a variety of confounding factors, however, no effort was made to directly compare the efficacies of these methods of SRS.

Radiosurgical Techniques

Unlike conventional radiotherapy, in which patients receive a target dose of radiation to the entire brain fractionated over numerous sessions, radiosurgery aims to deliver a high dose of radiation to a precise intracranial region during a single session.27 The ability to focus ionizing radiation on discrete brain lesions while sparing critical adjacent neurovascular structures may improve local tumor control as well as reduce the adverse effects associated with traditional radiation therapies.51 The Gamma Knife utilizes cross-firing beams from 201 cobalt-60 sources to deliver ionizing radiation (gamma rays) to an intracranial target. The most commonly used radiosurgical unit for pituitary lesions, this system allows for a high degree of 3D conformity between the radiation field and the target of interest and offers better preservation of surrounding normal structures than conventional radiotherapy.18,19 Similar to the Gamma Knife, LINAC-based systems deliver beams of photon radiation in multiple arcs to a defined intracranial structure,50 and allow neurosurgeons to target lesions with a high degree of fidelity and to minimize the extent of collateral damage to surrounding neurovascular elements.

Both the Gamma Knife and traditional LINAC-based systems require the use of a stereotactic frame for rigid immobilization of the head during the radiosurgical procedure. The CyberKnife is a newly developed LINAC-based system that uses image guidance software to adjust in real-time the precise location of radiation therapy and, thus, does not require the use of a stereotactic frame.1 Irrespective of the radiosurgical unit employed, dose selection and treatment parameters vary depending on the tumor location and size, relationship of the adenoma to the optic apparatus and other eloquent structures, dose and timing of any pretreatment conventional radiotherapy, and other patient-specific characteristics.

Results

Tables 1 and 2 summarize data obtained from case series in which stereotactic radiosurgical procedures were employed in the multimodal management of GH-secreting pituitary adenomas. Across all series, more than 1350 patients underwent SRS using either Gamma Knife- or LINAC-based systems for the treatment of primary or recurrent acromegaly. The mean duration of endocrinological and radiographic follow-up ranged from greater than 6 months to 100 months. The average tumor volume was between 0.9 cm3 and 11.3 cm3 and, where reported, 21% to 100% of patients harbored lesions that extended into the cavernous sinus. The mean marginal radiation dose employed across all series ranged from 14.3 to 34.4 Gy. Approximately 71% of patients throughout the series had undergone transsphenoidal or transcranial neurosurgical resection of their pituitary adenoma prior to radiosurgery, while 11% had received antecedent conventional fractionated radiotherapy. Although reported in only half of the case series, approximately 75% of patients had discontinued all suppressive medications for more than 6 to 8 weeks prior to radiosurgery. While the definition of true endocrinological remission was quite variable among the series, approximately 47% of patients fulfilled the given criteria for hormonal remission, and an additional 32% achieved endocrinological normalization after radiosurgery with adjunctive medical therapy. Compared with preradiosurgical volumes, on average more than 97% of tumors decreased or remained the same in size at the time of the latest follow-up.

TABLE 1:

Summary of previously reported case series involving SRS in patients with acromegaly (Part I)*

Authors & YearSRS UnitNo. of PatientsMean FU (mos)Interventions Prior to SRS (%)Off Medication During SRS (%)Mean Marginal Radiation Dose (Gy)Cavernous Sinus Invasion (%)
Hayashi et al., 2010GK2536surg (100)NA21.8100
Iwai et al., 2010GK2684surg (85)8520.235
Castinetti et al., 20094GK43100surg (70)53NA21
Cho et al., 2009CK635surg (83)NANANA
Swords et al., 2009GK1038.5CRT (100); surg (80)40NANA
Wan et al., 2009GK10367surg (14)10021.4NA
Jagannathan et al., 2008GK9557CRT (5); surg (100)712235
Losa et al., 2008GK8369CRT (1); surg (100)7625 (goal)NA
Pollock et al., 2008GK2747CRT (7); surg (93)10020NA
Tinnel et al., 2008GK935CRT (11); surg (75)56NANA
Pollock et al., 2007GK4663CRT (13); surg (93)592085
Roberts et al., 2007CK925surg (89)6721NA
Vik-Mo et al., 2007GK6166surg (92)NA26.5NA
Jezková et al., 2006GK9654CRT (11.5); surg (74)10032NA
Voges et al., 2006LINAC6454CRT (7); surg (53)NA16.589
Castinetti et al., 2005GK8249.5CRT (2); surg (77)4925.789
Kajiwara et al., 2005CK235CRT (10); surg (48)NA14.3NA
Kobayashi et al., 2005GK6763CRT (3); surg (73)3718.9NA
Attanasio et al., 2003GK3046CRT (13); surg (90)6020NA
Choi et al., 2003GK942.5surg (32)NA28.5NA
Jane et al., 2003GK64>18surg (100)10015NA
Petrovich et al., 2003GK641CRT (10); surg (95)NA1596
Swords et al., 2003LINAC1325CRT (100); surg (77)2310 (mode)67
Feigl et al., 2002GK955surg (100)NA15NA
Pollock et al., 2002GK2636CRT (21); surg (86)6920.170
Ikeda et al., 2001GK1756surg (100)10025100
Fukuoka et al., 2001GK942surg (89)NA20100
Izawa et al., 2000GK29>6surg (37)NA22.529
Shin et al., 2000GK643surg (67)10034.4100
Zhang et al., 2000GK6834CRT (4); surg (14)10031.3NA
Hayashi et al., 1999GK2216surg (49)NA22.524
Inoue et al., 1999GK12>24surg (100)10020.9100
Kim et al., 199923GK212none10022NA
Kim et al., 199924GK1127surg (55)NA28.7NA
Laws & Vance, 1999GK56NANANANANA
Mokry et al., 1999GK1046CRT (4); surg (96)NA16NA
Landolt et al., 1998GK16>17CRT (44); surg (100)6925NA
Lim et al., 1998GK1625.5CRT (2); surg (51)NA25.422
Martínez et al., 1998GK736surg (57)NA24.757
Mitsumori et al., 1998LINAC147CRT (22)NANA61
Morange-Ramos et al., 1998GK1520CRT (7); surg (87)NA28.776
Pan et al., 1998GK1629CRT (4); surg (16)NA28.6NA
Witt et al., 1998GK2032NANA19NA
Yoon et al., 1998LINAC249surg (96)NANANA
Park et al., 1996GK715surg (14)NA27.1NA

* CK = CyberKnife; CRT = conventional radiotherapy; FU = follow-up; GK = Gamma Knife; NA = not available; surg = transsphenoidal or transcranial surgery.

† Values represent data pertaining to both somatotroph and nonsomatotroph pituitary tumors.

‡ Median value.

TABLE 2:

Summary of previously reported case series involving SRS in patients with acromegaly (Part II)*

Authors & YearSRS UnitNo. of PatientsMean Tumor Vol (cm3)Tumor Growth Control (%)Criteria for Endocrin Remission§Endocrin Remission (%)Endocrin Control (%)Adverse Effects (%)
Hayashi et al., 2010GK25NA100NANA40**none
Iwai et al., 2010GK262.396GH <2 or GH <1 after OGTT & IGF-I = N384HA (4); HP (8)
Castinetti et al., 20094GK431.2100GH <2 or GH <1 after OGTT & IGF-I = N42NACNP (7); HP (21); TN (2)
Cho et al., 2009CK62.692GH <5 mIU/L33NAVC (8)
Swords et al., 2009GK10NA100GH <5 mIU/L & IGF-I = N1020HP (12)
Wan et al., 2009GK1032.3–21.595NANA37**BN (2); HP (2)
Jagannathan et al., 2008GK952.798IGF-I = N53NAHP (34); TLE (1); VC (4)
Losa et al., 2008GK83NA98GH <2.5 & IGF-I = N6021HA (6); HP (9)
Pollock et al., 2008GK27NA100GH <2 & IGF-I = N67NAHP (16)
Tinnel et al., 2008GK9NA100IGF-I = N44NACNP (11); HP (22)
Pollock et al., 2007GK463.3100GH <2 & IGF-I = N50NABN (2); HP (33); CAS (2)
Roberts et al., 2007CK92.5100IGF-I = N4412HP (33)
Vik-Mo et al., 2007GK611.2100GH <2.6 mIU/L after OGTT & IGF-I = N17NAHP (23)
Jezková et al., 2006GK962.2100GH <1 after OGTT & IGF-I = N44NAHP (27)
Voges et al., 2006LINAC643.097GH <2 & IGF-I = N37.547BT (3); HP (47); TLE (3); VC (1)
Castinetti et al., 2005GK82NANAGH <2 & IGF-I = N1723HP (17); TN (1); VC (1)
Kajiwara et al., 2005CK211.395NANANAnone
Kobayashi et al., 2005GK674.4100GH <217NAHP (15); VC (11)
Attanasio et al., 2003GK30NA100GH <2.5 & IGF-I = N2317HA (3); HP (7)
Choi et al., 2003GK91.4100GH <5 mIU/LNA50**none
Jane et al., 2003GK64NANAIGF-I = N36NAHP (28)
Petrovich et al., 2003GK63.7100NANA100**HP (4); VC (4)
Swords et al., 2003LINAC13NA100GH <5 mIU/L & IGF-I = N428none
Feigl et al., 2002GK93.894NANANAHP (28)
Pollock et al., 2002GK264.9100GH <2 & IGF-I = N4220BN (5); HP (16)
Ikeda et al., 2001GK17NA100GH <1 after OGTT or IGF-I = N82NAnone
Fukuoka et al., 2001GK94.9100GH <5 & IGF-I = N40NAnone
Izawa et al., 2000GK297.1100NANA41**BN (1); VC (1)
Shin et al., 2000GK61.1100GH <10 mIU/L & IGF-I <45067NACNP (6)
Zhang et al., 2000GK683.0100NA96NAHP (4); VC (1)
Hayashi et al., 1999GK227.3100NA41NAHP (5); VC (5)
Inoue et al., 1999GK12NA94NA58NANA
Kim et al., 199923GK2NA100NA0NANA
Kim et al., 199924GK110.9>68GH <545.5NAnone
Laws & Vance, 1999GK56NANAIGF-I = N25NANA
Mokry et al., 1999GK102.9100GH <7 & IGF-I <380NA40HP (30)
Landolt et al., 1998GK161.9>55GH <10 mIU/L & IGF-I <38070NAnone
Lim et al., 1998GK16NA92.5GH <238NAHA (36); HP (2); VC (2)
Martínez et al., 1998GK74.3100IGF-I = N71NACNP (3)
Mitsumori et al., 1998LINAC11.9100NA100NAHP (23); TLE (11)
Morange-Ramos et al., 1998GK151.5>37GH <5 & IGF-I = N20NAHP (16); TN (7)
Pan et al., 1998GK161.0100NA100NAnone
Witt et al., 1998GK20NA94IGF-I = N20NANA
Yoon et al., 1998LINAC2NA100GH <5100NAHP (29)
Park et al., 1996GK7NA100GH <557NAnone

* BN = brain necrosis; CAS = carotid artery stenosis; CNP = cranial nerve palsy; Endocrin = Endocrinological; HA = headache; HP = hypopituitarism;N = normal value when controlled for age and sex; OGTT = oral glucose tolerance test; TLE = temporal lobe epilepsy; TN = trigeminal neuralgia; VC = visual complications.

† Values represent data pertaining to both somatotroph and nonsomatotroph pituitary tumors.

‡ Median value.

§ GH in ng/ml or mIU/L (as specified); IGF-I in ng/ml.

¶ Endocrinological control indicates postradiosurgical hormonal normalization with adjuvant medical therapy.

** Percentages indicate overall rates of hormonal normalization irrespective of postradiosurgical medical therapy.

Endocrinological Remission and Control

Whereas the precise criteria for characterizing endocrinological remission following SRS were inconsistent across the case series, the most widely accepted definition is a random GH level less than 2 ng/ml or a GH level less than 1 ng/ml following an oral glucose tolerance test in addition to a normal IGF-I level when controlled for age and sex.35 Importantly, these measurements are recorded while the patient is not taking pituitary suppressive medications. If the above criteria are met after radiosurgery with the aid of adjunctive medical therapy, the patient is considered to have achieved endocrinological control.16 Using the aforementioned strict criteria for hormonal remission, the range of endocrinological normalization was 17% to 82%, and an additional 4% to 47% of patients achieved hormonal control following radiosurgery.2,4,5,14,16,21,33,45–47,53,54,57,58 For instance, Pollock et al.45 observed an endocrinological remission rate of 67% and Ikeda et al.14 observed normalized hormonal levels in 82% of patients following GKS. Using LINAC-based SRS, Voges et al.58 reported a true remission rate of 37.5% and an additional endocrinological control rate of 47% in their series of 64 patients with acromegaly. When more lenient definitions were employed, the range of hormonal remission rates was 0 to 100% while rates of endocrinological control ranged from 8% to 100% at the time of the latest follow-up.7–10,12,13,15,17,18,20,22–25,27,30,32,36,38–42,44,48,52,55,59–62 Using only a normalized IGF-I level as the criterion for hormonal remission, Jagannathan et al.18 reported an endocrinological normalization rate of 53% at a mean follow-up time of 57 months. Zhang et al.62 observed biochemical remission in 96% of their 68 patients, although the criteria for remission are not given. Not all series, however, documented such impressive rates of endocrinological remission at the time of last follow-up. As examples, Kobayashi et al.25 and Castinetti et al.5 observed hormonal normalization in only 17% of patients when they were not receiving medical therapy. Such disparities likely reflect important differences in patient populations, adenoma characteristics, preradiosurgical hormonal control, and treatment regimens.

Although disagreement existed across the case series, several studies identified factors that independently predicted postradiosurgical endocrinological outcomes. Choi et al.8 found that a greater maximum radiation dose was associated with a higher rate of hormonal remission. Kim et al.24 reported a similar finding, and also discovered that patients with larger tumor volumes were more likely to achieve biochemical remission than those with smaller masses. Interestingly, while the maximum radiation dose significantly predicted hormonal remission in these studies, Kim et al.,24 Losa et al.,33 Pollock et al.,47 and Zhang et al.62 found that the marginal radiation dose was not a significant prognostic factor. In addition, in the studies of Castinetti et al.5 and Jezková et al.,21 preradiosurgical GH and IGF-I levels were found to predict posttreatment outcomes. Not surprisingly, those patients with near-normal GH or IGF-I levels were more likely to achieve hormonal remission than patients with markedly abnormal baseline values. However, Landolt et al.26 and Pollock et al.,46,47 identified arguably the most meaningful prognostic indicator of postradiosurgical hormonal remission. In both series, the concomitant use of pituitary suppressive medications during radiosurgery was shown to reduce the overall rate of and increase the time to hormonal remission. Finally, despite a mean tumor growth control rate of 97% across all series, no study identified a significant correlation between change in adenoma size and eventual hormonal normalization.

Although the mean time to hormonal remission following adjuvant radiosurgery was not consistently reported across the case series in our analysis, several studies did record actuarial rates of endocrinological normalization. In the study by Jezková et al.,21 while only 15% of patients achieved hormonal normalization 12 months after SRS, 29%, 44%, and 57% of patients were found to be in remission at 36, 60, and 96 months, respectively. Moreover, Vik-Mo et al.57 reported normal IGF-I levels in 45%, 58%, and 86% of patients at 36, 60, and 120 months following radiosurgery, respectively. Finally, although Jagannathan et al.18 observed an absolute remission rate of 53% with a mean time to remission of 30 months, a more detailed analysis of the data indicates that 29%, 42%, and 53% of patients achieved normalized IGF-I levels at 24, 48, and greater than 85 months after radiosurgery, respectively.

Tumor Growth Control

The rate of tumor growth control, defined as reduction or stabilization of tumor volume, ranged from more than 37% to 100% across all series, with an average rate of control of 97%. Jagannathan et al.18 reported that 92% of patients with adequate radiographic follow-up demonstrated a decrease in tumor size following GKS and that an additional 6% showed no change in tumor volume. Voges et al.58 treated 64 patients with acromegaly with LINAC-based SRS and reported that 23% experienced a reduction in tumor volume while 73% had tumors that did not change significantly in size. To date, the largest series evaluating the use of the CyberKnife in the treatment armamentarium of acromegaly is by Roberts et al.48 In this study, 9 patients received CyberKnife SRS and none demonstrated tumor enlargement at the time of last follow-up. Despite these impressive statistics, the rate of tumor growth control did not correlate with rates of endocrinological remission.2,16,21,57

Adverse Effects

The overall rate of serious complications following radiosurgery was quite low across all series. New-onset anterior pituitary hormone deficiency was the most common adverse effect, and was noted in 0 to 47% of cases.2,4,5,9,13,16,18,20,21,25,32,33,38–40,44–48,54,55,57–59,61,62 Feigl et al.9 reported a 28% incidence of hypopituitarism following radiosurgery, and noted that the degree of hormonal dysfunction was related to the radiation dose received by the pituitary stalk. However, the true incidence of SRS-induced hypopituitarism is difficult to assess accurately, as many patients have undergone prior resection or conventional fractionated radiation therapy, both of which independently increase the likelihood of developing anterior pituitary hormone dysfunction. For instance, in the study by Jagannathan et al.,18 of the 4 patients who developed visual complications, 3 had received prior fractionated radiation therapy.

Despite the proximity of the optic apparatus to the pituitary gland, only 10 case series5,7,13,17,18,25,32,44,58,62 in our analysis reported postradiosurgical visual complications, with Kobayashi et al.25 demonstrating the highest incidence at 11%. The low rate of visual complications following SRS likely stems from each group's attempt to limit the dose received by the optic apparatus to 8–10 Gy. Moreover, Tinnel et al.55 reported new-onset cranial nerve palsies in 11% of patients, although cranial neuropathies were only observed in 3 other studies.4,36,52 Headache, trigeminal neuralgia, temporal lobe epilepsy, brain necrosis, and carotid artery stenosis were other documented complications of SRS, although these were noted relatively infrequently across all series. Although none of the case studies were adequately powered to identify parameters that predict postradiosurgical complication rates, several groups did note that adverse effects were more commonly observed in patients who had received prior fractionated radiation therapy.18,47

Discussion

Without proper control of systemic growth levels, patients with acromegaly will follow a course of insidious yet progressive decline. The use of pituitary suppressive medications, such as somatostatin agonists or GH receptor antagonists, may minimize some of the metabolic sequelae of GH excess, but many patients are either only partially controlled with these therapies or become resistant after extended treatment periods.37 In addition, medical therapy is not curative and, therefore, lifelong treatment is required for adequate hormonal control. Current estimates demonstrate that 75% to 90% of patients with GH overproduction harbor a GH-secreting pituitary adenoma, and surgical removal remains the first-line treatment modality.49 Not only does resection remove the source of GH excess, but it also relieves any compression or mass effect the tumor may be exerting on surrounding neurovascular structures.28 Surgical extirpation is effective in inducing hormonal remission in more than 68% to 95% of patients with GH-secreting adenomas, yet a select cohort of patients develop recurrent acromegaly due either to regrowth of previously resected adenomatous tissue or to continued growth of surgically inaccessible tumor.28,34 Prior to the development and modernization of current radiosurgical systems, fractionated radiation therapy was used in the treatment algorithm for patients with acromegaly refractory to medical and surgical interventions. Although early reports document endocrinological remission following radiotherapy in more than 60% of cases, these studies frequently employed definitions of remission that were more forgiving than current standards.27 Mitsumori et al.38 compared the efficacy of SRS and fractionated radiotherapy in the adjuvant treatment of hormone-secreting pituitary adenomas, and discovered that the overall incidence of endocrinological normalization was roughly equal between the 2 treatment modalities. However, patients who received SRS achieved remission in 8.5 months, whereas those in whom fractionated radiotherapy was administered did not reach hormonal normalization for 18 months. Similarly, Landolt et al.27 directly compared GKS to traditional fractionated radiation therapy and found that the percentage of hormonal normalization was roughly similar between the 2 groups, but that the time to remission was much shorter in the radiosurgical group (17 months vs 85 months, respectively). In addition to a more rapid normalization of hormone levels, SRS is also associated with a lower rate and narrower spectrum of adverse effects than conventional radiotherapy. In the study by Landolt et al.,27 16% of patients receiving fractionated radiotherapy developed new-onset hypopituitarism whereas no complications were observed in the treatment arm that underwent SRS. Though no prospective, randomized, controlled trials have directly compared these two forms of radiation treatment, the relative safety and efficacy of SRS compared with traditional radiotherapy have engendered its use in modern clinical practice.

Although recent case series have adhered to a strict definition of endocrinological remission, earlier studies varied widely in their criteria for hormonal cure, and thus a large range of remission rates was observed (0 to 100%). At present, most groups consider the following conditions sufficient for endocrinological remission: 1) a random GH level < 2 ng/ml, or 2) a GH level < 0.5 ng/ml following an oral glucose challenge in addition to a normal IGF-I level when corrected for age and sex. Importantly, all measurements must be obtained while the patient is not receiving pituitary suppressive medications. However, Peacey and Shalet43 demonstrated that GH feedback regulation was disrupted following radiation therapy, and therefore the interpretation of GH levels following radiosurgical procedures can be problematic. Moreover, given the diurnal and pulsatile secretion pattern of GH, it is often difficult to obtain accurate and true levels. On the other hand, IGF-I has a long half-life and stable concentration within the systemic circulation.37 Because GH exerts most of its action through IGF-I, many neurosurgeons and endocrinologists have found single IGF-I measurements to faithfully represent GH activity. In fact, of the studies in our analysis in which a normal IGF-I level was the only criterion for hormonal cure, the rates of endocrinological remission ranged from 20% to 71%.18,20,36,48,60 As hormonal remission rates following radiosurgery were noted in 17% to 82% of patients in studies in which the more stringent criteria were applied,2,4,5,14,16,21,33,45–47,53,54,57,58 it appears that the definition of endocrinological remission is of variable consequence.

More important in the postradiosurgical assessment of the patient with acromegaly is the overall length of follow-up. Both Jezková et al.21 and Jagannathan et al.18 observed remission rates less than 30% when patients were evaluated 24 months after SRS. However, these rates rose to more than 50% when follow-up was performed for more than 85 months. In addition, Vik-Mo et al.57 saw an endocrinological remission rate of 86% at 120 months compared with a 45% cure rate at 36 months of follow-up. As a result, to thoroughly assess the true efficacy of SRS in the management of acromegaly, patients should ideally receive routine endocrinological evaluations extending 84 to 120 months beyond the radiosurgical procedure. Lengthy and detailed follow-up is also necessary to diagnose cases of recurrent acromegaly. Jagannathan et al.18 reported on 3 patients who developed recurrent symptoms of GH excess at 36, 56, and 114 months after SRS. Therefore, as the latency between radiosurgery and hormonal cure or recurrence can be quite long, lengthy endocrinological and radiographic follow-up is necessary to determine the ultimate efficacy of SRS in acromegaly.

The use of somatostatin agonists and GH receptor antagonists in the adjuvant treatment of acromegaly is common practice.35,37 However, studies by Landolt et al.26 and Pollock et al.46,47 demonstrated that patients who concomitantly receive pituitary suppressive medications during radiosurgery experience lower rates of endocrinological normalization than those who terminate medical therapy more than 6 weeks prior to and 6 weeks after SRS. Although the precise mechanism governing this phenomenon is unknown, the current belief is that the suppressive medications place the tumor cells in a quiescent state in which their metabolic and proliferative potential is greatly diminished. By inhibiting cell cycling, these medical therapies reduce the sensitivity of somatotroph cells to the effects of ionizing radiation during DNA synthesis.47 However, as no large-scale, prospective, randomized controlled trials have evaluated this question, it is difficult to draw definitive conclusions from small observations. In fact, both Iwai et al.16 and Castinetti et al.4 observed that pituitary suppressive medication use did not correlate with eventual hormonal outcome, and these differences in observation may be due in part to confounding factors present within each series. For instance, when the concurrent use of pituitary suppressive therapies during radiosurgery is not randomized, patients who require medical therapy for hormonal or symptomatic control are less likely to terminate the medication for a protracted period while those with near-normal endocrine levels or milder symptoms will better tolerate the hiatus in treatment. Therefore, the difference in remission rates observed by Landolt et al. and Pollock et al. may simply reflect a more aggressive and extensive disease phenotype rather than a true effect of medical therapy. Nevertheless, the practice of discontinuing medical therapy during the radiosurgical procedure has gained clinical acceptance, and certain groups have adopted this strategy in light of these data.16 Irrespective of this controversy, pituitary suppressive medications are a critical component of the multimodal management algorithm for patients with acromegaly. For patients in whom radiosurgery is not completely curative, additional medical therapy can offer hormonal normalization in roughly 32% of patients, according to the series in our analysis.2,5,8,12,16,17,33,39,44,47,48,53,54,58,59

In addition to rates of hormonal cure of 17% to 82% following SRS, the mean rate of tumor growth control was more than 97% across the patient series (Table 2). Just as several studies demonstrated that endocrinological normalization increases with time, Mokry et al.39 reported that tumor volumes progressively decline following SRS. Nevertheless, the stabilization or reduction in adenoma size is not significantly associated with hormonal remission. As a result, except in cases in which the adenoma is compressing critical structures, tumor growth control is an unreliable measure of the success of SRS for the treatment of GH-secreting pituitary lesions. In the future, it will be interesting to determine whether an association between adenoma size and hormonal cure becomes significant as series with larger populations and longer follow-up are reported.

Although surgery remains the first-line treatment for GH-secreting adenomas, resection of tumors that invade the parasellar region is fraught with difficulty.28 Because numerous important neurovascular structures traverse the cavernous sinus, SRS offers a noninvasive means of accessing this region in a potentially safe manner. However, exposing the cavernous sinus to a high degree of ionizing radiation places the structures found within it at risk for injury. Nevertheless, in our analysis, new-onset cranial neuropathies and carotid artery stenosis were infrequently observed following SRS. Thus, unlike the optic apparatus, which is especially sensitive to radiation dosing, the structures traversing the cavernous sinus appear more resistant to injury.50,56 Kobayashi et al.25 reported postradiosurgical visual complications in 11% of the 67 patients with acromegaly in their study, yet new-onset optic neuropathies were only noted in a total of 10 case series in our review of the literature. To minimize damage to the optic apparatus, many groups attempt to limit the dose it receives to 8–10 Gy.11 In addition, inherent in the dose-planning algorithm is an estimation of the distance between the target tissue and the optic structures. While a distance of at least 5 mm is desired, Petrovich et al.6,44,50 demonstrated that distances of 1 to 2 mm are acceptable with highly conformal radiation profiles. Furthermore, postradiosurgical anterior hormone dysfunction was observed in 26 of the 45 case series in our analysis. The incidence of hypopituitarism ranged from 2% to 47% when reported, and the majority of this hypopituitarism was adequately controlled with supplemental medical therapy. Estimating the true incidence of hypopituitarism following radiosurgery, however, is difficult. Because many patients have received prior surgery or conventional radiotherapy, it is likely that new-onset anterior hormone dysregulation results from an accumulation of insults rendered through numerous treatment modalities.50 Overall, complications following SRS for the treatment of acromegaly are uncommon,35 and this low rate of adverse effects reflects the reliability with which stereotactic radiosurgical procedures can deliver ionizing radiation that is highly conformal to the target tissue.

When evaluating the efficacy and potential limitations of SRS, it is important to consider the duration of endocrinological and radiographic follow-up. Unlike surgery, SRS requires a protracted period of time before normalization of hormone levels is recognized. A similar degree of follow-up and observation is necessary to gauge the overall safety of radiosurgical procedures. Jagannathan et al.18 reported anterior hormone deficiencies in 34% of their 95 patients with acromegaly following SRS for failed transsphenoidal operations. A detailed analysis of these cases of new-onset hypopituitarism, however, reveals that the incidence was only 5% at 12 months after radiosurgery and that more than 49 months of follow-up were necessary to identify the 32 individuals with adverse effects. On the whole, despite a range of infrequent adverse effects, SRS is an efficacious component of the multimodal treatment paradigm for acromegaly. Although dose selection and other treatment parameters vary depending on an array of tumor- and patient-specific characteristics, it is our hope that future studies will more clearly define the optimal treatment strategy for acromegaly and identify the cohort of patients who will maximally benefit from SRS.

Conclusions

The goal of SRS in the management of GH-secreting pituitary lesions is to reduce hormone overproduction and control tumor growth while preserving normal brain tissue and minimizing adverse effects. In this regard, our analysis of the available literature concerning the use of SRS in acromegaly reveals that radiosurgical procedures induce endocrinological remission in 17% to 82% of patients and leads to effective tumor growth control in 97% of cases when data are analyzed across all series. In addition, because SRS is capable of precisely conforming the radiation field to the tumor target, the overall rate of adverse effects is remarkably low among the series in our analysis. Overall, SRS represents a safe and effective treatment option for patients with primary or recurrent acromegaly.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Weiss, Stapleton. Acquisition of data: Stapleton. Analysis and interpretation of data: Stapleton. Drafting the article: Stapleton. Critically revising the article: all authors. Reviewed final version of the manuscript and approved it for submission: all authors.

References

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    Attanasio REpaminonda PMotti EGiugni EVentrella LCozzi R: Gamma-Knife radiosurgery in acromegaly: a 4-year follow-up study. J Clin Endocrinol Metab 88:310531122003

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    Castinetti FMorange IDufour HRégis JBrue T: Radiotherapy and radiosurgery in acromegaly. Pituitary 12:3102009

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    Castinetti FNagai MMorange IDufour HCaron PChanson P: Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 94:340034072009

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    Castinetti FTaieb DKuhn JMChanson PTamura MJaquet P: Outcome of Gamma Knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. J Clin Endocrinol Metab 90:448344882005

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    Chen JCGiannotta SLYu CPetrovich ZLevy MApuzzo MLJ: Radiosurgical management of benign cavernous sinus tumors: dose profiles and acute complications. Neurosurgery 48:102210302001

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    Cho CBPark HJoo WIChough CKLee KJRha HK: Stereotactic radiosurgery with the CyberKnife for pituitary adenomas. J Korean Neurosurg Soc 45:1571632009

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    Choi JYChang JHChang JWHa YPark YGChung SS: Radiologic and hormonal response of functioning pituitary adenomas after Gamma Knife radiosurgery. Yonsei Med J 44:6026072003

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    Feigl GCBonelli CNBerghold AMokry M: Effects of Gamma Knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 97:4154212002

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    Fukuoka SIto TTakanashi MHojo ANakamura H: Gamma Knife radiosurgery for growth hormone-secreting pituitary adenomas invading the cavernous sinus. Stereotact Funct Neurosurg 76:2132172001

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    Girkin CAComey CHLunsford LDGoodman MLKline LB: Radiation optic neuropathy after stereotactic radiosurgery. Ophthalmology 104:163416431997

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    Hayashi MChernov MTamura NNagai MYomo SOchiai T: Gamma Knife robotic microradiosurgery of pituitary adenomas invading the cavernous sinus: treatment concept and results in 89 cases. J Neurooncol 98:1851942010

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    Hayashi MIzawa MHiyama HNakamura SAtsuchi SSato H: Gamma Knife radiosurgery for pituitary adenomas. Stereotact Funct Neurosurg 72:1111181999

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    Ikeda HJokura HYoshimoto T: Transsphenoidal surgery and adjuvant Gamma Knife treatment for growth hormone-secreting pituitary adenoma. J Neurosurg 95:2852912001

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    Inoue HKKohga HHirato MSasaki TIshihara JShibazaki T: Pituitary adenomas treated by microsurgery with or without Gamma Knife surgery: experience in 122 cases. Stereotact Funct Neurosurg 72:1251311999

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    Iwai YYamanaka KYoshimura MKawasaki IYamagami KYoshioka K: Gamma Knife radiosurgery for growth hormone-producing adenomas. J Clin Neurosci 17:2993042010

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    Jagannathan JSheehan JPPouratian NLaws ER JrSteiner LVance ML: Gamma Knife radiosurgery for acromegaly: outcomes after failed transsphenoidal surgery. Neurosurgery 62:126212702008

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    Jagannathan JYen CPPouratian NLaws ER JrSheehan JP: Stereotactic radiosurgery for pituitary adenomas: a comprehensive review of indications, techniques and long-term results using the Gamma Knife. J Neurooncol 92:3453562009

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    Jane JA JrVance MLWoodburn CJLaws ER Jr: Stereotactic radiosurgery for hypersecreting pituitary tumors: part of a multimodality approach. Neurosurg Focus 14:5e122003

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    Jezková JMarek JHána VKršek MWeiss VVladyka V: Gamma Knife radiosurgery for acromegaly—long-term experience. Clin Endocrinol (Oxf) 64:5885952006

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    Kajiwara KSaito KYoshikawa KKato SAkimura TNomura S: Image-guided stereotactic radiosurgery with the CyberKnife for pituitary adenomas. Minim Invasive Neurosurg 48:91962005

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    Kim MSLee SISim JH: Gamma Knife radiosurgery for functioning pituitary macroadenoma. Stereotact Funct Neurosurg 72:1191241999

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    Kim SHHuh RChang JWPark YGChung SS: Gamma Knife radiosurgery for functioning pituitary adenomas. Stereotact Funct Neurosurg 72:1011101999

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    Kobayashi TMori YUchiyama YKida YFujitani S: Longterm results of Gamma Knife surgery for growth hormone-producing pituitary adenoma: is the disease difficult to cure?. J Neurosurg 102:1191232005

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    Landolt AMHaller DLomax NScheib SSchubiger OSiegfried J: Octreotide may act as a radioprotective agent in acromegaly. J Clin Endocrinol Metab 85:128712892000

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    Landolt AMHaller DLomax NScheib SSchubiger OSiegfried J: Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy. J Neurosurg 88:100210081998

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    Laws ER Jr: Surgery for acromegaly: evolution of the techniques and outcomes. Rev Endocr Metab Disord 9:67702008

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    Laws ER JrSheehan JPSheehan JMJagannathan JJane JA JrOskouian R: Stereotactic radiosurgery for pituitary adenomas: a review of the literature. J Neurooncol 69:2572722004

  • 30

    Laws ER JrVance ML: Radiosurgery for pituitary tumors and craniopharyngiomas. Neurosurg Clin N Am 10:3273361999

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    Laws ER JrVance MLThapar K: Pituitary surgery for the management of acromegaly. Horm Res 53:71752000

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    Lim YLLeem WKim TSRhee BAKim GK: Four years' experiences in the treatment of pituitary adenomas with Gamma Knife radiosurgery. Stereotact Funct Neurosurg 70:Suppl 1951091998

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    Losa MGioia LPicozzi PFranzin AValle MGiovanelli M: The role of stereotactic radiotherapy in patients with growth hormone-secreting pituitary adenomas. J Clin Endocrinol Metab 93:254625522008

  • 34

    Ludecke DKAbe T: Transsphenoidal microsurgery for newly diagnosed acromegaly: a personal view after more than 1,000 operations. Neuroendocrinology 83:2302392006

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    Mahmoud-Ahmed ASSuh JSMayberg MR: Gamma Knife radiosurgery in the management of patients with acromegaly: a review. Pituitary 4:2232302001

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    Martínez RBravo GBurzaco JRey G: Pituitary tumors and Gamma Knife surgery. Stereotact Funct Neurosurg 70:1101181998

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    Melmed S: Medical progress: acromegaly. N Engl J Med 355:255825732006

  • 38

    Mitsumori MShrieve DCAlexander E IIIKaiser UBRichardson GEBlack PM: Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas. Int J Radiat Oncol Biol Phys 42:5735801998

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    Mokry MRamschak-Schwarzer SSimbrunner JGanz JCPendl G: A six year experience with the postoperative radiosurgical management of pituitary adenomas. Stereotact Funct Neurosurg 72:881001999

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    Morange-Ramos IRégis JDufour HAndrieu JMGrisoli FJaquet P: Short-term endocrinological results after Gamma Knife surgery of pituitary adenomas. Stereotact Funct Neurosurg 70:1271381998

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    Pan LZhang EWang BXu W: Pituitary adenomas: the effect of Gamma Knife radiosurgery on tumor growth and endocrinopathies. Stereotact Funct Neurosurg 70:1191261998

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    Park YGChang JWKim EYChung SS: Gamma Knife surgery in pituitary microadenomas. Yonsei Med J 37:1651731996

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    Peacey SRShalet SM: Insulin-like growth factor 1 measurement in diagnosis and management of acromegaly. Ann Clin Biochem 38:2973032001

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    Petrovich ZYu CGiannotta SLZee CSApuzzo MLJ: Gamma Knife radiosurgery for pituitary adenoma: early results. Neurosurgery 53:51612003

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    Pollock BEBrown PDNippoldt TBYoung WF Jr: Pituitary tumor type affects the chance of biochemical remission after radiosurgery of hormone-secreting pituitary adenomas. Neurosurgery 62:127112782008

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    Pollock BEJacob JTBrown PDNippoldt TB: Radiosurgery of growth hormone-producing pituitary adenomas: factors associated with biochemical remission. J Neurosurg 106:8338382007

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    Pollock BENippoldt TBStafford SLFoote RLAbboud CF: Results of stereotactic radiosurgery in patients with hormone-producing pituitary adenomas: factors associated with endocrine normalization. J Neurosurg 97:5255302002

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    Roberts BKOuyang DLLad SPChang SDHarsh GR IVAdler JR Jr: Efficacy and safety of CyberKnife radiosurgery for acromegaly. Pituitary 10:19252007

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    Sanno NTeramoto AOsamura RYHorvath EKovacs KLloyd RV: Pathology of pituitary tumors. Neurosurg Clin N Am 14:25392003

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    Sheehan JPNiranjan ASheehan JMJane JA JrLaws ER JrKondziolka D: Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 102:6786912005

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    Shih HALoeffler JS: Radiation therapy in acromegaly. Rev Endocr Metab Disord 9:59652008

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    Shin MKurita HSasaki TTago MMorita AUeki K: Stereotactic radiosurgery for pituitary adenoma invading the cavernous sinus. J Neurosurg 93:252000

  • 53

    Swords FMAllan CAPlowman PNSibtain AEvanson JChew SL: Stereotactic radiosurgery XVI: a treatment for previously irradiated pituitary adenomas. J Clin Endocrinol Metab 88:533453402003

  • 54

    Swords FMMonson JPBesser GMChew SLDrake WMGrossman AB: Gamma Knife radiosurgery: a safe and effective salvage treatment for pituitary tumours not controlled despite conventional radiotherapy. Eur J Endocrinol 161:8198282009

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    Tinnel BAHenderson MAWitt TCFakiris AJWorth RMDes Rosiers PM: Endocrine response after Gamma Knife-based stereotactic radiosurgery for secretory pituitary adenoma. Stereotact Funct Neurosurg 86:2922962008

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    Tishler RBLoeffler JSLunsford LDDuma CAlexander E IIIKooy HM: Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 27:2152211993

  • 57

    Vik-Mo EOØksnes MPedersen PHWentzel-Larsen TRødahl EThorsen F: Gamma Knife stereotactic radiosurgery for acromegaly. Eur J Endocrinol 157:2552632007

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Article Information

Address correspondence to: Martin H. Weiss, M.D., Department of Neurological Surgery, Keck School of Medicine, University of Southern California, 1200 North State Street, Suite 3300, Los Angeles, California 90033. email: weiss@usc.edu.

© AANS, except where prohibited by US copyright law.

Headings

References

1

Adler JR JrChang SDMurphy MJDoty JGeis PHancock SL: The CyberKnife: a frameless robotic system for radiosurgery. Stereotact Funct Neurosurg 69:1241281997

2

Attanasio REpaminonda PMotti EGiugni EVentrella LCozzi R: Gamma-Knife radiosurgery in acromegaly: a 4-year follow-up study. J Clin Endocrinol Metab 88:310531122003

3

Castinetti FMorange IDufour HRégis JBrue T: Radiotherapy and radiosurgery in acromegaly. Pituitary 12:3102009

4

Castinetti FNagai MMorange IDufour HCaron PChanson P: Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 94:340034072009

5

Castinetti FTaieb DKuhn JMChanson PTamura MJaquet P: Outcome of Gamma Knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. J Clin Endocrinol Metab 90:448344882005

6

Chen JCGiannotta SLYu CPetrovich ZLevy MApuzzo MLJ: Radiosurgical management of benign cavernous sinus tumors: dose profiles and acute complications. Neurosurgery 48:102210302001

7

Cho CBPark HJoo WIChough CKLee KJRha HK: Stereotactic radiosurgery with the CyberKnife for pituitary adenomas. J Korean Neurosurg Soc 45:1571632009

8

Choi JYChang JHChang JWHa YPark YGChung SS: Radiologic and hormonal response of functioning pituitary adenomas after Gamma Knife radiosurgery. Yonsei Med J 44:6026072003

9

Feigl GCBonelli CNBerghold AMokry M: Effects of Gamma Knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 97:4154212002

10

Fukuoka SIto TTakanashi MHojo ANakamura H: Gamma Knife radiosurgery for growth hormone-secreting pituitary adenomas invading the cavernous sinus. Stereotact Funct Neurosurg 76:2132172001

11

Girkin CAComey CHLunsford LDGoodman MLKline LB: Radiation optic neuropathy after stereotactic radiosurgery. Ophthalmology 104:163416431997

12

Hayashi MChernov MTamura NNagai MYomo SOchiai T: Gamma Knife robotic microradiosurgery of pituitary adenomas invading the cavernous sinus: treatment concept and results in 89 cases. J Neurooncol 98:1851942010

13

Hayashi MIzawa MHiyama HNakamura SAtsuchi SSato H: Gamma Knife radiosurgery for pituitary adenomas. Stereotact Funct Neurosurg 72:1111181999

14

Ikeda HJokura HYoshimoto T: Transsphenoidal surgery and adjuvant Gamma Knife treatment for growth hormone-secreting pituitary adenoma. J Neurosurg 95:2852912001

15

Inoue HKKohga HHirato MSasaki TIshihara JShibazaki T: Pituitary adenomas treated by microsurgery with or without Gamma Knife surgery: experience in 122 cases. Stereotact Funct Neurosurg 72:1251311999

16

Iwai YYamanaka KYoshimura MKawasaki IYamagami KYoshioka K: Gamma Knife radiosurgery for growth hormone-producing adenomas. J Clin Neurosci 17:2993042010

17

Izawa MHayashi MNakaya KSatoh HOchiai THori T: Gamma Knife radiosurgery for pituitary adenomas. J Neurosurg 93:19222000

18

Jagannathan JSheehan JPPouratian NLaws ER JrSteiner LVance ML: Gamma Knife radiosurgery for acromegaly: outcomes after failed transsphenoidal surgery. Neurosurgery 62:126212702008

19

Jagannathan JYen CPPouratian NLaws ER JrSheehan JP: Stereotactic radiosurgery for pituitary adenomas: a comprehensive review of indications, techniques and long-term results using the Gamma Knife. J Neurooncol 92:3453562009

20

Jane JA JrVance MLWoodburn CJLaws ER Jr: Stereotactic radiosurgery for hypersecreting pituitary tumors: part of a multimodality approach. Neurosurg Focus 14:5e122003

21

Jezková JMarek JHána VKršek MWeiss VVladyka V: Gamma Knife radiosurgery for acromegaly—long-term experience. Clin Endocrinol (Oxf) 64:5885952006

22

Kajiwara KSaito KYoshikawa KKato SAkimura TNomura S: Image-guided stereotactic radiosurgery with the CyberKnife for pituitary adenomas. Minim Invasive Neurosurg 48:91962005

23

Kim MSLee SISim JH: Gamma Knife radiosurgery for functioning pituitary macroadenoma. Stereotact Funct Neurosurg 72:1191241999

24

Kim SHHuh RChang JWPark YGChung SS: Gamma Knife radiosurgery for functioning pituitary adenomas. Stereotact Funct Neurosurg 72:1011101999

25

Kobayashi TMori YUchiyama YKida YFujitani S: Longterm results of Gamma Knife surgery for growth hormone-producing pituitary adenoma: is the disease difficult to cure?. J Neurosurg 102:1191232005

26

Landolt AMHaller DLomax NScheib SSchubiger OSiegfried J: Octreotide may act as a radioprotective agent in acromegaly. J Clin Endocrinol Metab 85:128712892000

27

Landolt AMHaller DLomax NScheib SSchubiger OSiegfried J: Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy. J Neurosurg 88:100210081998

28

Laws ER Jr: Surgery for acromegaly: evolution of the techniques and outcomes. Rev Endocr Metab Disord 9:67702008

29

Laws ER JrSheehan JPSheehan JMJagannathan JJane JA JrOskouian R: Stereotactic radiosurgery for pituitary adenomas: a review of the literature. J Neurooncol 69:2572722004

30

Laws ER JrVance ML: Radiosurgery for pituitary tumors and craniopharyngiomas. Neurosurg Clin N Am 10:3273361999

31

Laws ER JrVance MLThapar K: Pituitary surgery for the management of acromegaly. Horm Res 53:71752000

32

Lim YLLeem WKim TSRhee BAKim GK: Four years' experiences in the treatment of pituitary adenomas with Gamma Knife radiosurgery. Stereotact Funct Neurosurg 70:Suppl 1951091998

33

Losa MGioia LPicozzi PFranzin AValle MGiovanelli M: The role of stereotactic radiotherapy in patients with growth hormone-secreting pituitary adenomas. J Clin Endocrinol Metab 93:254625522008

34

Ludecke DKAbe T: Transsphenoidal microsurgery for newly diagnosed acromegaly: a personal view after more than 1,000 operations. Neuroendocrinology 83:2302392006

35

Mahmoud-Ahmed ASSuh JSMayberg MR: Gamma Knife radiosurgery in the management of patients with acromegaly: a review. Pituitary 4:2232302001

36

Martínez RBravo GBurzaco JRey G: Pituitary tumors and Gamma Knife surgery. Stereotact Funct Neurosurg 70:1101181998

37

Melmed S: Medical progress: acromegaly. N Engl J Med 355:255825732006

38

Mitsumori MShrieve DCAlexander E IIIKaiser UBRichardson GEBlack PM: Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas. Int J Radiat Oncol Biol Phys 42:5735801998

39

Mokry MRamschak-Schwarzer SSimbrunner JGanz JCPendl G: A six year experience with the postoperative radiosurgical management of pituitary adenomas. Stereotact Funct Neurosurg 72:881001999

40

Morange-Ramos IRégis JDufour HAndrieu JMGrisoli FJaquet P: Short-term endocrinological results after Gamma Knife surgery of pituitary adenomas. Stereotact Funct Neurosurg 70:1271381998

41

Pan LZhang EWang BXu W: Pituitary adenomas: the effect of Gamma Knife radiosurgery on tumor growth and endocrinopathies. Stereotact Funct Neurosurg 70:1191261998

42

Park YGChang JWKim EYChung SS: Gamma Knife surgery in pituitary microadenomas. Yonsei Med J 37:1651731996

43

Peacey SRShalet SM: Insulin-like growth factor 1 measurement in diagnosis and management of acromegaly. Ann Clin Biochem 38:2973032001

44

Petrovich ZYu CGiannotta SLZee CSApuzzo MLJ: Gamma Knife radiosurgery for pituitary adenoma: early results. Neurosurgery 53:51612003

45

Pollock BEBrown PDNippoldt TBYoung WF Jr: Pituitary tumor type affects the chance of biochemical remission after radiosurgery of hormone-secreting pituitary adenomas. Neurosurgery 62:127112782008

46

Pollock BEJacob JTBrown PDNippoldt TB: Radiosurgery of growth hormone-producing pituitary adenomas: factors associated with biochemical remission. J Neurosurg 106:8338382007

47

Pollock BENippoldt TBStafford SLFoote RLAbboud CF: Results of stereotactic radiosurgery in patients with hormone-producing pituitary adenomas: factors associated with endocrine normalization. J Neurosurg 97:5255302002

48

Roberts BKOuyang DLLad SPChang SDHarsh GR IVAdler JR Jr: Efficacy and safety of CyberKnife radiosurgery for acromegaly. Pituitary 10:19252007

49

Sanno NTeramoto AOsamura RYHorvath EKovacs KLloyd RV: Pathology of pituitary tumors. Neurosurg Clin N Am 14:25392003

50

Sheehan JPNiranjan ASheehan JMJane JA JrLaws ER JrKondziolka D: Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 102:6786912005

51

Shih HALoeffler JS: Radiation therapy in acromegaly. Rev Endocr Metab Disord 9:59652008

52

Shin MKurita HSasaki TTago MMorita AUeki K: Stereotactic radiosurgery for pituitary adenoma invading the cavernous sinus. J Neurosurg 93:252000

53

Swords FMAllan CAPlowman PNSibtain AEvanson JChew SL: Stereotactic radiosurgery XVI: a treatment for previously irradiated pituitary adenomas. J Clin Endocrinol Metab 88:533453402003

54

Swords FMMonson JPBesser GMChew SLDrake WMGrossman AB: Gamma Knife radiosurgery: a safe and effective salvage treatment for pituitary tumours not controlled despite conventional radiotherapy. Eur J Endocrinol 161:8198282009

55

Tinnel BAHenderson MAWitt TCFakiris AJWorth RMDes Rosiers PM: Endocrine response after Gamma Knife-based stereotactic radiosurgery for secretory pituitary adenoma. Stereotact Funct Neurosurg 86:2922962008

56

Tishler RBLoeffler JSLunsford LDDuma CAlexander E IIIKooy HM: Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 27:2152211993

57

Vik-Mo EOØksnes MPedersen PHWentzel-Larsen TRødahl EThorsen F: Gamma Knife stereotactic radiosurgery for acromegaly. Eur J Endocrinol 157:2552632007

58

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