Low-Dose Gamma Knife Radiosurgery for Acromegaly

Low-Dose Gamma Knife Radiosurgery for Acromegaly Abstract Background Remission rate is associated with higher dose of Gamma Knife Radiosurgery (GKRS; Gamma Knife: Elekta AB, Stockholm, Sweden) for acromegaly, but the dose ≥25 Gy is not always feasible when the functioning adenoma is close to optic apparatus Objective To evaluate the efficacy and safety of low-dose (<25 Gy) GKRS in the treatment of patients with acromegaly. Methods Single-center retrospective review of acromegaly cases treated with GKRS between June 1994 and December 2016. A total of 76 patients with the diagnosis of acromegaly who were treated with low-dose GKRS were selected for inclusion. Patients were treated with a median margin dose, isodose line, and treatment volume of 15.8 Gy, 57.5%, and 4.8 mL, respectively. Any identifiable portion of the optic apparatus was limited to a radiation dose of 10 Gy. All patients underwent full endocrine, ophthalmological, and imaging evaluation prior to and after GKRS treatments, and results of these were analyzed. Results Biochemical remission was achieved in 33 (43.4%) patients. Actuarial remission rates were 20.3%, 49.9%, and 76.3% at 4, 8, and 12 yr, respectively. Absence of cavernous sinus invasion (P = .042) and lower baseline insulin-like growth factor-1 levels (P = .019) were significant predictors of remission. New hormone deficiencies were found in 9 (11.8%) patients. Actuarial hormone deficiency rates were 3%, 14%, and 22.2% at 4, 8, and 10 yr, respectively. Two (2.6%) patients who achieved initial remission experienced recurrence. No optic complications were encountered. CONCLUSION Reasonable remission and new hormone deficiency rates can be achieved with low-dose GKRS for acromegaly. These rates may be comparable to those with standard GKRS margin doses. Acromegaly, Gamma-knife, Low dose, Stereotactic radiosurgery ABBREVIATIONS ABBREVIATIONS ACTH adrenocorticotropic hormone CI confidence interval CS cavernous sinus GH growth hormone GKRS Gamma Knife Radiosurgery Gy Gray HR Hazard ratio IGF insulin-like growth factor OGTT oral glucose tolerance test RT radiation therapy SRS stereotactic radiosurgery TSH thyroxin-stimulating hormone Despite the extensive literature on the radiosurgical outcomes for acromegaly, conclusions drawn from analyses of these series have been limited by the heterogeneity in patient selection, radiosurgical techniques, follow-up lengths, and biochemical remission criteria.1-29 The biochemical remission rates vary widely, ranging from 17% to 65% at 3 to 4 yr following stereotactic radiosurgery (SRS). The reported positive predictors of remission include high radiation dose, small tumor volume, and low initial serum growth hormone (GH) and insulin-like growth factor (IGF)-1 levels.3,13,19,25,28 Despite the high remission rates associated with increased radiation doses, risk of hormone deficit and neurovascular injury may limit the generalizability of such practice. Hence, the minimum effective radiation dose for hormone remission remains controversial. In this study, we investigated the endocrine outcomes, efficacy, and safety of patients with acromegaly who underwent Gamma Knife Radiosurgery (GKRS; Gamma Knife: Elekta AB, Stockholm, Sweden) using low margin doses of <25 Gy. METHODS Patient Population This was a single-center retrospective review of acromegaly cases treated with GKRS (Elekta AB) between June 1994 and December 2016. The study was approved by the Institutional Review Board of our hospital. Due to retrospective study design and expedited review, there was no patient consent. Inclusion criteria included the following: age >18 yr, diagnosis of acromegaly, and treatment using low-dose GKRS with margin dose of <25 Gy. Patients who underwent prior surgical resections were not excluded. Those who were treated with margin doses ≥25 Gy were excluded. Radiosurgical Technique The GKRS procedure has been previously described in detail.3,12,15,20 Briefly, all patients underwent stereotactic frame placement under local anesthesia in the operating room prior to magnetic resonance imaging (MRI) for treatment planning. Treatments were performed using Leksell Gamma Knife Unit (Elekta AB). Treatment parameters and dose plans were dictated by patient's neurological and ophthalmological examination results, tumor location and size, distance between tumor and optic apparatus, and previous treatments (i.e., radiation). The median margin dose, isodose line, and treatment volume were 15.8 Gy (range: 11.9-22), 57.5% (range: 50-80), and 4.8 mL (range: 0.8-58.1). Any identifiable portion of the optic apparatus was limited to a radiation dose of 10 Gy. The radiosurgical treatment parameters can be found in Table 1. TABLE 1. Characteristics in 76 Patients With Acromegaly Treated With SRS Characteristics Value Interquartile range Percentage Median age (yr) 42 33.5-51.7 Sex (F:M) 42:34 Median tumor volume (mL) 2.75 1.4-5.6 No. of patients with CS extension 39 51.3% No. of patients with suprasellar extension 10 13.2% No. of prior TSS 70 92.1%  0 6  1 60  2 9  3 1 No. of prior craniotomy 4 5.3% No. of prior RT 6 7.9% Median Pre-SRS IGF-1 level (ng/mL) 891 629-1038 Median Pre-SRS GH level (ng/mL) 11.05 5.02-25.09 Median Pre-SRS PRL level (ng/mL) 11 6.4-20.9 Pretreatment hormone deficiency 14 18.4%  Hypothyroidism 5  Hypogonadism 8  Hypoadrenalism 3 Median imaging FU (mo) 65.8 38.0-105.9 Median endocrine FU (mo) 72.8 39.7-115.9 SRS treatment parameters  Median margin radiation dose (Gy) 15.8 12.5-18.0  Median maximal radiation dose (Gy) 26.7 22.7-30.0  Median isodose level (%) 57.5 55.0-60.8  Median maximal optic chiasm radiation dose (Gy) 6.4 4.3-9.0  Median treatment volume (mL) 4.8 2.8-7.4 No. of Pre-SRS visual deficits 18 23.7% No. of Pre-SRS medical therapy 3 3.9% No. of Pre-SRS surgical pathology 39 51.3%  Plurihormonal adenoma 15  Mammosomatotroph adenoma 10  Somatotroph adenoma 9  Acidophillic adenoma 3  Gonadotroph adenoma 1  Chromophobe adenoma 1  Median GH stain (+-++++) 4 3.5-4  Median PRL stain (+-++++) 1.5 1-2 No. of repeat GK after initial 3 3.9% Characteristics Value Interquartile range Percentage Median age (yr) 42 33.5-51.7 Sex (F:M) 42:34 Median tumor volume (mL) 2.75 1.4-5.6 No. of patients with CS extension 39 51.3% No. of patients with suprasellar extension 10 13.2% No. of prior TSS 70 92.1%  0 6  1 60  2 9  3 1 No. of prior craniotomy 4 5.3% No. of prior RT 6 7.9% Median Pre-SRS IGF-1 level (ng/mL) 891 629-1038 Median Pre-SRS GH level (ng/mL) 11.05 5.02-25.09 Median Pre-SRS PRL level (ng/mL) 11 6.4-20.9 Pretreatment hormone deficiency 14 18.4%  Hypothyroidism 5  Hypogonadism 8  Hypoadrenalism 3 Median imaging FU (mo) 65.8 38.0-105.9 Median endocrine FU (mo) 72.8 39.7-115.9 SRS treatment parameters  Median margin radiation dose (Gy) 15.8 12.5-18.0  Median maximal radiation dose (Gy) 26.7 22.7-30.0  Median isodose level (%) 57.5 55.0-60.8  Median maximal optic chiasm radiation dose (Gy) 6.4 4.3-9.0  Median treatment volume (mL) 4.8 2.8-7.4 No. of Pre-SRS visual deficits 18 23.7% No. of Pre-SRS medical therapy 3 3.9% No. of Pre-SRS surgical pathology 39 51.3%  Plurihormonal adenoma 15  Mammosomatotroph adenoma 10  Somatotroph adenoma 9  Acidophillic adenoma 3  Gonadotroph adenoma 1  Chromophobe adenoma 1  Median GH stain (+-++++) 4 3.5-4  Median PRL stain (+-++++) 1.5 1-2 No. of repeat GK after initial 3 3.9% CS: cavernous sinus, F: female, FU: follow-up; SRS: stereotactic radiosurgery, M: male, RT: radiotherapy, TSS: transsphenoidal surgery, TV: tumor volume View Large TABLE 1. Characteristics in 76 Patients With Acromegaly Treated With SRS Characteristics Value Interquartile range Percentage Median age (yr) 42 33.5-51.7 Sex (F:M) 42:34 Median tumor volume (mL) 2.75 1.4-5.6 No. of patients with CS extension 39 51.3% No. of patients with suprasellar extension 10 13.2% No. of prior TSS 70 92.1%  0 6  1 60  2 9  3 1 No. of prior craniotomy 4 5.3% No. of prior RT 6 7.9% Median Pre-SRS IGF-1 level (ng/mL) 891 629-1038 Median Pre-SRS GH level (ng/mL) 11.05 5.02-25.09 Median Pre-SRS PRL level (ng/mL) 11 6.4-20.9 Pretreatment hormone deficiency 14 18.4%  Hypothyroidism 5  Hypogonadism 8  Hypoadrenalism 3 Median imaging FU (mo) 65.8 38.0-105.9 Median endocrine FU (mo) 72.8 39.7-115.9 SRS treatment parameters  Median margin radiation dose (Gy) 15.8 12.5-18.0  Median maximal radiation dose (Gy) 26.7 22.7-30.0  Median isodose level (%) 57.5 55.0-60.8  Median maximal optic chiasm radiation dose (Gy) 6.4 4.3-9.0  Median treatment volume (mL) 4.8 2.8-7.4 No. of Pre-SRS visual deficits 18 23.7% No. of Pre-SRS medical therapy 3 3.9% No. of Pre-SRS surgical pathology 39 51.3%  Plurihormonal adenoma 15  Mammosomatotroph adenoma 10  Somatotroph adenoma 9  Acidophillic adenoma 3  Gonadotroph adenoma 1  Chromophobe adenoma 1  Median GH stain (+-++++) 4 3.5-4  Median PRL stain (+-++++) 1.5 1-2 No. of repeat GK after initial 3 3.9% Characteristics Value Interquartile range Percentage Median age (yr) 42 33.5-51.7 Sex (F:M) 42:34 Median tumor volume (mL) 2.75 1.4-5.6 No. of patients with CS extension 39 51.3% No. of patients with suprasellar extension 10 13.2% No. of prior TSS 70 92.1%  0 6  1 60  2 9  3 1 No. of prior craniotomy 4 5.3% No. of prior RT 6 7.9% Median Pre-SRS IGF-1 level (ng/mL) 891 629-1038 Median Pre-SRS GH level (ng/mL) 11.05 5.02-25.09 Median Pre-SRS PRL level (ng/mL) 11 6.4-20.9 Pretreatment hormone deficiency 14 18.4%  Hypothyroidism 5  Hypogonadism 8  Hypoadrenalism 3 Median imaging FU (mo) 65.8 38.0-105.9 Median endocrine FU (mo) 72.8 39.7-115.9 SRS treatment parameters  Median margin radiation dose (Gy) 15.8 12.5-18.0  Median maximal radiation dose (Gy) 26.7 22.7-30.0  Median isodose level (%) 57.5 55.0-60.8  Median maximal optic chiasm radiation dose (Gy) 6.4 4.3-9.0  Median treatment volume (mL) 4.8 2.8-7.4 No. of Pre-SRS visual deficits 18 23.7% No. of Pre-SRS medical therapy 3 3.9% No. of Pre-SRS surgical pathology 39 51.3%  Plurihormonal adenoma 15  Mammosomatotroph adenoma 10  Somatotroph adenoma 9  Acidophillic adenoma 3  Gonadotroph adenoma 1  Chromophobe adenoma 1  Median GH stain (+-++++) 4 3.5-4  Median PRL stain (+-++++) 1.5 1-2 No. of repeat GK after initial 3 3.9% CS: cavernous sinus, F: female, FU: follow-up; SRS: stereotactic radiosurgery, M: male, RT: radiotherapy, TSS: transsphenoidal surgery, TV: tumor volume View Large Clinical, Hormone, and Imaging Evaluations The diagnosis of acromegaly was based on a combination of MRI findings, clinical features, and biochemical assessment according to the recent endocrine guidelines.5 Patients who had prior surgical resection, the endocrine evaluations and MRIs were performed at 3 mo following surgery. Endocrine evaluations included GH, IGF-1, adrenocorticotropic hormone (ACTH), serum cortisol, prolactin, total and free T4, thyroxin-stimulating hormone (TSH), luteinizing hormone, follicle-stimulating hormone, and testosterone (in males) levels. Oral glucose tolerance test (OGTT) was performed for those with inconclusive GH and IGF-1 results. Ophthalmological evaluations included visual acuity and field testing. Imaging studies obtained included contrasted MRIs with thin slices and volumetric sequences through the region of the sella turcica. Medications to lower GH and/or IGF-1 and SRS were recommended for individuals with persistent hormone instability following SRS. We did not prescribe anti-GH medications prior to SRS; therefore, we were not concerned with the radioresistant effects of anti-GH medications.23,26 A total of 9 patients (11.8%) who underwent GKRS began medical therapy 2 to 6 wk following radiosurgery. Clinical, endocrine, and imaging evaluations were performed at 6-mo intervals for the first 2 yr following GKRS. Remission was defined as normal age-matched and gender-matched serum IGF-1 levels, GH <1 ng/mL after OGTT, or random GH <1 ng/mL. New pituitary hormone deficiencies were defined as the following: thyrotropin deficiency, defined as low free T4 level with normal or diminished TSH; ACTH deficiency, defined as low serum cortisol level with a concomitant low ACTH level; gonadotropin deficiency, defined as low plasma testosterone with low or normal gonadotropin levels in men, amenorrhea with low plasma estradiol and low or normal gonadotropin levels in premenopausal women, or low or normal gonadotropin levels in postmenopausal women; and somatotropin deficiency, defined as subnormal GH response in an insulin tolerance test (peak GH < 5 ng/mL). Tumor control was defined as stable or decreased adenoma volume on MRI. Tumor progression was defined as >10% increase in adenoma volume, while tumor regression was defined as >10% decrease in adenoma volume found on MRI.17 Statistics Statistical analyses were performed using SPSS version 22 (IBM Corp., Armonk, New York). Descriptive statistics were performed for all available data. Univariate and multivariate analyses were performed using the Cox proportional hazards model to evaluate for predictors of biochemical remission and new hormone deficiencies. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Time-dependent analyses for biochemical remission and development of new hormone deficiencies were performed using Kaplan–Meier and actuarial methods, and differences between function curves were analyzed using the Log-rank test. Statistical significance was defined as P < .05, and all tests were two-tailed. RESULTS Baseline Demographics A total of 601 patients with pituitary adenomas were treated with GKRS (Elekta AB) at our institution, and 96 patients had diagnoses of acromegaly. Among these, 76 patients were treated with GKRS using low margin doses of <25 Gy, and were selected for inclusion. Indications for GKRS included failure to achieve hormone remission or visible residual or recurrent adenomas following surgical resection, and patient preference. Table 1 describes the baseline characteristic of the patients who underwent low-dose GKRS for acromegaly. Median age was 42 yr (range: 16-76), and females were comprised of 55.3% of the patient cohort. The median pre-GKRS adenoma volume was 2.8 mL (range: 0.1-49.5 mL). Adenomas with cavernous sinus (CS) and suprasellar extensions on MRI were 51.3% and 13.2% of the patients. Prior surgical resections, via transsphenoidal approach and craniotomy, were performed in 92.1% and 5.3% of the patients. In addition, 7.9% of the patients had undergone prior fractionated radiation therapy (RT). Primary SRS was performed in 6 patients comprising 3 patients with age >60 yr old with multiple medical comorbidities and three patients who refused surgical resection due to personal preferences. The median IGF-1, GH, and prolactin levels before GKRS treatments were 891 ng/mL (range: 205-1463), 11.05 ng/mL (range: 1.13-117), and 11 ng/mL (range: 1-334). Pre-GKRS hormone deficiencies were found in 18.4%. Visual deficits prior to GKRS were 23.7%, and 3.9% of the patients underwent medical treatment prior to GKRS. Six (18.4%) patients were continued on medical therapy at the time of GKRS. Surgical pathology was available in 51.3% of the patients. Median imaging and endocrine follow-ups were 65.8 mo (range: 4.8-228.9) and 72.8 mo (range: 6.1-235). Imaging Outcomes The median imaging follow-up period after SRS was 65.8 mo (range: 4.8-228.9 mo). The follow-up durations were as follows: >2 yr (66 patients), >4 yr (50 patients), >6 yr (38 patients), and >8 yr (25 patients). A total of 58 patients (76.3%) presented a decrease in tumor volume in their last available MRI study; 17 patients (22.4%) presented no change in tumor size; and 1 patient (1.3%) experienced tumor enlargement. Thus, the overall tumor control rate was 98.7%. Actuarial tumor control rates were 100%, 93.8%, 93.8%, and 93.8% at 6, 8, 10, and 12 yr following GKRS. Figure 1 presents typical post-SRS tumor volumes and endocrine changes in acromegaly patients. FIGURE 1. View largeDownload slide A, Kaplan–Meier analysis for endocrine remission after SRS. The actuarial remission rates at 2, 4, 6, 8, 10, and 12 yr postradiosurgery were 8.4%, 20.3%, 39.9%, 49.9%, 67.5%, and 82.6%, respectively. B, With cavernous sinus invasion, C, a preradiosurgical IGF-1 level was significantly related the rate of endocrine remission. D, Analysis using 18 Gy as the cutoff, which demonstrated no difference in remission rate with Cox regression (HR = 1.971 [0.967-4.018], P = .062). E, The incidence of hypopituitarism after SRS for acromegaly. The actuarial incidence rates at 4, 6, 8, 10, and 12 yr postradiosurgery were 3%, 7.7%, 14.0%, 22.2%, and 28.2%, respectively. F, The distribution of specific hormone deficits after SRS. The highest incidence of hormone deficits occurred 9 to 10 yr after SRS. FIGURE 1. View largeDownload slide A, Kaplan–Meier analysis for endocrine remission after SRS. The actuarial remission rates at 2, 4, 6, 8, 10, and 12 yr postradiosurgery were 8.4%, 20.3%, 39.9%, 49.9%, 67.5%, and 82.6%, respectively. B, With cavernous sinus invasion, C, a preradiosurgical IGF-1 level was significantly related the rate of endocrine remission. D, Analysis using 18 Gy as the cutoff, which demonstrated no difference in remission rate with Cox regression (HR = 1.971 [0.967-4.018], P = .062). E, The incidence of hypopituitarism after SRS for acromegaly. The actuarial incidence rates at 4, 6, 8, 10, and 12 yr postradiosurgery were 3%, 7.7%, 14.0%, 22.2%, and 28.2%, respectively. F, The distribution of specific hormone deficits after SRS. The highest incidence of hormone deficits occurred 9 to 10 yr after SRS. Biochemical Remission Biochemical remission was achieved in 33 (43.4%) patients at the last follow-up. Remission by specific criteria can be found in Table 2. Of the 6 patients who did not undergo prior surgical resection, only 1 (16.7%) patient achieved biochemical remission at final follow-up. Actuarial biochemical remission rates were 8.4%, 20.3%, 39.9%, 49.9%, 67.5%, and 76.3% at 2, 4, 6, 8, 10, and 12 yr following GKRS (Figure 1A). Absence of CS invasion (HR 0.339 [0.160-0.716], P = .005), lower pre-GKRS IGF-1 levels (HR 0.998 [0.996-1.000], P = .026), lower pre-GKRS GH levels (HR 0.971 [0.945-0.998], P = .036), no medical therapy at the time of GKRS treatments (HR 4.595 [1.037-20.359], P = .045), and mammosomatotroph adenoma found on surgical pathology (HR 4.054 [1.447-11.356], P = .008) were found to be predictors of biochemical remission in univariate analysis (Table 3). However, only absence of CS invasion (HR 0.345 [0.124-0.946], P = .042) and lower pre-GKRS IGF-1 (HR 0.998 [0.996-1.000], P = .019) remained statistically significant in multivariate analysis. Biochemical remission was achieved significantly earlier (P = .005) in patients without CS invasion compared to those with CS invasion (Figure 1B). Similarly, patients with pre-GKRS IGF-1 levels ≤2 times the normal limit (age- and gender-adjusted) achieved earlier remission (P = .026) compared to those with pre-GKRS IGF-1 levels >2 times the normal limit (Figure 1C). In concerning, the results may be driven by the patients treated with 18 to 24 Gy margin dose as 20 Gy is certainly effective for pituitary adenoma. We analyze using 18 Gy as the cutoff, which demonstrated no difference in remission rate with Cox regression (HR = 1.971 [0.967-4.018], P = .062; Figure 1D). One example case is illustrated in Figure 2. FIGURE 2. View largeDownload slide SRS was performed for a 51-yr-old man with poor control of GH after surgical resection. The patient did not receive long-acting octreotide, endocrine remission was achieved 66 mo after SRS. However, he developed new hormone deficiencies, including GH deficiency at 66 mo. FIGURE 2. View largeDownload slide SRS was performed for a 51-yr-old man with poor control of GH after surgical resection. The patient did not receive long-acting octreotide, endocrine remission was achieved 66 mo after SRS. However, he developed new hormone deficiencies, including GH deficiency at 66 mo. TABLE 2. Hormone Outcomes in 76 Patients Remission criteria Patients Remission (n) Median time to remission (mo) OGTT GH < 1 μg/dL 3 116 (61.6-175.3) OGTT GH < 1 μg/dL 1 15.1 IGF-1 normalization and random GH < 1 μg/dL 18 62.6 (1.4-216.1) IGF-1 normalization 2 20.8 (15.6-25.9) Random GH < 1 μg/dL 9 57.4 (11.8-141.6) Total remission 76 33 (43.4%) Recurrence after initial remission Case no. TV (mL) Dose margin/max (Gy) Time to remission post-SRS (mo) Time to recurrence postremission (mo) Subsequent treatment 1 3.4 12.0/20.69 89.7 13.1 Medication (Octreotide) 2 2 20/28.57 11.8 38.3 Medication (Octreotide) Repeat GKRS Case no. Initial/repeat TV (mL) Dose Margin/max (Gy) Time to repeat GK postinitial GKRS (mo) Hormone outcome after repeat GK (mo) Reason for repeat GK Initial Repeat 1 26.7/7.8 12.0/21.8 12.0/21.8 91.2 Remission Poor hormone control 2 4.4/1.8 17.0/28.8 18.0/30.0 42 Remission Poor hormone control 3 5.7/4.8 12.0/20.1 12.0/21.8 98.4 No remission currently Poor hormone control and tumor enlarge Remission criteria Patients Remission (n) Median time to remission (mo) OGTT GH < 1 μg/dL 3 116 (61.6-175.3) OGTT GH < 1 μg/dL 1 15.1 IGF-1 normalization and random GH < 1 μg/dL 18 62.6 (1.4-216.1) IGF-1 normalization 2 20.8 (15.6-25.9) Random GH < 1 μg/dL 9 57.4 (11.8-141.6) Total remission 76 33 (43.4%) Recurrence after initial remission Case no. TV (mL) Dose margin/max (Gy) Time to remission post-SRS (mo) Time to recurrence postremission (mo) Subsequent treatment 1 3.4 12.0/20.69 89.7 13.1 Medication (Octreotide) 2 2 20/28.57 11.8 38.3 Medication (Octreotide) Repeat GKRS Case no. Initial/repeat TV (mL) Dose Margin/max (Gy) Time to repeat GK postinitial GKRS (mo) Hormone outcome after repeat GK (mo) Reason for repeat GK Initial Repeat 1 26.7/7.8 12.0/21.8 12.0/21.8 91.2 Remission Poor hormone control 2 4.4/1.8 17.0/28.8 18.0/30.0 42 Remission Poor hormone control 3 5.7/4.8 12.0/20.1 12.0/21.8 98.4 No remission currently Poor hormone control and tumor enlarge FU: follow-up; GKRS, Gamma Knife Radiosurgery; OGTT: oral glucose tolerance test, SRS: stereotactic radiosurgery, mo: months View Large TABLE 2. Hormone Outcomes in 76 Patients Remission criteria Patients Remission (n) Median time to remission (mo) OGTT GH < 1 μg/dL 3 116 (61.6-175.3) OGTT GH < 1 μg/dL 1 15.1 IGF-1 normalization and random GH < 1 μg/dL 18 62.6 (1.4-216.1) IGF-1 normalization 2 20.8 (15.6-25.9) Random GH < 1 μg/dL 9 57.4 (11.8-141.6) Total remission 76 33 (43.4%) Recurrence after initial remission Case no. TV (mL) Dose margin/max (Gy) Time to remission post-SRS (mo) Time to recurrence postremission (mo) Subsequent treatment 1 3.4 12.0/20.69 89.7 13.1 Medication (Octreotide) 2 2 20/28.57 11.8 38.3 Medication (Octreotide) Repeat GKRS Case no. Initial/repeat TV (mL) Dose Margin/max (Gy) Time to repeat GK postinitial GKRS (mo) Hormone outcome after repeat GK (mo) Reason for repeat GK Initial Repeat 1 26.7/7.8 12.0/21.8 12.0/21.8 91.2 Remission Poor hormone control 2 4.4/1.8 17.0/28.8 18.0/30.0 42 Remission Poor hormone control 3 5.7/4.8 12.0/20.1 12.0/21.8 98.4 No remission currently Poor hormone control and tumor enlarge Remission criteria Patients Remission (n) Median time to remission (mo) OGTT GH < 1 μg/dL 3 116 (61.6-175.3) OGTT GH < 1 μg/dL 1 15.1 IGF-1 normalization and random GH < 1 μg/dL 18 62.6 (1.4-216.1) IGF-1 normalization 2 20.8 (15.6-25.9) Random GH < 1 μg/dL 9 57.4 (11.8-141.6) Total remission 76 33 (43.4%) Recurrence after initial remission Case no. TV (mL) Dose margin/max (Gy) Time to remission post-SRS (mo) Time to recurrence postremission (mo) Subsequent treatment 1 3.4 12.0/20.69 89.7 13.1 Medication (Octreotide) 2 2 20/28.57 11.8 38.3 Medication (Octreotide) Repeat GKRS Case no. Initial/repeat TV (mL) Dose Margin/max (Gy) Time to repeat GK postinitial GKRS (mo) Hormone outcome after repeat GK (mo) Reason for repeat GK Initial Repeat 1 26.7/7.8 12.0/21.8 12.0/21.8 91.2 Remission Poor hormone control 2 4.4/1.8 17.0/28.8 18.0/30.0 42 Remission Poor hormone control 3 5.7/4.8 12.0/20.1 12.0/21.8 98.4 No remission currently Poor hormone control and tumor enlarge FU: follow-up; GKRS, Gamma Knife Radiosurgery; OGTT: oral glucose tolerance test, SRS: stereotactic radiosurgery, mo: months View Large TABLE 3. Prognostic Factors for Endocrine Remission Remission Nonremission (n = 33) (n = 43) Cox univariate Cox multivariate P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Age (yr) 39.8 ± 11.9 44.5 ± 14.1 .931 0.999 (0.974-1.025) Gender (female %) 19 (57.6%) 23 (53.5%) .847 0.933 (0.462-1.886) Margin dose (Gy) 15.9 ± 3.3 15.4 ± 2.6 .068 1.124 (0.991-1.274) .184 1.113 (0.950-1.305) Maximal dose (Gy) 26.7 ± 4.2 26.6 ± 3.9 .716 1.015 (0.938-1.098) Tumor volume (mL) 3.9 ± 3.7 5.3 ± 8.3 .349 0.961 (0.885-1.044) Tumor extension  CS invasion (n) 15(45.5%) 24(55.8%) .005 0.339 (0.160-0.716) .042 0.345 (0.124-0.946)  Suprasellar expansion (n) 4(12.1%) 5(14%) .673 1.255 (0.438-3.595) Pre-SRS radiotherapy (n) 2(6.1%) 4(9.8%) .980 1.019 (0.240-4.316) Initial IGF-1 (ng/mL) 818.7 ± 313.7 902.2 ± 315.5 .026 0.998 (0.996-1.000) .019 0.998 (0.996-1.000) Initial GH (ng/mL) 15.8 ± 21.7 21.7 ± 22.0 .036 0.971 (0.945-0.998) .991 1.000 (0.973-1.029) Initial PRL (ng/mL) 12.2 ± 9.5 34.8 ± 70.7 .250 0.971 (0.923-1.021) Medication during SRS 2(6.1%) 4(9.3%) .045 4.595 (1.037-20.359) .214 2.722 (0.561-13.197) Pre-SRS Surgical pathology  Plurihormonal adenoma (n) 5(15.2%) 10(23.3%) .280 1.741 (0.637-4.756)  Mammosomatotroph adenoma (n) 5(15.2%) 5(11.6%) .008 4.054 (1.447-11.356) .269 1.892 (0.611-5.866)  Somatotroph adenoma (n) 5(15.2%) 4(9.3%) .579 0.758 (0.284-2.019)  Acidophillic adenoma (n) 0 3(7%) .424 0.045 (0.000-80.056)  GH stain (+) 3.5 ± 1 3.5 ± 1.23 .899 0.004 (0.000-2.886E + 34)  PRL stain (+) 1.7 ± 0.58 1.4 ± 0.55 .730 0.612 (0.038-9.931) Remission Nonremission (n = 33) (n = 43) Cox univariate Cox multivariate P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Age (yr) 39.8 ± 11.9 44.5 ± 14.1 .931 0.999 (0.974-1.025) Gender (female %) 19 (57.6%) 23 (53.5%) .847 0.933 (0.462-1.886) Margin dose (Gy) 15.9 ± 3.3 15.4 ± 2.6 .068 1.124 (0.991-1.274) .184 1.113 (0.950-1.305) Maximal dose (Gy) 26.7 ± 4.2 26.6 ± 3.9 .716 1.015 (0.938-1.098) Tumor volume (mL) 3.9 ± 3.7 5.3 ± 8.3 .349 0.961 (0.885-1.044) Tumor extension  CS invasion (n) 15(45.5%) 24(55.8%) .005 0.339 (0.160-0.716) .042 0.345 (0.124-0.946)  Suprasellar expansion (n) 4(12.1%) 5(14%) .673 1.255 (0.438-3.595) Pre-SRS radiotherapy (n) 2(6.1%) 4(9.8%) .980 1.019 (0.240-4.316) Initial IGF-1 (ng/mL) 818.7 ± 313.7 902.2 ± 315.5 .026 0.998 (0.996-1.000) .019 0.998 (0.996-1.000) Initial GH (ng/mL) 15.8 ± 21.7 21.7 ± 22.0 .036 0.971 (0.945-0.998) .991 1.000 (0.973-1.029) Initial PRL (ng/mL) 12.2 ± 9.5 34.8 ± 70.7 .250 0.971 (0.923-1.021) Medication during SRS 2(6.1%) 4(9.3%) .045 4.595 (1.037-20.359) .214 2.722 (0.561-13.197) Pre-SRS Surgical pathology  Plurihormonal adenoma (n) 5(15.2%) 10(23.3%) .280 1.741 (0.637-4.756)  Mammosomatotroph adenoma (n) 5(15.2%) 5(11.6%) .008 4.054 (1.447-11.356) .269 1.892 (0.611-5.866)  Somatotroph adenoma (n) 5(15.2%) 4(9.3%) .579 0.758 (0.284-2.019)  Acidophillic adenoma (n) 0 3(7%) .424 0.045 (0.000-80.056)  GH stain (+) 3.5 ± 1 3.5 ± 1.23 .899 0.004 (0.000-2.886E + 34)  PRL stain (+) 1.7 ± 0.58 1.4 ± 0.55 .730 0.612 (0.038-9.931) CS: cavernous sinus, Gy: gray, SRS: stereotactic radiosurgery. View Large TABLE 3. Prognostic Factors for Endocrine Remission Remission Nonremission (n = 33) (n = 43) Cox univariate Cox multivariate P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Age (yr) 39.8 ± 11.9 44.5 ± 14.1 .931 0.999 (0.974-1.025) Gender (female %) 19 (57.6%) 23 (53.5%) .847 0.933 (0.462-1.886) Margin dose (Gy) 15.9 ± 3.3 15.4 ± 2.6 .068 1.124 (0.991-1.274) .184 1.113 (0.950-1.305) Maximal dose (Gy) 26.7 ± 4.2 26.6 ± 3.9 .716 1.015 (0.938-1.098) Tumor volume (mL) 3.9 ± 3.7 5.3 ± 8.3 .349 0.961 (0.885-1.044) Tumor extension  CS invasion (n) 15(45.5%) 24(55.8%) .005 0.339 (0.160-0.716) .042 0.345 (0.124-0.946)  Suprasellar expansion (n) 4(12.1%) 5(14%) .673 1.255 (0.438-3.595) Pre-SRS radiotherapy (n) 2(6.1%) 4(9.8%) .980 1.019 (0.240-4.316) Initial IGF-1 (ng/mL) 818.7 ± 313.7 902.2 ± 315.5 .026 0.998 (0.996-1.000) .019 0.998 (0.996-1.000) Initial GH (ng/mL) 15.8 ± 21.7 21.7 ± 22.0 .036 0.971 (0.945-0.998) .991 1.000 (0.973-1.029) Initial PRL (ng/mL) 12.2 ± 9.5 34.8 ± 70.7 .250 0.971 (0.923-1.021) Medication during SRS 2(6.1%) 4(9.3%) .045 4.595 (1.037-20.359) .214 2.722 (0.561-13.197) Pre-SRS Surgical pathology  Plurihormonal adenoma (n) 5(15.2%) 10(23.3%) .280 1.741 (0.637-4.756)  Mammosomatotroph adenoma (n) 5(15.2%) 5(11.6%) .008 4.054 (1.447-11.356) .269 1.892 (0.611-5.866)  Somatotroph adenoma (n) 5(15.2%) 4(9.3%) .579 0.758 (0.284-2.019)  Acidophillic adenoma (n) 0 3(7%) .424 0.045 (0.000-80.056)  GH stain (+) 3.5 ± 1 3.5 ± 1.23 .899 0.004 (0.000-2.886E + 34)  PRL stain (+) 1.7 ± 0.58 1.4 ± 0.55 .730 0.612 (0.038-9.931) Remission Nonremission (n = 33) (n = 43) Cox univariate Cox multivariate P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Age (yr) 39.8 ± 11.9 44.5 ± 14.1 .931 0.999 (0.974-1.025) Gender (female %) 19 (57.6%) 23 (53.5%) .847 0.933 (0.462-1.886) Margin dose (Gy) 15.9 ± 3.3 15.4 ± 2.6 .068 1.124 (0.991-1.274) .184 1.113 (0.950-1.305) Maximal dose (Gy) 26.7 ± 4.2 26.6 ± 3.9 .716 1.015 (0.938-1.098) Tumor volume (mL) 3.9 ± 3.7 5.3 ± 8.3 .349 0.961 (0.885-1.044) Tumor extension  CS invasion (n) 15(45.5%) 24(55.8%) .005 0.339 (0.160-0.716) .042 0.345 (0.124-0.946)  Suprasellar expansion (n) 4(12.1%) 5(14%) .673 1.255 (0.438-3.595) Pre-SRS radiotherapy (n) 2(6.1%) 4(9.8%) .980 1.019 (0.240-4.316) Initial IGF-1 (ng/mL) 818.7 ± 313.7 902.2 ± 315.5 .026 0.998 (0.996-1.000) .019 0.998 (0.996-1.000) Initial GH (ng/mL) 15.8 ± 21.7 21.7 ± 22.0 .036 0.971 (0.945-0.998) .991 1.000 (0.973-1.029) Initial PRL (ng/mL) 12.2 ± 9.5 34.8 ± 70.7 .250 0.971 (0.923-1.021) Medication during SRS 2(6.1%) 4(9.3%) .045 4.595 (1.037-20.359) .214 2.722 (0.561-13.197) Pre-SRS Surgical pathology  Plurihormonal adenoma (n) 5(15.2%) 10(23.3%) .280 1.741 (0.637-4.756)  Mammosomatotroph adenoma (n) 5(15.2%) 5(11.6%) .008 4.054 (1.447-11.356) .269 1.892 (0.611-5.866)  Somatotroph adenoma (n) 5(15.2%) 4(9.3%) .579 0.758 (0.284-2.019)  Acidophillic adenoma (n) 0 3(7%) .424 0.045 (0.000-80.056)  GH stain (+) 3.5 ± 1 3.5 ± 1.23 .899 0.004 (0.000-2.886E + 34)  PRL stain (+) 1.7 ± 0.58 1.4 ± 0.55 .730 0.612 (0.038-9.931) CS: cavernous sinus, Gy: gray, SRS: stereotactic radiosurgery. View Large Recurrences Two (2.6%) patients who achieved initial biochemical remission following GKRS treatment experienced recurrence. The intervals between initial remission and recurrence were 13 and 38 mo (Table 2). Pre-GKRS tumor volumes for the 2 recurrences were 3.4 and 2 mL. The prescribed margin doses were 12 and 20 Gy. Tumor volumes for these 2 patients decreased to 0.33 and 0.35 mL, respectively. Both patients were managed medically after their recurrences. Medication Use After SRS No patients in our study received Somavert post-SRS. However, 15 of our patients did receive Cabergoline (n = 3), Somatostatin (n = 7), Octreotide (n = 7), and Bromocriptine (n = 2) after SRS. They received medication due to GKRS failure. Eight of them achieved hormone normalization after medication. Repeat GKRS Treatments Three (3.9%) patients underwent repeat GKRS (Table 2), due to failure to achieve biochemical remission following initial GKRS. They all had smaller tumor volumes at the time of their repeat GKRS compared to the time of initial treatment. Time intervals between initial and repeat GKRS were 91, 42, and 98 mo. Two patients achieved biochemical remission at 5 and 30 mo following repeat GKRS. New Hormone Deficiency after SRS New hormone deficiencies were found in nine (11.8%) patients, and the median time to the development of new hormone deficiencies was 83.6 mo (range: 25.1-127.6) after GKRS. Actuarial hormone deficiency rates were 3%, 7.7%, 14%, and 22.2% at 4, 6, 8, and 10 yr following GKRS (Figure 1E). The most common new hormone deficiencies were ACTH, gonadotropin, and GH. Figure 1F demonstrates the distribution of new hormone deficiencies over time. Following GKRS, actuarial hypothyroidism rates were 0%, 0%, and 4.3% at 2, 6, and 10 yr; actuarial hypogonadism rates were 0%, 3%, and 7.2% at 2, 6, and 10 yr; actuarial hypocortisolism rates were 0%, 3.8%, and 15.1% at 2, 6, and 10 yr; actuarial GH deficiency rates were 0%, 2.5%, and 5.6% at 2, 6, and 10 yr. Presence of CS invasion was a predictor of post-GKRS new hormone deficiencies on univariate (HR 0.145 [0.029-0.726], P = .019) and multivariate (HR 0.162 [0.032-0.815], P = .027) analyses (Table 4). TABLE 4. Prognostic Factors for Development of New Hormone Deficiency after SRS Cox Univariate analysis Cox Multivariate analysis P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Gender (female vs. male) .055 0.214 (0.044-1.034) .082 0.247 (0.051-1.197) Margin dose (>15.8 vs. <15.8 Gy) .578 1.453 (0.389-5.431) Maximum dose (>26.7 vs. <26.7 Gy) .602 1.419 (0.380-5.302) Tumor volume (>2.8 vs. <2.8 mL) .793 0.799 (0.214-2.979) Treatment volume (>4.8 vs. <4.8 mL) .740 1.250 (0.335-4.657) Tumor extension  Cavernous sinus invasion (yes vs. no) .019 0.145 (0.029-0.726) .027 0.162 (0.032-0.815)  Suprasellar extension (yes vs. no) .235 2.604 (0.536-12.649) Prior hormone deficiency .416 0.421 (0.053-3.378) Age (>42 vs. <42y) .413 1.735 (0.464-6.486) Pre-GK vision deficits (yes vs. no) .412 0.417 (0.051-3.379) Cox Univariate analysis Cox Multivariate analysis P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Gender (female vs. male) .055 0.214 (0.044-1.034) .082 0.247 (0.051-1.197) Margin dose (>15.8 vs. <15.8 Gy) .578 1.453 (0.389-5.431) Maximum dose (>26.7 vs. <26.7 Gy) .602 1.419 (0.380-5.302) Tumor volume (>2.8 vs. <2.8 mL) .793 0.799 (0.214-2.979) Treatment volume (>4.8 vs. <4.8 mL) .740 1.250 (0.335-4.657) Tumor extension  Cavernous sinus invasion (yes vs. no) .019 0.145 (0.029-0.726) .027 0.162 (0.032-0.815)  Suprasellar extension (yes vs. no) .235 2.604 (0.536-12.649) Prior hormone deficiency .416 0.421 (0.053-3.378) Age (>42 vs. <42y) .413 1.735 (0.464-6.486) Pre-GK vision deficits (yes vs. no) .412 0.417 (0.051-3.379) CS: cavernous sinus, Gy: gray, SRS: stereotactic radiosurgery. View Large TABLE 4. Prognostic Factors for Development of New Hormone Deficiency after SRS Cox Univariate analysis Cox Multivariate analysis P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Gender (female vs. male) .055 0.214 (0.044-1.034) .082 0.247 (0.051-1.197) Margin dose (>15.8 vs. <15.8 Gy) .578 1.453 (0.389-5.431) Maximum dose (>26.7 vs. <26.7 Gy) .602 1.419 (0.380-5.302) Tumor volume (>2.8 vs. <2.8 mL) .793 0.799 (0.214-2.979) Treatment volume (>4.8 vs. <4.8 mL) .740 1.250 (0.335-4.657) Tumor extension  Cavernous sinus invasion (yes vs. no) .019 0.145 (0.029-0.726) .027 0.162 (0.032-0.815)  Suprasellar extension (yes vs. no) .235 2.604 (0.536-12.649) Prior hormone deficiency .416 0.421 (0.053-3.378) Age (>42 vs. <42y) .413 1.735 (0.464-6.486) Pre-GK vision deficits (yes vs. no) .412 0.417 (0.051-3.379) Cox Univariate analysis Cox Multivariate analysis P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Gender (female vs. male) .055 0.214 (0.044-1.034) .082 0.247 (0.051-1.197) Margin dose (>15.8 vs. <15.8 Gy) .578 1.453 (0.389-5.431) Maximum dose (>26.7 vs. <26.7 Gy) .602 1.419 (0.380-5.302) Tumor volume (>2.8 vs. <2.8 mL) .793 0.799 (0.214-2.979) Treatment volume (>4.8 vs. <4.8 mL) .740 1.250 (0.335-4.657) Tumor extension  Cavernous sinus invasion (yes vs. no) .019 0.145 (0.029-0.726) .027 0.162 (0.032-0.815)  Suprasellar extension (yes vs. no) .235 2.604 (0.536-12.649) Prior hormone deficiency .416 0.421 (0.053-3.378) Age (>42 vs. <42y) .413 1.735 (0.464-6.486) Pre-GK vision deficits (yes vs. no) .412 0.417 (0.051-3.379) CS: cavernous sinus, Gy: gray, SRS: stereotactic radiosurgery. View Large Other Complications No complications were encountered in this study. No new visual deficits, cranial nerve palsies, cerebrovascular accidents, or radiation-induced tumors were detected during the follow-up period. DISCUSSION Higher margin doses are generally suggested in the radiosurgical treatment of functioning pituitary adenomas. Most margin doses reported have exceeded 20 Gy, and the suggested margin dose often around 25 Gy.1,2,13,15,16,19,22 In the past, it was reasonable to expect hormone remission in 50% of patients within the 2 to 4 yr following radiosurgery. Many studies have also indicated that stronger doses can reduce the time required for hormone remission. Remission criteria and methods used to track acromegaly patients were vary considerably. A review of studies based on series with more than 50 acromegaly patients and tracking periods exceeding 4 yr (Table 5) revealed that the administration of 25 to 35 Gy could indeed achieve hormone remission more rapidly than the administration of 16 to 18 Gy, without causing a notable increase in the likelihood of hypopituitarism. The incidence rates of nearly all other complications were also under 2%. TABLE 5. Literature Review of Outcomes after SRSa Remission criteria Remission New hormone deficiency Authors, year Series no. (n) Median/ mean FU (mo) Margin dose (Gy) TV control rate (%) OGTT GH <1 ng/mL Normal IGF-1 GH <1 ng/mL GH <2 ng/mL GH <2.5 ng/mL Year (yr) Rate (%) Year (yr) Rate (%) Individual hypopituitarism (%) Castinetti et al, 200522 82 49.5 25.7 N/A V V 3 17 N/A 17 Kobayashi et al, 200521 67 63.0 18.9 N/A N/A N/A 10 N/A 11 Jezkova et al, 200619 96 54.0 35.0 100 V V 3 29 N/A 27 Hypogonadism 7 5 44 Hypoadrenalism 7 8 57 Hypothyroidism 20 Voges et al, 200629 64 54.3 16.5 88.2 V V 3 29 5 27 5 50 7 63 Vik-Mo et al, 200716 53 66.0 26.5 100 V V V N/A 17 8 23 Jagannathan et al, 200715 95 57.6 22.0 98.0 V 2.5 53 N/A 34 Losa et al, 200813 83 69.0 25 97.6 V V 5 53 5 8.5 Kobayashi, 200911 71 64.0 18.9 N/A V N/A 5 N/A 15 Wan et al, 200910 103 67.0 21.4 95.1 V V N/A 37 N/A 2 Franzin et al, 20122 103 71 23 97.3 V V 5 57 N/A 7.8 Hypogonadism 5.2 Hypoadrenalism 6 10 80 Hypothyroidism 3.2 bLee et al, 20141 136 61.5/68.2 25.0 98.5 V V 4 65 4 11 Hypogonadism 14 6 73 6 29 Hypoadrenalism 12 8 83 8 44 Hypothyroidism 23 GH deficiency 1.5 Present, 2017 76 72.8 15.8 98.7 V V V 4 20 4 3 Hypogonadism 3.9 6 40 6 8 Hypoadrenalism 6.6 8 50 8 14 Hypothyroidism 1.3 12 76 12 28 GH deficiency 3.9 Remission criteria Remission New hormone deficiency Authors, year Series no. (n) Median/ mean FU (mo) Margin dose (Gy) TV control rate (%) OGTT GH <1 ng/mL Normal IGF-1 GH <1 ng/mL GH <2 ng/mL GH <2.5 ng/mL Year (yr) Rate (%) Year (yr) Rate (%) Individual hypopituitarism (%) Castinetti et al, 200522 82 49.5 25.7 N/A V V 3 17 N/A 17 Kobayashi et al, 200521 67 63.0 18.9 N/A N/A N/A 10 N/A 11 Jezkova et al, 200619 96 54.0 35.0 100 V V 3 29 N/A 27 Hypogonadism 7 5 44 Hypoadrenalism 7 8 57 Hypothyroidism 20 Voges et al, 200629 64 54.3 16.5 88.2 V V 3 29 5 27 5 50 7 63 Vik-Mo et al, 200716 53 66.0 26.5 100 V V V N/A 17 8 23 Jagannathan et al, 200715 95 57.6 22.0 98.0 V 2.5 53 N/A 34 Losa et al, 200813 83 69.0 25 97.6 V V 5 53 5 8.5 Kobayashi, 200911 71 64.0 18.9 N/A V N/A 5 N/A 15 Wan et al, 200910 103 67.0 21.4 95.1 V V N/A 37 N/A 2 Franzin et al, 20122 103 71 23 97.3 V V 5 57 N/A 7.8 Hypogonadism 5.2 Hypoadrenalism 6 10 80 Hypothyroidism 3.2 bLee et al, 20141 136 61.5/68.2 25.0 98.5 V V 4 65 4 11 Hypogonadism 14 6 73 6 29 Hypoadrenalism 12 8 83 8 44 Hypothyroidism 23 GH deficiency 1.5 Present, 2017 76 72.8 15.8 98.7 V V V 4 20 4 3 Hypogonadism 3.9 6 40 6 8 Hypoadrenalism 6.6 8 50 8 14 Hypothyroidism 1.3 12 76 12 28 GH deficiency 3.9 FU: follow-up, GH: growth hormone, Gy: gray, IGF-1: insulin-like growth factor-1, mo: months, N/A: not available, OGTT: oral glucose tolerance test, SRS: stereotactic radiosurgery. aNumber of patients > 50, follow-up > 4 yr. bLee et al, 20141: Remission criteria is OGTT GH < 1 ng/mL and/or Normal IGF-1 View Large TABLE 5. Literature Review of Outcomes after SRSa Remission criteria Remission New hormone deficiency Authors, year Series no. (n) Median/ mean FU (mo) Margin dose (Gy) TV control rate (%) OGTT GH <1 ng/mL Normal IGF-1 GH <1 ng/mL GH <2 ng/mL GH <2.5 ng/mL Year (yr) Rate (%) Year (yr) Rate (%) Individual hypopituitarism (%) Castinetti et al, 200522 82 49.5 25.7 N/A V V 3 17 N/A 17 Kobayashi et al, 200521 67 63.0 18.9 N/A N/A N/A 10 N/A 11 Jezkova et al, 200619 96 54.0 35.0 100 V V 3 29 N/A 27 Hypogonadism 7 5 44 Hypoadrenalism 7 8 57 Hypothyroidism 20 Voges et al, 200629 64 54.3 16.5 88.2 V V 3 29 5 27 5 50 7 63 Vik-Mo et al, 200716 53 66.0 26.5 100 V V V N/A 17 8 23 Jagannathan et al, 200715 95 57.6 22.0 98.0 V 2.5 53 N/A 34 Losa et al, 200813 83 69.0 25 97.6 V V 5 53 5 8.5 Kobayashi, 200911 71 64.0 18.9 N/A V N/A 5 N/A 15 Wan et al, 200910 103 67.0 21.4 95.1 V V N/A 37 N/A 2 Franzin et al, 20122 103 71 23 97.3 V V 5 57 N/A 7.8 Hypogonadism 5.2 Hypoadrenalism 6 10 80 Hypothyroidism 3.2 bLee et al, 20141 136 61.5/68.2 25.0 98.5 V V 4 65 4 11 Hypogonadism 14 6 73 6 29 Hypoadrenalism 12 8 83 8 44 Hypothyroidism 23 GH deficiency 1.5 Present, 2017 76 72.8 15.8 98.7 V V V 4 20 4 3 Hypogonadism 3.9 6 40 6 8 Hypoadrenalism 6.6 8 50 8 14 Hypothyroidism 1.3 12 76 12 28 GH deficiency 3.9 Remission criteria Remission New hormone deficiency Authors, year Series no. (n) Median/ mean FU (mo) Margin dose (Gy) TV control rate (%) OGTT GH <1 ng/mL Normal IGF-1 GH <1 ng/mL GH <2 ng/mL GH <2.5 ng/mL Year (yr) Rate (%) Year (yr) Rate (%) Individual hypopituitarism (%) Castinetti et al, 200522 82 49.5 25.7 N/A V V 3 17 N/A 17 Kobayashi et al, 200521 67 63.0 18.9 N/A N/A N/A 10 N/A 11 Jezkova et al, 200619 96 54.0 35.0 100 V V 3 29 N/A 27 Hypogonadism 7 5 44 Hypoadrenalism 7 8 57 Hypothyroidism 20 Voges et al, 200629 64 54.3 16.5 88.2 V V 3 29 5 27 5 50 7 63 Vik-Mo et al, 200716 53 66.0 26.5 100 V V V N/A 17 8 23 Jagannathan et al, 200715 95 57.6 22.0 98.0 V 2.5 53 N/A 34 Losa et al, 200813 83 69.0 25 97.6 V V 5 53 5 8.5 Kobayashi, 200911 71 64.0 18.9 N/A V N/A 5 N/A 15 Wan et al, 200910 103 67.0 21.4 95.1 V V N/A 37 N/A 2 Franzin et al, 20122 103 71 23 97.3 V V 5 57 N/A 7.8 Hypogonadism 5.2 Hypoadrenalism 6 10 80 Hypothyroidism 3.2 bLee et al, 20141 136 61.5/68.2 25.0 98.5 V V 4 65 4 11 Hypogonadism 14 6 73 6 29 Hypoadrenalism 12 8 83 8 44 Hypothyroidism 23 GH deficiency 1.5 Present, 2017 76 72.8 15.8 98.7 V V V 4 20 4 3 Hypogonadism 3.9 6 40 6 8 Hypoadrenalism 6.6 8 50 8 14 Hypothyroidism 1.3 12 76 12 28 GH deficiency 3.9 FU: follow-up, GH: growth hormone, Gy: gray, IGF-1: insulin-like growth factor-1, mo: months, N/A: not available, OGTT: oral glucose tolerance test, SRS: stereotactic radiosurgery. aNumber of patients > 50, follow-up > 4 yr. bLee et al, 20141: Remission criteria is OGTT GH < 1 ng/mL and/or Normal IGF-1 View Large However, in the case of sellar tumors, high radiation doses cannot always be prescribed without greatly increasing the risk of complications. The optic nerve and optical apparatus are believed to have very low tolerance for even low amounts of radiation (eg, 8-10 Gy)30-38; therefore, the amount of radiation administered to sellar tumors must generally be lowered. The visual impairment and visual field deficits caused by radiation-induced optic neuritis are irreversible that patients are typically unable to accept. This has led researchers to conduct a variety of experiments in the hopes of elucidating the precise dosages. Results from this work have in-turn resulted in the formulation of numerous guidelines aimed at protecting the optic nerve.30,31,33-37 Such guidelines include recommendations which define the minimum distance that must exist between a sellar tumor and the optic nerve before radiosurgery. In cases where the sellar tumor is truly inseparable from the optic nerve, either hypofractionated methods must be adopted,30,31,33,35 or reduced doses of radiation (eg, <20 Gy) in the treatment. We aimed to evaluate the effectiveness of low-dose GKRS (Elekta AB) on acromegaly patients and to elucidate the risks associated with damage to the optic apparatus and hypothalamic injury. In our series, stricter criteria (random GH < 1 and IGF-1 normalization) resulted in the following postradiosurgery actuarial remission rates: 2 yr (8.4%,), 4 yr (20.3%), 6 yr (39.9%), 8 yr (49.9%), 10 yr (67.5%), and 12 yr (76.3%). In a systemic review and a Kaplan–Meier analysis performed on previous acromegaly series which follow-up data collected >10 yr, patients presented slower remission but not poorer overall remission rates than those in the series published by Vik-Mo and Kobayahi.11,16 Adopting loosening the criteria (random GH < 2.5 and IGF-1 normalization) resulted in the following postradiosurgery actuarial remission rates: 2 yr (16.5%), 4 yr (31.6%), 6 yr (51.0%), 8 yr (67.1%), 10 yr (90.1%), and 12 yr (90.1%); still, patients presented slower remission but not poorer overall remission rates compared to results of high-dose GKRS series published by Losa et al,13 Franzin et al,2 and Lee et al1 (Table 5). In contrast to the 2 studies that utilized low-dose radiation in the treatment of GH-producing adenomas, the focuses of our study were the safety and efficacy of low-dose GKRS for small GH-secreting adenoma.21,29 Kobayashi et al21 reported a GH normalization rate of 4.8% and tumor control rate of 100% after GKRS using a mean margin dose of 18.9 Gy and a mean follow-up duration of 63.3 mo in a study comprising 67 patients with GH-producing adenomas with mean tumor volume of 5.4 mL. The authors concluded that endocrine remission was difficult to achieve for large tumors with low-dose radiation. In contrast, the median tumor volume in our study was 2.8 mL, which was approximately half of what was reported in the study by Kobayashi et al.21 Hence, our GH-producing adenoma cohort may be inherently distinct from that of the Kobayashi et al21 study. Although Voges et al29 reported hormone normalization rate of 46.9% among 64 patients with GH-producing adenomas treated with margin dose of up to 20 Gy, they focus on macroadenomas (mean tumor volume: 4.3 mL) in general and no predictors of endocrine remission/new hormone deficiency in relation to GH-producing adenoma treatment was analyzed. In addition, the treatment modality used in the study was linear accelerator-based radiosurgery. From the results of present study, low-dose radiosurgery for GH adenomas seems feasible. However, the lowest effective radiation dose for GH adenomas remains unclear. Although there was no statistical difference in remission rates between margin doses of ≥18 and <18 Gy, there appears to be a trend (P = .062) towards higher remission rates for those treated with margin doses of ≥18 Gy. Hence, in cases where radiation dose to the optic apparatus could not be constrained to 10 Gy or less, margin doses <18 Gy may be considered. The current study found a new hormone deficiency rate of 11.8% after a median latency period of 83.6 mo. These rates seem to be considerably lower compared to those reported by Lee et al,1 who found a new hormone deficiency rate of 31.6% after a median latency period of 50.5 mo. In contrast, Losa et al13 reported a low new hormone deficit incidence of 8.5%. Franzin et al2 also reported a low incidence of 4.9%. Although a wide range (2%-63%) of post-SRS hypopituitarism has been reported in the literature, most studies report rates of 30%-50% at approximately 3 yr following SRS.1-28 Therefore, our rate of new hormone deficiency appears to be consistent with the rates reported in the literature, despite the use of lower margin doses compared to the doses used by other radiosurgical series. No other complications were observed during the follow-up period of this current study, supporting the safety profile of low-dose GKRS in patients with acromegaly. Factors associated with improved biochemical remission rates remain controversial. Higher radiation doses, smaller tumor volumes, lower pre-SRS IGF-1, and GH levels, and absence of CS invasion have been reported to be predictors of remission following SRS.5,6,13,19,28 However, other studies have also reported that radiation dose, tumor volume, and tumor extension fail to reliably predict biochemical remission.8,13,19,28 Absence of CS invasion (P = .005), lower pre-GKRS IGF-1 (P = .026), and GH (P = .036) levels, not on medical therapy during GKRS (P = .045), and mammosomatotroph adenoma found on surgical pathology (P = .008) were found to be significant predictors of biochemical remission in this study. However, in subsequent multivariate analysis, only absence of CS invasion (P = .042) and lower pre-GKRS IGF-1 levels (P = .019) remained significant predictors of remission. Significantly, earlier biochemical remission was achieved in patients without CS invasion and those with age- and gender-adjusted pre-GKRS IGF-1 levels ≤2 times the normal limit (Figure 1). In addition, CS invasion was also found to be a predictor of new hormone deficiencies following GKRS (P = .027). Previous studies have described the recurrence of acromegaly following resection or RT.1,2,15,19,29 Thus, it should not be surprising to observe recurrence after low-dose radiosurgery. Nonetheless, the latency of such recurrences makes it likely that the true long-term rate of recurrence has been underestimated. In this study, we observed recurrence after initial SRS induced remission in 2.6% of cases. Three of the patients underwent a second GKRS due to poor control over hormone levels, and two of these patients presented rapid hormone remission after the second GKRS (at 24 and 26 mo). We believe that repeated GKRS may compensate for the low doses used in our approach, such that rapid control over hormone levels could be expected. It also appears that patients who undergo 2 GKRS with lower doses may have decreased risk of hypopituitarism. Thus, it appears that repeated GKRS can help to control hormone levels. However, the timing and indications (recurrence or failure to achieve remission) for repeat SRS treatment remain unclear. We acknowledge that the remission rates achieved with low-dose GKRS may be at the lower end of the spectrum of remission rates reported in the literature. Therefore, low-dose GKRS may be considered as salvage therapy in patients with residual tumor in close proximity to optic apparatus after transsphenoidal surgery or in patients who have similar tumors but unable to undergo surgery due to medical comorbidities or patient preference. Therefore, we would not recommend this as first-line therapy given the lower hormone remission rates. For those patients who do not achieve remission patients, long-term anti-hormonal medications and repeat GKRS may be treatment options. However, efficacy and safety of repeat GKRS in these setting are unknown and future studies are necessary. Study Limitations This retrospective study has a number of limitations that should be noted. The patients included in this study were treated over a period of time from the 1990s to the 2010s; during this period, improvements in laboratory tests may affect the sensitivities and specificities of hormone detection. In addition, advancements in imaging sequences and magnet field strengths during this period have also improved tumor detection rates. It is also important to note that the study may suffer from selection bias, as these patients who were treated with low margin dose represent only a subset of patients with acromegaly who underwent GKRS. We also acknowledge that the inclusion of patients who had prior RT may introduce addition bias to the analysis. However, time intervals between RT and GKRS were at least 5 yr for all these patients, and the effects of RT were no longer apparent at the time of GKRS. Hence, these were considered RT treatment failures. The small number of patients with recurrences precluded further analysis of this cohort, and similarly, the small cohort of patients who underwent repeat GKRS precluded subgroup analysis. We also acknowledge that we are left with a small cohort with longer follow-ups which coincide with the expected times of hormonal normalization, and the power to detect dose response may be limited by our small sample size. In addition, the follow-up periods in our study range widely, and thus it is important to note that delayed complications may not have been captured in patients with short follow-up periods. Future studies with larger cohorts and longer follow-ups may help elucidate the efficacy and safety of repeat SRS for acromegaly. CONCLUSION GKRS (Elekta AB) is an effective treatment for patients with persistent acromegaly despite after surgical resection. Despite the high biochemical remission and low hypopituitarism rates, high radiation doses to the sellar region pose unknown and unnecessary risks to optic apparatus. Low-dose GKRS represents an alternative treatment option in reducing the exposure of critical neurovascular structures in close proximity to the sella turcica to radiation. Lose-dose GKRS may offer comparable remission and new hormone deficiency rates compared to standard GKRS margin doses. However, the latency to remission for low-dose GKRS appears to be longer. Additional studies directly comparing low- and standard-dose GKRS are necessary to clarify differences in efficacy and safety between the two treatments. In addition, further studies are required to further elucidate the latent effects of low-dose GKRS treatments and recurrences after initial remission. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Lee CC , Vance ML , Xu Z et al. . Stereotactic radiosurgery for acromegaly . J Clin Endocrinol Metab . 2014 ; 99 ( 4 ): 1273 – 1281 . Google Scholar Crossref Search ADS PubMed 2. Franzin A , Spatola G , Losa M , Picozzi P , Mortini P . Results of gamma knife radiosurgery in acromegaly . Int J Endocrinol . 2012 ; 342034 . 3. Sheehan JP , Pouratian N , Steiner L , Laws ER , Vance ML . Gamma Knife surgery for pituitary adenomas: factors related to radiological and endocrine outcomes . J Neurosurg . 2011 ; 114 ( 2 ): 303 – 309 . Google Scholar Crossref Search ADS PubMed 4. Loeffler JS , Shih HA . Radiation therapy in the management of pituitary adenomas . 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Transsphenoidal surgery and adjuvant gamma knife treatment for growth hormone-secreting pituitary adenoma . J Neurosurg . 2001 ; 95 ( 2 ): 285 – 291 . Google Scholar Crossref Search ADS PubMed 25. Zhang N , Pan L , Wang EM , Dai JZ , Wang BJ , Cai PW . Radiosurgery for growth hormone-producing pituitary adenomas . J Neurosurg . 2000 ; 93 ( Suppl 3 ): 6 – 9 . Google Scholar Crossref Search ADS PubMed 26. Landolt AM , Haller D , Lomax N et al. . Octreotide may act as a radioprotective agent in acromegaly . J Clin Endocrinol Metab . 2000 ; 85 ( 3 ): 1287 – 1289 . Google Scholar Crossref Search ADS PubMed 27. Landolt AM , Haller D , Lomax N et al. . Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy . J Neurosurg . 1998 ; 88 ( 6 ): 1002 – 1008 . Google Scholar Crossref Search ADS PubMed 28. Motti ED , Losa M , Pieralli S et al. . Stereotactic radiosurgery of pituitary adenomas . Metabolism . 1996 ; 45 ( 8 Suppl 1 ): 111 – 114 . Google Scholar Crossref Search ADS PubMed 29. Voges J , Kocher M , Runge M et al. . Linear accelerator radiosurgery for pituitary macroadenomas . Cancer . 2006 ; 107 ( 6 ): 1355 – 1364 . Google Scholar Crossref Search ADS PubMed 30. Hiniker SM , Modlin LA , Choi CY et al. . Dose-response modeling of the visual pathway tolerance to single-fraction and hypofractionated stereotactic radiosurgery . Semin Radiat Oncol . 2016 ; 26 ( 2 ): 97 – 104 . Google Scholar Crossref Search ADS PubMed 31. Pollock BE , Link MJ , Leavitt JA , Stafford SL . Dose-volume analysis of radiation-induced optic neuropathy after single-fraction stereotactic radiosurgery . Neurosurgery . 2014 ; 75 ( 4 ): 456 – 460 ; discussion 460 . Google Scholar Crossref Search ADS PubMed 32. Lee CC , Chen CJ , Yen CP et al. . Whole-sellar stereotactic radiosurgery for functioning pituitary adenomas . Neurosurgery . 2014 ; 75 ( 3 ): 227 – 237 ; discussion 237 . Google Scholar Crossref Search ADS PubMed 33. Leavitt JA , Stafford SL , Link MJ , Pollock BE . Long-term evaluation of radiation-induced optic neuropathy after single-fraction stereotactic radiosurgery . Int J Radiat Oncol Biol Phys . 2013 ; 87 ( 3 ): 524 – 527 . Google Scholar Crossref Search ADS PubMed 34. Mayo C , Martel MK , Marks LB , Flickinger J , Nam J , Kirkpatrick J . Radiation dose-volume effects of optic nerves and chiasm . Int J Radiat Oncol Biol Phys . 2010 ; 76 ( 3 Suppl ): S28 – S35 . Google Scholar Crossref Search ADS PubMed 35. Hasegawa T , Kobayashi T , Kida Y . Tolerance of the optic apparatus in single-fraction irradiation using stereotactic radiosurgery: evaluation in 100 patients with craniopharyngioma . Neurosurgery . 2010 ; 66 ( 4 ): 688 – 695 ; discussion 694-685 . Google Scholar Crossref Search ADS PubMed 36. Stafford SL , Pollock BE , Leavitt JA et al. . A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery . Int J Radiat Oncol Biol Phys . 2003 ; 55 ( 5 ): 1177 – 1181 . Google Scholar Crossref Search ADS PubMed 37. Leber KA , Bergloff J , Pendl G . Dose—response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery . J Neurosurg . 1998 ; 88 ( 1 ): 43 – 50 . Google Scholar Crossref Search ADS PubMed 38. Tishler RB , Loeffler JS , Lunsford LD et al. . Tolerance of cranial nerves of the cavernous sinus to radiosurgery . Int J Radiat Oncol Biol Phys . 1993 ; 27 ( 2 ): 215 – 221 . Google Scholar Crossref Search ADS PubMed COMMENT This manuscript is a retrospective study from a single institution in the treatment of acromegaly using Gamma Knife (Elekta AB) with <25 Gy margin dose. The aim of this study was to evaluate the effectiveness of low-dose SRS on acromegaly patients and to elucidate adverse radiation effects for optic apparatus and hypothalamus. Six patients underwent prior fractionated radiation therapy. The inclusion of patients who had prior RT may introduce a bias, The median imaging and endocrine follow-up was 65.8 months and 72.8 months, respectively. Overall tumor control rate was 98.7%. Biochemical remission rates were 20.3% at 4 years, 49.9% at 8 years, and 76.3% at 8 years. Absence of cavernous sinus invasion and lower baseline IGF-1 were significant predictor of remission. Authors had shown low-dose SRS took longer biochemical remission periods despite of reasonable biochemical remission rates. Thus, the results of this study suggest that low-dose SRS may offer comparable biochemical remission and new hormone deficiency rates compared to standard radiosurgery dose. Future studies to compare directly low- and standard-dose SRS may clarify differences in efficacy and safety between both method. Hideyuki Kano Pittsburgh, Pennsylvania Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Low-Dose Gamma Knife Radiosurgery for Acromegaly

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Abstract

Abstract Background Remission rate is associated with higher dose of Gamma Knife Radiosurgery (GKRS; Gamma Knife: Elekta AB, Stockholm, Sweden) for acromegaly, but the dose ≥25 Gy is not always feasible when the functioning adenoma is close to optic apparatus Objective To evaluate the efficacy and safety of low-dose (<25 Gy) GKRS in the treatment of patients with acromegaly. Methods Single-center retrospective review of acromegaly cases treated with GKRS between June 1994 and December 2016. A total of 76 patients with the diagnosis of acromegaly who were treated with low-dose GKRS were selected for inclusion. Patients were treated with a median margin dose, isodose line, and treatment volume of 15.8 Gy, 57.5%, and 4.8 mL, respectively. Any identifiable portion of the optic apparatus was limited to a radiation dose of 10 Gy. All patients underwent full endocrine, ophthalmological, and imaging evaluation prior to and after GKRS treatments, and results of these were analyzed. Results Biochemical remission was achieved in 33 (43.4%) patients. Actuarial remission rates were 20.3%, 49.9%, and 76.3% at 4, 8, and 12 yr, respectively. Absence of cavernous sinus invasion (P = .042) and lower baseline insulin-like growth factor-1 levels (P = .019) were significant predictors of remission. New hormone deficiencies were found in 9 (11.8%) patients. Actuarial hormone deficiency rates were 3%, 14%, and 22.2% at 4, 8, and 10 yr, respectively. Two (2.6%) patients who achieved initial remission experienced recurrence. No optic complications were encountered. CONCLUSION Reasonable remission and new hormone deficiency rates can be achieved with low-dose GKRS for acromegaly. These rates may be comparable to those with standard GKRS margin doses. Acromegaly, Gamma-knife, Low dose, Stereotactic radiosurgery ABBREVIATIONS ABBREVIATIONS ACTH adrenocorticotropic hormone CI confidence interval CS cavernous sinus GH growth hormone GKRS Gamma Knife Radiosurgery Gy Gray HR Hazard ratio IGF insulin-like growth factor OGTT oral glucose tolerance test RT radiation therapy SRS stereotactic radiosurgery TSH thyroxin-stimulating hormone Despite the extensive literature on the radiosurgical outcomes for acromegaly, conclusions drawn from analyses of these series have been limited by the heterogeneity in patient selection, radiosurgical techniques, follow-up lengths, and biochemical remission criteria.1-29 The biochemical remission rates vary widely, ranging from 17% to 65% at 3 to 4 yr following stereotactic radiosurgery (SRS). The reported positive predictors of remission include high radiation dose, small tumor volume, and low initial serum growth hormone (GH) and insulin-like growth factor (IGF)-1 levels.3,13,19,25,28 Despite the high remission rates associated with increased radiation doses, risk of hormone deficit and neurovascular injury may limit the generalizability of such practice. Hence, the minimum effective radiation dose for hormone remission remains controversial. In this study, we investigated the endocrine outcomes, efficacy, and safety of patients with acromegaly who underwent Gamma Knife Radiosurgery (GKRS; Gamma Knife: Elekta AB, Stockholm, Sweden) using low margin doses of <25 Gy. METHODS Patient Population This was a single-center retrospective review of acromegaly cases treated with GKRS (Elekta AB) between June 1994 and December 2016. The study was approved by the Institutional Review Board of our hospital. Due to retrospective study design and expedited review, there was no patient consent. Inclusion criteria included the following: age >18 yr, diagnosis of acromegaly, and treatment using low-dose GKRS with margin dose of <25 Gy. Patients who underwent prior surgical resections were not excluded. Those who were treated with margin doses ≥25 Gy were excluded. Radiosurgical Technique The GKRS procedure has been previously described in detail.3,12,15,20 Briefly, all patients underwent stereotactic frame placement under local anesthesia in the operating room prior to magnetic resonance imaging (MRI) for treatment planning. Treatments were performed using Leksell Gamma Knife Unit (Elekta AB). Treatment parameters and dose plans were dictated by patient's neurological and ophthalmological examination results, tumor location and size, distance between tumor and optic apparatus, and previous treatments (i.e., radiation). The median margin dose, isodose line, and treatment volume were 15.8 Gy (range: 11.9-22), 57.5% (range: 50-80), and 4.8 mL (range: 0.8-58.1). Any identifiable portion of the optic apparatus was limited to a radiation dose of 10 Gy. The radiosurgical treatment parameters can be found in Table 1. TABLE 1. Characteristics in 76 Patients With Acromegaly Treated With SRS Characteristics Value Interquartile range Percentage Median age (yr) 42 33.5-51.7 Sex (F:M) 42:34 Median tumor volume (mL) 2.75 1.4-5.6 No. of patients with CS extension 39 51.3% No. of patients with suprasellar extension 10 13.2% No. of prior TSS 70 92.1%  0 6  1 60  2 9  3 1 No. of prior craniotomy 4 5.3% No. of prior RT 6 7.9% Median Pre-SRS IGF-1 level (ng/mL) 891 629-1038 Median Pre-SRS GH level (ng/mL) 11.05 5.02-25.09 Median Pre-SRS PRL level (ng/mL) 11 6.4-20.9 Pretreatment hormone deficiency 14 18.4%  Hypothyroidism 5  Hypogonadism 8  Hypoadrenalism 3 Median imaging FU (mo) 65.8 38.0-105.9 Median endocrine FU (mo) 72.8 39.7-115.9 SRS treatment parameters  Median margin radiation dose (Gy) 15.8 12.5-18.0  Median maximal radiation dose (Gy) 26.7 22.7-30.0  Median isodose level (%) 57.5 55.0-60.8  Median maximal optic chiasm radiation dose (Gy) 6.4 4.3-9.0  Median treatment volume (mL) 4.8 2.8-7.4 No. of Pre-SRS visual deficits 18 23.7% No. of Pre-SRS medical therapy 3 3.9% No. of Pre-SRS surgical pathology 39 51.3%  Plurihormonal adenoma 15  Mammosomatotroph adenoma 10  Somatotroph adenoma 9  Acidophillic adenoma 3  Gonadotroph adenoma 1  Chromophobe adenoma 1  Median GH stain (+-++++) 4 3.5-4  Median PRL stain (+-++++) 1.5 1-2 No. of repeat GK after initial 3 3.9% Characteristics Value Interquartile range Percentage Median age (yr) 42 33.5-51.7 Sex (F:M) 42:34 Median tumor volume (mL) 2.75 1.4-5.6 No. of patients with CS extension 39 51.3% No. of patients with suprasellar extension 10 13.2% No. of prior TSS 70 92.1%  0 6  1 60  2 9  3 1 No. of prior craniotomy 4 5.3% No. of prior RT 6 7.9% Median Pre-SRS IGF-1 level (ng/mL) 891 629-1038 Median Pre-SRS GH level (ng/mL) 11.05 5.02-25.09 Median Pre-SRS PRL level (ng/mL) 11 6.4-20.9 Pretreatment hormone deficiency 14 18.4%  Hypothyroidism 5  Hypogonadism 8  Hypoadrenalism 3 Median imaging FU (mo) 65.8 38.0-105.9 Median endocrine FU (mo) 72.8 39.7-115.9 SRS treatment parameters  Median margin radiation dose (Gy) 15.8 12.5-18.0  Median maximal radiation dose (Gy) 26.7 22.7-30.0  Median isodose level (%) 57.5 55.0-60.8  Median maximal optic chiasm radiation dose (Gy) 6.4 4.3-9.0  Median treatment volume (mL) 4.8 2.8-7.4 No. of Pre-SRS visual deficits 18 23.7% No. of Pre-SRS medical therapy 3 3.9% No. of Pre-SRS surgical pathology 39 51.3%  Plurihormonal adenoma 15  Mammosomatotroph adenoma 10  Somatotroph adenoma 9  Acidophillic adenoma 3  Gonadotroph adenoma 1  Chromophobe adenoma 1  Median GH stain (+-++++) 4 3.5-4  Median PRL stain (+-++++) 1.5 1-2 No. of repeat GK after initial 3 3.9% CS: cavernous sinus, F: female, FU: follow-up; SRS: stereotactic radiosurgery, M: male, RT: radiotherapy, TSS: transsphenoidal surgery, TV: tumor volume View Large TABLE 1. Characteristics in 76 Patients With Acromegaly Treated With SRS Characteristics Value Interquartile range Percentage Median age (yr) 42 33.5-51.7 Sex (F:M) 42:34 Median tumor volume (mL) 2.75 1.4-5.6 No. of patients with CS extension 39 51.3% No. of patients with suprasellar extension 10 13.2% No. of prior TSS 70 92.1%  0 6  1 60  2 9  3 1 No. of prior craniotomy 4 5.3% No. of prior RT 6 7.9% Median Pre-SRS IGF-1 level (ng/mL) 891 629-1038 Median Pre-SRS GH level (ng/mL) 11.05 5.02-25.09 Median Pre-SRS PRL level (ng/mL) 11 6.4-20.9 Pretreatment hormone deficiency 14 18.4%  Hypothyroidism 5  Hypogonadism 8  Hypoadrenalism 3 Median imaging FU (mo) 65.8 38.0-105.9 Median endocrine FU (mo) 72.8 39.7-115.9 SRS treatment parameters  Median margin radiation dose (Gy) 15.8 12.5-18.0  Median maximal radiation dose (Gy) 26.7 22.7-30.0  Median isodose level (%) 57.5 55.0-60.8  Median maximal optic chiasm radiation dose (Gy) 6.4 4.3-9.0  Median treatment volume (mL) 4.8 2.8-7.4 No. of Pre-SRS visual deficits 18 23.7% No. of Pre-SRS medical therapy 3 3.9% No. of Pre-SRS surgical pathology 39 51.3%  Plurihormonal adenoma 15  Mammosomatotroph adenoma 10  Somatotroph adenoma 9  Acidophillic adenoma 3  Gonadotroph adenoma 1  Chromophobe adenoma 1  Median GH stain (+-++++) 4 3.5-4  Median PRL stain (+-++++) 1.5 1-2 No. of repeat GK after initial 3 3.9% Characteristics Value Interquartile range Percentage Median age (yr) 42 33.5-51.7 Sex (F:M) 42:34 Median tumor volume (mL) 2.75 1.4-5.6 No. of patients with CS extension 39 51.3% No. of patients with suprasellar extension 10 13.2% No. of prior TSS 70 92.1%  0 6  1 60  2 9  3 1 No. of prior craniotomy 4 5.3% No. of prior RT 6 7.9% Median Pre-SRS IGF-1 level (ng/mL) 891 629-1038 Median Pre-SRS GH level (ng/mL) 11.05 5.02-25.09 Median Pre-SRS PRL level (ng/mL) 11 6.4-20.9 Pretreatment hormone deficiency 14 18.4%  Hypothyroidism 5  Hypogonadism 8  Hypoadrenalism 3 Median imaging FU (mo) 65.8 38.0-105.9 Median endocrine FU (mo) 72.8 39.7-115.9 SRS treatment parameters  Median margin radiation dose (Gy) 15.8 12.5-18.0  Median maximal radiation dose (Gy) 26.7 22.7-30.0  Median isodose level (%) 57.5 55.0-60.8  Median maximal optic chiasm radiation dose (Gy) 6.4 4.3-9.0  Median treatment volume (mL) 4.8 2.8-7.4 No. of Pre-SRS visual deficits 18 23.7% No. of Pre-SRS medical therapy 3 3.9% No. of Pre-SRS surgical pathology 39 51.3%  Plurihormonal adenoma 15  Mammosomatotroph adenoma 10  Somatotroph adenoma 9  Acidophillic adenoma 3  Gonadotroph adenoma 1  Chromophobe adenoma 1  Median GH stain (+-++++) 4 3.5-4  Median PRL stain (+-++++) 1.5 1-2 No. of repeat GK after initial 3 3.9% CS: cavernous sinus, F: female, FU: follow-up; SRS: stereotactic radiosurgery, M: male, RT: radiotherapy, TSS: transsphenoidal surgery, TV: tumor volume View Large Clinical, Hormone, and Imaging Evaluations The diagnosis of acromegaly was based on a combination of MRI findings, clinical features, and biochemical assessment according to the recent endocrine guidelines.5 Patients who had prior surgical resection, the endocrine evaluations and MRIs were performed at 3 mo following surgery. Endocrine evaluations included GH, IGF-1, adrenocorticotropic hormone (ACTH), serum cortisol, prolactin, total and free T4, thyroxin-stimulating hormone (TSH), luteinizing hormone, follicle-stimulating hormone, and testosterone (in males) levels. Oral glucose tolerance test (OGTT) was performed for those with inconclusive GH and IGF-1 results. Ophthalmological evaluations included visual acuity and field testing. Imaging studies obtained included contrasted MRIs with thin slices and volumetric sequences through the region of the sella turcica. Medications to lower GH and/or IGF-1 and SRS were recommended for individuals with persistent hormone instability following SRS. We did not prescribe anti-GH medications prior to SRS; therefore, we were not concerned with the radioresistant effects of anti-GH medications.23,26 A total of 9 patients (11.8%) who underwent GKRS began medical therapy 2 to 6 wk following radiosurgery. Clinical, endocrine, and imaging evaluations were performed at 6-mo intervals for the first 2 yr following GKRS. Remission was defined as normal age-matched and gender-matched serum IGF-1 levels, GH <1 ng/mL after OGTT, or random GH <1 ng/mL. New pituitary hormone deficiencies were defined as the following: thyrotropin deficiency, defined as low free T4 level with normal or diminished TSH; ACTH deficiency, defined as low serum cortisol level with a concomitant low ACTH level; gonadotropin deficiency, defined as low plasma testosterone with low or normal gonadotropin levels in men, amenorrhea with low plasma estradiol and low or normal gonadotropin levels in premenopausal women, or low or normal gonadotropin levels in postmenopausal women; and somatotropin deficiency, defined as subnormal GH response in an insulin tolerance test (peak GH < 5 ng/mL). Tumor control was defined as stable or decreased adenoma volume on MRI. Tumor progression was defined as >10% increase in adenoma volume, while tumor regression was defined as >10% decrease in adenoma volume found on MRI.17 Statistics Statistical analyses were performed using SPSS version 22 (IBM Corp., Armonk, New York). Descriptive statistics were performed for all available data. Univariate and multivariate analyses were performed using the Cox proportional hazards model to evaluate for predictors of biochemical remission and new hormone deficiencies. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Time-dependent analyses for biochemical remission and development of new hormone deficiencies were performed using Kaplan–Meier and actuarial methods, and differences between function curves were analyzed using the Log-rank test. Statistical significance was defined as P < .05, and all tests were two-tailed. RESULTS Baseline Demographics A total of 601 patients with pituitary adenomas were treated with GKRS (Elekta AB) at our institution, and 96 patients had diagnoses of acromegaly. Among these, 76 patients were treated with GKRS using low margin doses of <25 Gy, and were selected for inclusion. Indications for GKRS included failure to achieve hormone remission or visible residual or recurrent adenomas following surgical resection, and patient preference. Table 1 describes the baseline characteristic of the patients who underwent low-dose GKRS for acromegaly. Median age was 42 yr (range: 16-76), and females were comprised of 55.3% of the patient cohort. The median pre-GKRS adenoma volume was 2.8 mL (range: 0.1-49.5 mL). Adenomas with cavernous sinus (CS) and suprasellar extensions on MRI were 51.3% and 13.2% of the patients. Prior surgical resections, via transsphenoidal approach and craniotomy, were performed in 92.1% and 5.3% of the patients. In addition, 7.9% of the patients had undergone prior fractionated radiation therapy (RT). Primary SRS was performed in 6 patients comprising 3 patients with age >60 yr old with multiple medical comorbidities and three patients who refused surgical resection due to personal preferences. The median IGF-1, GH, and prolactin levels before GKRS treatments were 891 ng/mL (range: 205-1463), 11.05 ng/mL (range: 1.13-117), and 11 ng/mL (range: 1-334). Pre-GKRS hormone deficiencies were found in 18.4%. Visual deficits prior to GKRS were 23.7%, and 3.9% of the patients underwent medical treatment prior to GKRS. Six (18.4%) patients were continued on medical therapy at the time of GKRS. Surgical pathology was available in 51.3% of the patients. Median imaging and endocrine follow-ups were 65.8 mo (range: 4.8-228.9) and 72.8 mo (range: 6.1-235). Imaging Outcomes The median imaging follow-up period after SRS was 65.8 mo (range: 4.8-228.9 mo). The follow-up durations were as follows: >2 yr (66 patients), >4 yr (50 patients), >6 yr (38 patients), and >8 yr (25 patients). A total of 58 patients (76.3%) presented a decrease in tumor volume in their last available MRI study; 17 patients (22.4%) presented no change in tumor size; and 1 patient (1.3%) experienced tumor enlargement. Thus, the overall tumor control rate was 98.7%. Actuarial tumor control rates were 100%, 93.8%, 93.8%, and 93.8% at 6, 8, 10, and 12 yr following GKRS. Figure 1 presents typical post-SRS tumor volumes and endocrine changes in acromegaly patients. FIGURE 1. View largeDownload slide A, Kaplan–Meier analysis for endocrine remission after SRS. The actuarial remission rates at 2, 4, 6, 8, 10, and 12 yr postradiosurgery were 8.4%, 20.3%, 39.9%, 49.9%, 67.5%, and 82.6%, respectively. B, With cavernous sinus invasion, C, a preradiosurgical IGF-1 level was significantly related the rate of endocrine remission. D, Analysis using 18 Gy as the cutoff, which demonstrated no difference in remission rate with Cox regression (HR = 1.971 [0.967-4.018], P = .062). E, The incidence of hypopituitarism after SRS for acromegaly. The actuarial incidence rates at 4, 6, 8, 10, and 12 yr postradiosurgery were 3%, 7.7%, 14.0%, 22.2%, and 28.2%, respectively. F, The distribution of specific hormone deficits after SRS. The highest incidence of hormone deficits occurred 9 to 10 yr after SRS. FIGURE 1. View largeDownload slide A, Kaplan–Meier analysis for endocrine remission after SRS. The actuarial remission rates at 2, 4, 6, 8, 10, and 12 yr postradiosurgery were 8.4%, 20.3%, 39.9%, 49.9%, 67.5%, and 82.6%, respectively. B, With cavernous sinus invasion, C, a preradiosurgical IGF-1 level was significantly related the rate of endocrine remission. D, Analysis using 18 Gy as the cutoff, which demonstrated no difference in remission rate with Cox regression (HR = 1.971 [0.967-4.018], P = .062). E, The incidence of hypopituitarism after SRS for acromegaly. The actuarial incidence rates at 4, 6, 8, 10, and 12 yr postradiosurgery were 3%, 7.7%, 14.0%, 22.2%, and 28.2%, respectively. F, The distribution of specific hormone deficits after SRS. The highest incidence of hormone deficits occurred 9 to 10 yr after SRS. Biochemical Remission Biochemical remission was achieved in 33 (43.4%) patients at the last follow-up. Remission by specific criteria can be found in Table 2. Of the 6 patients who did not undergo prior surgical resection, only 1 (16.7%) patient achieved biochemical remission at final follow-up. Actuarial biochemical remission rates were 8.4%, 20.3%, 39.9%, 49.9%, 67.5%, and 76.3% at 2, 4, 6, 8, 10, and 12 yr following GKRS (Figure 1A). Absence of CS invasion (HR 0.339 [0.160-0.716], P = .005), lower pre-GKRS IGF-1 levels (HR 0.998 [0.996-1.000], P = .026), lower pre-GKRS GH levels (HR 0.971 [0.945-0.998], P = .036), no medical therapy at the time of GKRS treatments (HR 4.595 [1.037-20.359], P = .045), and mammosomatotroph adenoma found on surgical pathology (HR 4.054 [1.447-11.356], P = .008) were found to be predictors of biochemical remission in univariate analysis (Table 3). However, only absence of CS invasion (HR 0.345 [0.124-0.946], P = .042) and lower pre-GKRS IGF-1 (HR 0.998 [0.996-1.000], P = .019) remained statistically significant in multivariate analysis. Biochemical remission was achieved significantly earlier (P = .005) in patients without CS invasion compared to those with CS invasion (Figure 1B). Similarly, patients with pre-GKRS IGF-1 levels ≤2 times the normal limit (age- and gender-adjusted) achieved earlier remission (P = .026) compared to those with pre-GKRS IGF-1 levels >2 times the normal limit (Figure 1C). In concerning, the results may be driven by the patients treated with 18 to 24 Gy margin dose as 20 Gy is certainly effective for pituitary adenoma. We analyze using 18 Gy as the cutoff, which demonstrated no difference in remission rate with Cox regression (HR = 1.971 [0.967-4.018], P = .062; Figure 1D). One example case is illustrated in Figure 2. FIGURE 2. View largeDownload slide SRS was performed for a 51-yr-old man with poor control of GH after surgical resection. The patient did not receive long-acting octreotide, endocrine remission was achieved 66 mo after SRS. However, he developed new hormone deficiencies, including GH deficiency at 66 mo. FIGURE 2. View largeDownload slide SRS was performed for a 51-yr-old man with poor control of GH after surgical resection. The patient did not receive long-acting octreotide, endocrine remission was achieved 66 mo after SRS. However, he developed new hormone deficiencies, including GH deficiency at 66 mo. TABLE 2. Hormone Outcomes in 76 Patients Remission criteria Patients Remission (n) Median time to remission (mo) OGTT GH < 1 μg/dL 3 116 (61.6-175.3) OGTT GH < 1 μg/dL 1 15.1 IGF-1 normalization and random GH < 1 μg/dL 18 62.6 (1.4-216.1) IGF-1 normalization 2 20.8 (15.6-25.9) Random GH < 1 μg/dL 9 57.4 (11.8-141.6) Total remission 76 33 (43.4%) Recurrence after initial remission Case no. TV (mL) Dose margin/max (Gy) Time to remission post-SRS (mo) Time to recurrence postremission (mo) Subsequent treatment 1 3.4 12.0/20.69 89.7 13.1 Medication (Octreotide) 2 2 20/28.57 11.8 38.3 Medication (Octreotide) Repeat GKRS Case no. Initial/repeat TV (mL) Dose Margin/max (Gy) Time to repeat GK postinitial GKRS (mo) Hormone outcome after repeat GK (mo) Reason for repeat GK Initial Repeat 1 26.7/7.8 12.0/21.8 12.0/21.8 91.2 Remission Poor hormone control 2 4.4/1.8 17.0/28.8 18.0/30.0 42 Remission Poor hormone control 3 5.7/4.8 12.0/20.1 12.0/21.8 98.4 No remission currently Poor hormone control and tumor enlarge Remission criteria Patients Remission (n) Median time to remission (mo) OGTT GH < 1 μg/dL 3 116 (61.6-175.3) OGTT GH < 1 μg/dL 1 15.1 IGF-1 normalization and random GH < 1 μg/dL 18 62.6 (1.4-216.1) IGF-1 normalization 2 20.8 (15.6-25.9) Random GH < 1 μg/dL 9 57.4 (11.8-141.6) Total remission 76 33 (43.4%) Recurrence after initial remission Case no. TV (mL) Dose margin/max (Gy) Time to remission post-SRS (mo) Time to recurrence postremission (mo) Subsequent treatment 1 3.4 12.0/20.69 89.7 13.1 Medication (Octreotide) 2 2 20/28.57 11.8 38.3 Medication (Octreotide) Repeat GKRS Case no. Initial/repeat TV (mL) Dose Margin/max (Gy) Time to repeat GK postinitial GKRS (mo) Hormone outcome after repeat GK (mo) Reason for repeat GK Initial Repeat 1 26.7/7.8 12.0/21.8 12.0/21.8 91.2 Remission Poor hormone control 2 4.4/1.8 17.0/28.8 18.0/30.0 42 Remission Poor hormone control 3 5.7/4.8 12.0/20.1 12.0/21.8 98.4 No remission currently Poor hormone control and tumor enlarge FU: follow-up; GKRS, Gamma Knife Radiosurgery; OGTT: oral glucose tolerance test, SRS: stereotactic radiosurgery, mo: months View Large TABLE 2. Hormone Outcomes in 76 Patients Remission criteria Patients Remission (n) Median time to remission (mo) OGTT GH < 1 μg/dL 3 116 (61.6-175.3) OGTT GH < 1 μg/dL 1 15.1 IGF-1 normalization and random GH < 1 μg/dL 18 62.6 (1.4-216.1) IGF-1 normalization 2 20.8 (15.6-25.9) Random GH < 1 μg/dL 9 57.4 (11.8-141.6) Total remission 76 33 (43.4%) Recurrence after initial remission Case no. TV (mL) Dose margin/max (Gy) Time to remission post-SRS (mo) Time to recurrence postremission (mo) Subsequent treatment 1 3.4 12.0/20.69 89.7 13.1 Medication (Octreotide) 2 2 20/28.57 11.8 38.3 Medication (Octreotide) Repeat GKRS Case no. Initial/repeat TV (mL) Dose Margin/max (Gy) Time to repeat GK postinitial GKRS (mo) Hormone outcome after repeat GK (mo) Reason for repeat GK Initial Repeat 1 26.7/7.8 12.0/21.8 12.0/21.8 91.2 Remission Poor hormone control 2 4.4/1.8 17.0/28.8 18.0/30.0 42 Remission Poor hormone control 3 5.7/4.8 12.0/20.1 12.0/21.8 98.4 No remission currently Poor hormone control and tumor enlarge Remission criteria Patients Remission (n) Median time to remission (mo) OGTT GH < 1 μg/dL 3 116 (61.6-175.3) OGTT GH < 1 μg/dL 1 15.1 IGF-1 normalization and random GH < 1 μg/dL 18 62.6 (1.4-216.1) IGF-1 normalization 2 20.8 (15.6-25.9) Random GH < 1 μg/dL 9 57.4 (11.8-141.6) Total remission 76 33 (43.4%) Recurrence after initial remission Case no. TV (mL) Dose margin/max (Gy) Time to remission post-SRS (mo) Time to recurrence postremission (mo) Subsequent treatment 1 3.4 12.0/20.69 89.7 13.1 Medication (Octreotide) 2 2 20/28.57 11.8 38.3 Medication (Octreotide) Repeat GKRS Case no. Initial/repeat TV (mL) Dose Margin/max (Gy) Time to repeat GK postinitial GKRS (mo) Hormone outcome after repeat GK (mo) Reason for repeat GK Initial Repeat 1 26.7/7.8 12.0/21.8 12.0/21.8 91.2 Remission Poor hormone control 2 4.4/1.8 17.0/28.8 18.0/30.0 42 Remission Poor hormone control 3 5.7/4.8 12.0/20.1 12.0/21.8 98.4 No remission currently Poor hormone control and tumor enlarge FU: follow-up; GKRS, Gamma Knife Radiosurgery; OGTT: oral glucose tolerance test, SRS: stereotactic radiosurgery, mo: months View Large TABLE 3. Prognostic Factors for Endocrine Remission Remission Nonremission (n = 33) (n = 43) Cox univariate Cox multivariate P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Age (yr) 39.8 ± 11.9 44.5 ± 14.1 .931 0.999 (0.974-1.025) Gender (female %) 19 (57.6%) 23 (53.5%) .847 0.933 (0.462-1.886) Margin dose (Gy) 15.9 ± 3.3 15.4 ± 2.6 .068 1.124 (0.991-1.274) .184 1.113 (0.950-1.305) Maximal dose (Gy) 26.7 ± 4.2 26.6 ± 3.9 .716 1.015 (0.938-1.098) Tumor volume (mL) 3.9 ± 3.7 5.3 ± 8.3 .349 0.961 (0.885-1.044) Tumor extension  CS invasion (n) 15(45.5%) 24(55.8%) .005 0.339 (0.160-0.716) .042 0.345 (0.124-0.946)  Suprasellar expansion (n) 4(12.1%) 5(14%) .673 1.255 (0.438-3.595) Pre-SRS radiotherapy (n) 2(6.1%) 4(9.8%) .980 1.019 (0.240-4.316) Initial IGF-1 (ng/mL) 818.7 ± 313.7 902.2 ± 315.5 .026 0.998 (0.996-1.000) .019 0.998 (0.996-1.000) Initial GH (ng/mL) 15.8 ± 21.7 21.7 ± 22.0 .036 0.971 (0.945-0.998) .991 1.000 (0.973-1.029) Initial PRL (ng/mL) 12.2 ± 9.5 34.8 ± 70.7 .250 0.971 (0.923-1.021) Medication during SRS 2(6.1%) 4(9.3%) .045 4.595 (1.037-20.359) .214 2.722 (0.561-13.197) Pre-SRS Surgical pathology  Plurihormonal adenoma (n) 5(15.2%) 10(23.3%) .280 1.741 (0.637-4.756)  Mammosomatotroph adenoma (n) 5(15.2%) 5(11.6%) .008 4.054 (1.447-11.356) .269 1.892 (0.611-5.866)  Somatotroph adenoma (n) 5(15.2%) 4(9.3%) .579 0.758 (0.284-2.019)  Acidophillic adenoma (n) 0 3(7%) .424 0.045 (0.000-80.056)  GH stain (+) 3.5 ± 1 3.5 ± 1.23 .899 0.004 (0.000-2.886E + 34)  PRL stain (+) 1.7 ± 0.58 1.4 ± 0.55 .730 0.612 (0.038-9.931) Remission Nonremission (n = 33) (n = 43) Cox univariate Cox multivariate P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Age (yr) 39.8 ± 11.9 44.5 ± 14.1 .931 0.999 (0.974-1.025) Gender (female %) 19 (57.6%) 23 (53.5%) .847 0.933 (0.462-1.886) Margin dose (Gy) 15.9 ± 3.3 15.4 ± 2.6 .068 1.124 (0.991-1.274) .184 1.113 (0.950-1.305) Maximal dose (Gy) 26.7 ± 4.2 26.6 ± 3.9 .716 1.015 (0.938-1.098) Tumor volume (mL) 3.9 ± 3.7 5.3 ± 8.3 .349 0.961 (0.885-1.044) Tumor extension  CS invasion (n) 15(45.5%) 24(55.8%) .005 0.339 (0.160-0.716) .042 0.345 (0.124-0.946)  Suprasellar expansion (n) 4(12.1%) 5(14%) .673 1.255 (0.438-3.595) Pre-SRS radiotherapy (n) 2(6.1%) 4(9.8%) .980 1.019 (0.240-4.316) Initial IGF-1 (ng/mL) 818.7 ± 313.7 902.2 ± 315.5 .026 0.998 (0.996-1.000) .019 0.998 (0.996-1.000) Initial GH (ng/mL) 15.8 ± 21.7 21.7 ± 22.0 .036 0.971 (0.945-0.998) .991 1.000 (0.973-1.029) Initial PRL (ng/mL) 12.2 ± 9.5 34.8 ± 70.7 .250 0.971 (0.923-1.021) Medication during SRS 2(6.1%) 4(9.3%) .045 4.595 (1.037-20.359) .214 2.722 (0.561-13.197) Pre-SRS Surgical pathology  Plurihormonal adenoma (n) 5(15.2%) 10(23.3%) .280 1.741 (0.637-4.756)  Mammosomatotroph adenoma (n) 5(15.2%) 5(11.6%) .008 4.054 (1.447-11.356) .269 1.892 (0.611-5.866)  Somatotroph adenoma (n) 5(15.2%) 4(9.3%) .579 0.758 (0.284-2.019)  Acidophillic adenoma (n) 0 3(7%) .424 0.045 (0.000-80.056)  GH stain (+) 3.5 ± 1 3.5 ± 1.23 .899 0.004 (0.000-2.886E + 34)  PRL stain (+) 1.7 ± 0.58 1.4 ± 0.55 .730 0.612 (0.038-9.931) CS: cavernous sinus, Gy: gray, SRS: stereotactic radiosurgery. View Large TABLE 3. Prognostic Factors for Endocrine Remission Remission Nonremission (n = 33) (n = 43) Cox univariate Cox multivariate P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Age (yr) 39.8 ± 11.9 44.5 ± 14.1 .931 0.999 (0.974-1.025) Gender (female %) 19 (57.6%) 23 (53.5%) .847 0.933 (0.462-1.886) Margin dose (Gy) 15.9 ± 3.3 15.4 ± 2.6 .068 1.124 (0.991-1.274) .184 1.113 (0.950-1.305) Maximal dose (Gy) 26.7 ± 4.2 26.6 ± 3.9 .716 1.015 (0.938-1.098) Tumor volume (mL) 3.9 ± 3.7 5.3 ± 8.3 .349 0.961 (0.885-1.044) Tumor extension  CS invasion (n) 15(45.5%) 24(55.8%) .005 0.339 (0.160-0.716) .042 0.345 (0.124-0.946)  Suprasellar expansion (n) 4(12.1%) 5(14%) .673 1.255 (0.438-3.595) Pre-SRS radiotherapy (n) 2(6.1%) 4(9.8%) .980 1.019 (0.240-4.316) Initial IGF-1 (ng/mL) 818.7 ± 313.7 902.2 ± 315.5 .026 0.998 (0.996-1.000) .019 0.998 (0.996-1.000) Initial GH (ng/mL) 15.8 ± 21.7 21.7 ± 22.0 .036 0.971 (0.945-0.998) .991 1.000 (0.973-1.029) Initial PRL (ng/mL) 12.2 ± 9.5 34.8 ± 70.7 .250 0.971 (0.923-1.021) Medication during SRS 2(6.1%) 4(9.3%) .045 4.595 (1.037-20.359) .214 2.722 (0.561-13.197) Pre-SRS Surgical pathology  Plurihormonal adenoma (n) 5(15.2%) 10(23.3%) .280 1.741 (0.637-4.756)  Mammosomatotroph adenoma (n) 5(15.2%) 5(11.6%) .008 4.054 (1.447-11.356) .269 1.892 (0.611-5.866)  Somatotroph adenoma (n) 5(15.2%) 4(9.3%) .579 0.758 (0.284-2.019)  Acidophillic adenoma (n) 0 3(7%) .424 0.045 (0.000-80.056)  GH stain (+) 3.5 ± 1 3.5 ± 1.23 .899 0.004 (0.000-2.886E + 34)  PRL stain (+) 1.7 ± 0.58 1.4 ± 0.55 .730 0.612 (0.038-9.931) Remission Nonremission (n = 33) (n = 43) Cox univariate Cox multivariate P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Age (yr) 39.8 ± 11.9 44.5 ± 14.1 .931 0.999 (0.974-1.025) Gender (female %) 19 (57.6%) 23 (53.5%) .847 0.933 (0.462-1.886) Margin dose (Gy) 15.9 ± 3.3 15.4 ± 2.6 .068 1.124 (0.991-1.274) .184 1.113 (0.950-1.305) Maximal dose (Gy) 26.7 ± 4.2 26.6 ± 3.9 .716 1.015 (0.938-1.098) Tumor volume (mL) 3.9 ± 3.7 5.3 ± 8.3 .349 0.961 (0.885-1.044) Tumor extension  CS invasion (n) 15(45.5%) 24(55.8%) .005 0.339 (0.160-0.716) .042 0.345 (0.124-0.946)  Suprasellar expansion (n) 4(12.1%) 5(14%) .673 1.255 (0.438-3.595) Pre-SRS radiotherapy (n) 2(6.1%) 4(9.8%) .980 1.019 (0.240-4.316) Initial IGF-1 (ng/mL) 818.7 ± 313.7 902.2 ± 315.5 .026 0.998 (0.996-1.000) .019 0.998 (0.996-1.000) Initial GH (ng/mL) 15.8 ± 21.7 21.7 ± 22.0 .036 0.971 (0.945-0.998) .991 1.000 (0.973-1.029) Initial PRL (ng/mL) 12.2 ± 9.5 34.8 ± 70.7 .250 0.971 (0.923-1.021) Medication during SRS 2(6.1%) 4(9.3%) .045 4.595 (1.037-20.359) .214 2.722 (0.561-13.197) Pre-SRS Surgical pathology  Plurihormonal adenoma (n) 5(15.2%) 10(23.3%) .280 1.741 (0.637-4.756)  Mammosomatotroph adenoma (n) 5(15.2%) 5(11.6%) .008 4.054 (1.447-11.356) .269 1.892 (0.611-5.866)  Somatotroph adenoma (n) 5(15.2%) 4(9.3%) .579 0.758 (0.284-2.019)  Acidophillic adenoma (n) 0 3(7%) .424 0.045 (0.000-80.056)  GH stain (+) 3.5 ± 1 3.5 ± 1.23 .899 0.004 (0.000-2.886E + 34)  PRL stain (+) 1.7 ± 0.58 1.4 ± 0.55 .730 0.612 (0.038-9.931) CS: cavernous sinus, Gy: gray, SRS: stereotactic radiosurgery. View Large Recurrences Two (2.6%) patients who achieved initial biochemical remission following GKRS treatment experienced recurrence. The intervals between initial remission and recurrence were 13 and 38 mo (Table 2). Pre-GKRS tumor volumes for the 2 recurrences were 3.4 and 2 mL. The prescribed margin doses were 12 and 20 Gy. Tumor volumes for these 2 patients decreased to 0.33 and 0.35 mL, respectively. Both patients were managed medically after their recurrences. Medication Use After SRS No patients in our study received Somavert post-SRS. However, 15 of our patients did receive Cabergoline (n = 3), Somatostatin (n = 7), Octreotide (n = 7), and Bromocriptine (n = 2) after SRS. They received medication due to GKRS failure. Eight of them achieved hormone normalization after medication. Repeat GKRS Treatments Three (3.9%) patients underwent repeat GKRS (Table 2), due to failure to achieve biochemical remission following initial GKRS. They all had smaller tumor volumes at the time of their repeat GKRS compared to the time of initial treatment. Time intervals between initial and repeat GKRS were 91, 42, and 98 mo. Two patients achieved biochemical remission at 5 and 30 mo following repeat GKRS. New Hormone Deficiency after SRS New hormone deficiencies were found in nine (11.8%) patients, and the median time to the development of new hormone deficiencies was 83.6 mo (range: 25.1-127.6) after GKRS. Actuarial hormone deficiency rates were 3%, 7.7%, 14%, and 22.2% at 4, 6, 8, and 10 yr following GKRS (Figure 1E). The most common new hormone deficiencies were ACTH, gonadotropin, and GH. Figure 1F demonstrates the distribution of new hormone deficiencies over time. Following GKRS, actuarial hypothyroidism rates were 0%, 0%, and 4.3% at 2, 6, and 10 yr; actuarial hypogonadism rates were 0%, 3%, and 7.2% at 2, 6, and 10 yr; actuarial hypocortisolism rates were 0%, 3.8%, and 15.1% at 2, 6, and 10 yr; actuarial GH deficiency rates were 0%, 2.5%, and 5.6% at 2, 6, and 10 yr. Presence of CS invasion was a predictor of post-GKRS new hormone deficiencies on univariate (HR 0.145 [0.029-0.726], P = .019) and multivariate (HR 0.162 [0.032-0.815], P = .027) analyses (Table 4). TABLE 4. Prognostic Factors for Development of New Hormone Deficiency after SRS Cox Univariate analysis Cox Multivariate analysis P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Gender (female vs. male) .055 0.214 (0.044-1.034) .082 0.247 (0.051-1.197) Margin dose (>15.8 vs. <15.8 Gy) .578 1.453 (0.389-5.431) Maximum dose (>26.7 vs. <26.7 Gy) .602 1.419 (0.380-5.302) Tumor volume (>2.8 vs. <2.8 mL) .793 0.799 (0.214-2.979) Treatment volume (>4.8 vs. <4.8 mL) .740 1.250 (0.335-4.657) Tumor extension  Cavernous sinus invasion (yes vs. no) .019 0.145 (0.029-0.726) .027 0.162 (0.032-0.815)  Suprasellar extension (yes vs. no) .235 2.604 (0.536-12.649) Prior hormone deficiency .416 0.421 (0.053-3.378) Age (>42 vs. <42y) .413 1.735 (0.464-6.486) Pre-GK vision deficits (yes vs. no) .412 0.417 (0.051-3.379) Cox Univariate analysis Cox Multivariate analysis P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Gender (female vs. male) .055 0.214 (0.044-1.034) .082 0.247 (0.051-1.197) Margin dose (>15.8 vs. <15.8 Gy) .578 1.453 (0.389-5.431) Maximum dose (>26.7 vs. <26.7 Gy) .602 1.419 (0.380-5.302) Tumor volume (>2.8 vs. <2.8 mL) .793 0.799 (0.214-2.979) Treatment volume (>4.8 vs. <4.8 mL) .740 1.250 (0.335-4.657) Tumor extension  Cavernous sinus invasion (yes vs. no) .019 0.145 (0.029-0.726) .027 0.162 (0.032-0.815)  Suprasellar extension (yes vs. no) .235 2.604 (0.536-12.649) Prior hormone deficiency .416 0.421 (0.053-3.378) Age (>42 vs. <42y) .413 1.735 (0.464-6.486) Pre-GK vision deficits (yes vs. no) .412 0.417 (0.051-3.379) CS: cavernous sinus, Gy: gray, SRS: stereotactic radiosurgery. View Large TABLE 4. Prognostic Factors for Development of New Hormone Deficiency after SRS Cox Univariate analysis Cox Multivariate analysis P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Gender (female vs. male) .055 0.214 (0.044-1.034) .082 0.247 (0.051-1.197) Margin dose (>15.8 vs. <15.8 Gy) .578 1.453 (0.389-5.431) Maximum dose (>26.7 vs. <26.7 Gy) .602 1.419 (0.380-5.302) Tumor volume (>2.8 vs. <2.8 mL) .793 0.799 (0.214-2.979) Treatment volume (>4.8 vs. <4.8 mL) .740 1.250 (0.335-4.657) Tumor extension  Cavernous sinus invasion (yes vs. no) .019 0.145 (0.029-0.726) .027 0.162 (0.032-0.815)  Suprasellar extension (yes vs. no) .235 2.604 (0.536-12.649) Prior hormone deficiency .416 0.421 (0.053-3.378) Age (>42 vs. <42y) .413 1.735 (0.464-6.486) Pre-GK vision deficits (yes vs. no) .412 0.417 (0.051-3.379) Cox Univariate analysis Cox Multivariate analysis P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Gender (female vs. male) .055 0.214 (0.044-1.034) .082 0.247 (0.051-1.197) Margin dose (>15.8 vs. <15.8 Gy) .578 1.453 (0.389-5.431) Maximum dose (>26.7 vs. <26.7 Gy) .602 1.419 (0.380-5.302) Tumor volume (>2.8 vs. <2.8 mL) .793 0.799 (0.214-2.979) Treatment volume (>4.8 vs. <4.8 mL) .740 1.250 (0.335-4.657) Tumor extension  Cavernous sinus invasion (yes vs. no) .019 0.145 (0.029-0.726) .027 0.162 (0.032-0.815)  Suprasellar extension (yes vs. no) .235 2.604 (0.536-12.649) Prior hormone deficiency .416 0.421 (0.053-3.378) Age (>42 vs. <42y) .413 1.735 (0.464-6.486) Pre-GK vision deficits (yes vs. no) .412 0.417 (0.051-3.379) CS: cavernous sinus, Gy: gray, SRS: stereotactic radiosurgery. View Large Other Complications No complications were encountered in this study. No new visual deficits, cranial nerve palsies, cerebrovascular accidents, or radiation-induced tumors were detected during the follow-up period. DISCUSSION Higher margin doses are generally suggested in the radiosurgical treatment of functioning pituitary adenomas. Most margin doses reported have exceeded 20 Gy, and the suggested margin dose often around 25 Gy.1,2,13,15,16,19,22 In the past, it was reasonable to expect hormone remission in 50% of patients within the 2 to 4 yr following radiosurgery. Many studies have also indicated that stronger doses can reduce the time required for hormone remission. Remission criteria and methods used to track acromegaly patients were vary considerably. A review of studies based on series with more than 50 acromegaly patients and tracking periods exceeding 4 yr (Table 5) revealed that the administration of 25 to 35 Gy could indeed achieve hormone remission more rapidly than the administration of 16 to 18 Gy, without causing a notable increase in the likelihood of hypopituitarism. The incidence rates of nearly all other complications were also under 2%. TABLE 5. Literature Review of Outcomes after SRSa Remission criteria Remission New hormone deficiency Authors, year Series no. (n) Median/ mean FU (mo) Margin dose (Gy) TV control rate (%) OGTT GH <1 ng/mL Normal IGF-1 GH <1 ng/mL GH <2 ng/mL GH <2.5 ng/mL Year (yr) Rate (%) Year (yr) Rate (%) Individual hypopituitarism (%) Castinetti et al, 200522 82 49.5 25.7 N/A V V 3 17 N/A 17 Kobayashi et al, 200521 67 63.0 18.9 N/A N/A N/A 10 N/A 11 Jezkova et al, 200619 96 54.0 35.0 100 V V 3 29 N/A 27 Hypogonadism 7 5 44 Hypoadrenalism 7 8 57 Hypothyroidism 20 Voges et al, 200629 64 54.3 16.5 88.2 V V 3 29 5 27 5 50 7 63 Vik-Mo et al, 200716 53 66.0 26.5 100 V V V N/A 17 8 23 Jagannathan et al, 200715 95 57.6 22.0 98.0 V 2.5 53 N/A 34 Losa et al, 200813 83 69.0 25 97.6 V V 5 53 5 8.5 Kobayashi, 200911 71 64.0 18.9 N/A V N/A 5 N/A 15 Wan et al, 200910 103 67.0 21.4 95.1 V V N/A 37 N/A 2 Franzin et al, 20122 103 71 23 97.3 V V 5 57 N/A 7.8 Hypogonadism 5.2 Hypoadrenalism 6 10 80 Hypothyroidism 3.2 bLee et al, 20141 136 61.5/68.2 25.0 98.5 V V 4 65 4 11 Hypogonadism 14 6 73 6 29 Hypoadrenalism 12 8 83 8 44 Hypothyroidism 23 GH deficiency 1.5 Present, 2017 76 72.8 15.8 98.7 V V V 4 20 4 3 Hypogonadism 3.9 6 40 6 8 Hypoadrenalism 6.6 8 50 8 14 Hypothyroidism 1.3 12 76 12 28 GH deficiency 3.9 Remission criteria Remission New hormone deficiency Authors, year Series no. (n) Median/ mean FU (mo) Margin dose (Gy) TV control rate (%) OGTT GH <1 ng/mL Normal IGF-1 GH <1 ng/mL GH <2 ng/mL GH <2.5 ng/mL Year (yr) Rate (%) Year (yr) Rate (%) Individual hypopituitarism (%) Castinetti et al, 200522 82 49.5 25.7 N/A V V 3 17 N/A 17 Kobayashi et al, 200521 67 63.0 18.9 N/A N/A N/A 10 N/A 11 Jezkova et al, 200619 96 54.0 35.0 100 V V 3 29 N/A 27 Hypogonadism 7 5 44 Hypoadrenalism 7 8 57 Hypothyroidism 20 Voges et al, 200629 64 54.3 16.5 88.2 V V 3 29 5 27 5 50 7 63 Vik-Mo et al, 200716 53 66.0 26.5 100 V V V N/A 17 8 23 Jagannathan et al, 200715 95 57.6 22.0 98.0 V 2.5 53 N/A 34 Losa et al, 200813 83 69.0 25 97.6 V V 5 53 5 8.5 Kobayashi, 200911 71 64.0 18.9 N/A V N/A 5 N/A 15 Wan et al, 200910 103 67.0 21.4 95.1 V V N/A 37 N/A 2 Franzin et al, 20122 103 71 23 97.3 V V 5 57 N/A 7.8 Hypogonadism 5.2 Hypoadrenalism 6 10 80 Hypothyroidism 3.2 bLee et al, 20141 136 61.5/68.2 25.0 98.5 V V 4 65 4 11 Hypogonadism 14 6 73 6 29 Hypoadrenalism 12 8 83 8 44 Hypothyroidism 23 GH deficiency 1.5 Present, 2017 76 72.8 15.8 98.7 V V V 4 20 4 3 Hypogonadism 3.9 6 40 6 8 Hypoadrenalism 6.6 8 50 8 14 Hypothyroidism 1.3 12 76 12 28 GH deficiency 3.9 FU: follow-up, GH: growth hormone, Gy: gray, IGF-1: insulin-like growth factor-1, mo: months, N/A: not available, OGTT: oral glucose tolerance test, SRS: stereotactic radiosurgery. aNumber of patients > 50, follow-up > 4 yr. bLee et al, 20141: Remission criteria is OGTT GH < 1 ng/mL and/or Normal IGF-1 View Large TABLE 5. Literature Review of Outcomes after SRSa Remission criteria Remission New hormone deficiency Authors, year Series no. (n) Median/ mean FU (mo) Margin dose (Gy) TV control rate (%) OGTT GH <1 ng/mL Normal IGF-1 GH <1 ng/mL GH <2 ng/mL GH <2.5 ng/mL Year (yr) Rate (%) Year (yr) Rate (%) Individual hypopituitarism (%) Castinetti et al, 200522 82 49.5 25.7 N/A V V 3 17 N/A 17 Kobayashi et al, 200521 67 63.0 18.9 N/A N/A N/A 10 N/A 11 Jezkova et al, 200619 96 54.0 35.0 100 V V 3 29 N/A 27 Hypogonadism 7 5 44 Hypoadrenalism 7 8 57 Hypothyroidism 20 Voges et al, 200629 64 54.3 16.5 88.2 V V 3 29 5 27 5 50 7 63 Vik-Mo et al, 200716 53 66.0 26.5 100 V V V N/A 17 8 23 Jagannathan et al, 200715 95 57.6 22.0 98.0 V 2.5 53 N/A 34 Losa et al, 200813 83 69.0 25 97.6 V V 5 53 5 8.5 Kobayashi, 200911 71 64.0 18.9 N/A V N/A 5 N/A 15 Wan et al, 200910 103 67.0 21.4 95.1 V V N/A 37 N/A 2 Franzin et al, 20122 103 71 23 97.3 V V 5 57 N/A 7.8 Hypogonadism 5.2 Hypoadrenalism 6 10 80 Hypothyroidism 3.2 bLee et al, 20141 136 61.5/68.2 25.0 98.5 V V 4 65 4 11 Hypogonadism 14 6 73 6 29 Hypoadrenalism 12 8 83 8 44 Hypothyroidism 23 GH deficiency 1.5 Present, 2017 76 72.8 15.8 98.7 V V V 4 20 4 3 Hypogonadism 3.9 6 40 6 8 Hypoadrenalism 6.6 8 50 8 14 Hypothyroidism 1.3 12 76 12 28 GH deficiency 3.9 Remission criteria Remission New hormone deficiency Authors, year Series no. (n) Median/ mean FU (mo) Margin dose (Gy) TV control rate (%) OGTT GH <1 ng/mL Normal IGF-1 GH <1 ng/mL GH <2 ng/mL GH <2.5 ng/mL Year (yr) Rate (%) Year (yr) Rate (%) Individual hypopituitarism (%) Castinetti et al, 200522 82 49.5 25.7 N/A V V 3 17 N/A 17 Kobayashi et al, 200521 67 63.0 18.9 N/A N/A N/A 10 N/A 11 Jezkova et al, 200619 96 54.0 35.0 100 V V 3 29 N/A 27 Hypogonadism 7 5 44 Hypoadrenalism 7 8 57 Hypothyroidism 20 Voges et al, 200629 64 54.3 16.5 88.2 V V 3 29 5 27 5 50 7 63 Vik-Mo et al, 200716 53 66.0 26.5 100 V V V N/A 17 8 23 Jagannathan et al, 200715 95 57.6 22.0 98.0 V 2.5 53 N/A 34 Losa et al, 200813 83 69.0 25 97.6 V V 5 53 5 8.5 Kobayashi, 200911 71 64.0 18.9 N/A V N/A 5 N/A 15 Wan et al, 200910 103 67.0 21.4 95.1 V V N/A 37 N/A 2 Franzin et al, 20122 103 71 23 97.3 V V 5 57 N/A 7.8 Hypogonadism 5.2 Hypoadrenalism 6 10 80 Hypothyroidism 3.2 bLee et al, 20141 136 61.5/68.2 25.0 98.5 V V 4 65 4 11 Hypogonadism 14 6 73 6 29 Hypoadrenalism 12 8 83 8 44 Hypothyroidism 23 GH deficiency 1.5 Present, 2017 76 72.8 15.8 98.7 V V V 4 20 4 3 Hypogonadism 3.9 6 40 6 8 Hypoadrenalism 6.6 8 50 8 14 Hypothyroidism 1.3 12 76 12 28 GH deficiency 3.9 FU: follow-up, GH: growth hormone, Gy: gray, IGF-1: insulin-like growth factor-1, mo: months, N/A: not available, OGTT: oral glucose tolerance test, SRS: stereotactic radiosurgery. aNumber of patients > 50, follow-up > 4 yr. bLee et al, 20141: Remission criteria is OGTT GH < 1 ng/mL and/or Normal IGF-1 View Large However, in the case of sellar tumors, high radiation doses cannot always be prescribed without greatly increasing the risk of complications. The optic nerve and optical apparatus are believed to have very low tolerance for even low amounts of radiation (eg, 8-10 Gy)30-38; therefore, the amount of radiation administered to sellar tumors must generally be lowered. The visual impairment and visual field deficits caused by radiation-induced optic neuritis are irreversible that patients are typically unable to accept. This has led researchers to conduct a variety of experiments in the hopes of elucidating the precise dosages. Results from this work have in-turn resulted in the formulation of numerous guidelines aimed at protecting the optic nerve.30,31,33-37 Such guidelines include recommendations which define the minimum distance that must exist between a sellar tumor and the optic nerve before radiosurgery. In cases where the sellar tumor is truly inseparable from the optic nerve, either hypofractionated methods must be adopted,30,31,33,35 or reduced doses of radiation (eg, <20 Gy) in the treatment. We aimed to evaluate the effectiveness of low-dose GKRS (Elekta AB) on acromegaly patients and to elucidate the risks associated with damage to the optic apparatus and hypothalamic injury. In our series, stricter criteria (random GH < 1 and IGF-1 normalization) resulted in the following postradiosurgery actuarial remission rates: 2 yr (8.4%,), 4 yr (20.3%), 6 yr (39.9%), 8 yr (49.9%), 10 yr (67.5%), and 12 yr (76.3%). In a systemic review and a Kaplan–Meier analysis performed on previous acromegaly series which follow-up data collected >10 yr, patients presented slower remission but not poorer overall remission rates than those in the series published by Vik-Mo and Kobayahi.11,16 Adopting loosening the criteria (random GH < 2.5 and IGF-1 normalization) resulted in the following postradiosurgery actuarial remission rates: 2 yr (16.5%), 4 yr (31.6%), 6 yr (51.0%), 8 yr (67.1%), 10 yr (90.1%), and 12 yr (90.1%); still, patients presented slower remission but not poorer overall remission rates compared to results of high-dose GKRS series published by Losa et al,13 Franzin et al,2 and Lee et al1 (Table 5). In contrast to the 2 studies that utilized low-dose radiation in the treatment of GH-producing adenomas, the focuses of our study were the safety and efficacy of low-dose GKRS for small GH-secreting adenoma.21,29 Kobayashi et al21 reported a GH normalization rate of 4.8% and tumor control rate of 100% after GKRS using a mean margin dose of 18.9 Gy and a mean follow-up duration of 63.3 mo in a study comprising 67 patients with GH-producing adenomas with mean tumor volume of 5.4 mL. The authors concluded that endocrine remission was difficult to achieve for large tumors with low-dose radiation. In contrast, the median tumor volume in our study was 2.8 mL, which was approximately half of what was reported in the study by Kobayashi et al.21 Hence, our GH-producing adenoma cohort may be inherently distinct from that of the Kobayashi et al21 study. Although Voges et al29 reported hormone normalization rate of 46.9% among 64 patients with GH-producing adenomas treated with margin dose of up to 20 Gy, they focus on macroadenomas (mean tumor volume: 4.3 mL) in general and no predictors of endocrine remission/new hormone deficiency in relation to GH-producing adenoma treatment was analyzed. In addition, the treatment modality used in the study was linear accelerator-based radiosurgery. From the results of present study, low-dose radiosurgery for GH adenomas seems feasible. However, the lowest effective radiation dose for GH adenomas remains unclear. Although there was no statistical difference in remission rates between margin doses of ≥18 and <18 Gy, there appears to be a trend (P = .062) towards higher remission rates for those treated with margin doses of ≥18 Gy. Hence, in cases where radiation dose to the optic apparatus could not be constrained to 10 Gy or less, margin doses <18 Gy may be considered. The current study found a new hormone deficiency rate of 11.8% after a median latency period of 83.6 mo. These rates seem to be considerably lower compared to those reported by Lee et al,1 who found a new hormone deficiency rate of 31.6% after a median latency period of 50.5 mo. In contrast, Losa et al13 reported a low new hormone deficit incidence of 8.5%. Franzin et al2 also reported a low incidence of 4.9%. Although a wide range (2%-63%) of post-SRS hypopituitarism has been reported in the literature, most studies report rates of 30%-50% at approximately 3 yr following SRS.1-28 Therefore, our rate of new hormone deficiency appears to be consistent with the rates reported in the literature, despite the use of lower margin doses compared to the doses used by other radiosurgical series. No other complications were observed during the follow-up period of this current study, supporting the safety profile of low-dose GKRS in patients with acromegaly. Factors associated with improved biochemical remission rates remain controversial. Higher radiation doses, smaller tumor volumes, lower pre-SRS IGF-1, and GH levels, and absence of CS invasion have been reported to be predictors of remission following SRS.5,6,13,19,28 However, other studies have also reported that radiation dose, tumor volume, and tumor extension fail to reliably predict biochemical remission.8,13,19,28 Absence of CS invasion (P = .005), lower pre-GKRS IGF-1 (P = .026), and GH (P = .036) levels, not on medical therapy during GKRS (P = .045), and mammosomatotroph adenoma found on surgical pathology (P = .008) were found to be significant predictors of biochemical remission in this study. However, in subsequent multivariate analysis, only absence of CS invasion (P = .042) and lower pre-GKRS IGF-1 levels (P = .019) remained significant predictors of remission. Significantly, earlier biochemical remission was achieved in patients without CS invasion and those with age- and gender-adjusted pre-GKRS IGF-1 levels ≤2 times the normal limit (Figure 1). In addition, CS invasion was also found to be a predictor of new hormone deficiencies following GKRS (P = .027). Previous studies have described the recurrence of acromegaly following resection or RT.1,2,15,19,29 Thus, it should not be surprising to observe recurrence after low-dose radiosurgery. Nonetheless, the latency of such recurrences makes it likely that the true long-term rate of recurrence has been underestimated. In this study, we observed recurrence after initial SRS induced remission in 2.6% of cases. Three of the patients underwent a second GKRS due to poor control over hormone levels, and two of these patients presented rapid hormone remission after the second GKRS (at 24 and 26 mo). We believe that repeated GKRS may compensate for the low doses used in our approach, such that rapid control over hormone levels could be expected. It also appears that patients who undergo 2 GKRS with lower doses may have decreased risk of hypopituitarism. Thus, it appears that repeated GKRS can help to control hormone levels. However, the timing and indications (recurrence or failure to achieve remission) for repeat SRS treatment remain unclear. We acknowledge that the remission rates achieved with low-dose GKRS may be at the lower end of the spectrum of remission rates reported in the literature. Therefore, low-dose GKRS may be considered as salvage therapy in patients with residual tumor in close proximity to optic apparatus after transsphenoidal surgery or in patients who have similar tumors but unable to undergo surgery due to medical comorbidities or patient preference. Therefore, we would not recommend this as first-line therapy given the lower hormone remission rates. For those patients who do not achieve remission patients, long-term anti-hormonal medications and repeat GKRS may be treatment options. However, efficacy and safety of repeat GKRS in these setting are unknown and future studies are necessary. Study Limitations This retrospective study has a number of limitations that should be noted. The patients included in this study were treated over a period of time from the 1990s to the 2010s; during this period, improvements in laboratory tests may affect the sensitivities and specificities of hormone detection. In addition, advancements in imaging sequences and magnet field strengths during this period have also improved tumor detection rates. It is also important to note that the study may suffer from selection bias, as these patients who were treated with low margin dose represent only a subset of patients with acromegaly who underwent GKRS. We also acknowledge that the inclusion of patients who had prior RT may introduce addition bias to the analysis. However, time intervals between RT and GKRS were at least 5 yr for all these patients, and the effects of RT were no longer apparent at the time of GKRS. Hence, these were considered RT treatment failures. The small number of patients with recurrences precluded further analysis of this cohort, and similarly, the small cohort of patients who underwent repeat GKRS precluded subgroup analysis. We also acknowledge that we are left with a small cohort with longer follow-ups which coincide with the expected times of hormonal normalization, and the power to detect dose response may be limited by our small sample size. In addition, the follow-up periods in our study range widely, and thus it is important to note that delayed complications may not have been captured in patients with short follow-up periods. Future studies with larger cohorts and longer follow-ups may help elucidate the efficacy and safety of repeat SRS for acromegaly. CONCLUSION GKRS (Elekta AB) is an effective treatment for patients with persistent acromegaly despite after surgical resection. Despite the high biochemical remission and low hypopituitarism rates, high radiation doses to the sellar region pose unknown and unnecessary risks to optic apparatus. Low-dose GKRS represents an alternative treatment option in reducing the exposure of critical neurovascular structures in close proximity to the sella turcica to radiation. Lose-dose GKRS may offer comparable remission and new hormone deficiency rates compared to standard GKRS margin doses. However, the latency to remission for low-dose GKRS appears to be longer. Additional studies directly comparing low- and standard-dose GKRS are necessary to clarify differences in efficacy and safety between the two treatments. In addition, further studies are required to further elucidate the latent effects of low-dose GKRS treatments and recurrences after initial remission. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Lee CC , Vance ML , Xu Z et al. . Stereotactic radiosurgery for acromegaly . J Clin Endocrinol Metab . 2014 ; 99 ( 4 ): 1273 – 1281 . Google Scholar Crossref Search ADS PubMed 2. Franzin A , Spatola G , Losa M , Picozzi P , Mortini P . Results of gamma knife radiosurgery in acromegaly . Int J Endocrinol . 2012 ; 342034 . 3. Sheehan JP , Pouratian N , Steiner L , Laws ER , Vance ML . Gamma Knife surgery for pituitary adenomas: factors related to radiological and endocrine outcomes . J Neurosurg . 2011 ; 114 ( 2 ): 303 – 309 . Google Scholar Crossref Search ADS PubMed 4. Loeffler JS , Shih HA . Radiation therapy in the management of pituitary adenomas . 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Google Scholar Crossref Search ADS PubMed 29. Voges J , Kocher M , Runge M et al. . Linear accelerator radiosurgery for pituitary macroadenomas . Cancer . 2006 ; 107 ( 6 ): 1355 – 1364 . Google Scholar Crossref Search ADS PubMed 30. Hiniker SM , Modlin LA , Choi CY et al. . Dose-response modeling of the visual pathway tolerance to single-fraction and hypofractionated stereotactic radiosurgery . Semin Radiat Oncol . 2016 ; 26 ( 2 ): 97 – 104 . Google Scholar Crossref Search ADS PubMed 31. Pollock BE , Link MJ , Leavitt JA , Stafford SL . Dose-volume analysis of radiation-induced optic neuropathy after single-fraction stereotactic radiosurgery . Neurosurgery . 2014 ; 75 ( 4 ): 456 – 460 ; discussion 460 . Google Scholar Crossref Search ADS PubMed 32. Lee CC , Chen CJ , Yen CP et al. . Whole-sellar stereotactic radiosurgery for functioning pituitary adenomas . Neurosurgery . 2014 ; 75 ( 3 ): 227 – 237 ; discussion 237 . Google Scholar Crossref Search ADS PubMed 33. Leavitt JA , Stafford SL , Link MJ , Pollock BE . Long-term evaluation of radiation-induced optic neuropathy after single-fraction stereotactic radiosurgery . Int J Radiat Oncol Biol Phys . 2013 ; 87 ( 3 ): 524 – 527 . Google Scholar Crossref Search ADS PubMed 34. Mayo C , Martel MK , Marks LB , Flickinger J , Nam J , Kirkpatrick J . Radiation dose-volume effects of optic nerves and chiasm . Int J Radiat Oncol Biol Phys . 2010 ; 76 ( 3 Suppl ): S28 – S35 . Google Scholar Crossref Search ADS PubMed 35. Hasegawa T , Kobayashi T , Kida Y . Tolerance of the optic apparatus in single-fraction irradiation using stereotactic radiosurgery: evaluation in 100 patients with craniopharyngioma . Neurosurgery . 2010 ; 66 ( 4 ): 688 – 695 ; discussion 694-685 . Google Scholar Crossref Search ADS PubMed 36. Stafford SL , Pollock BE , Leavitt JA et al. . A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery . Int J Radiat Oncol Biol Phys . 2003 ; 55 ( 5 ): 1177 – 1181 . Google Scholar Crossref Search ADS PubMed 37. Leber KA , Bergloff J , Pendl G . Dose—response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery . J Neurosurg . 1998 ; 88 ( 1 ): 43 – 50 . Google Scholar Crossref Search ADS PubMed 38. Tishler RB , Loeffler JS , Lunsford LD et al. . Tolerance of cranial nerves of the cavernous sinus to radiosurgery . Int J Radiat Oncol Biol Phys . 1993 ; 27 ( 2 ): 215 – 221 . Google Scholar Crossref Search ADS PubMed COMMENT This manuscript is a retrospective study from a single institution in the treatment of acromegaly using Gamma Knife (Elekta AB) with <25 Gy margin dose. The aim of this study was to evaluate the effectiveness of low-dose SRS on acromegaly patients and to elucidate adverse radiation effects for optic apparatus and hypothalamus. Six patients underwent prior fractionated radiation therapy. The inclusion of patients who had prior RT may introduce a bias, The median imaging and endocrine follow-up was 65.8 months and 72.8 months, respectively. Overall tumor control rate was 98.7%. Biochemical remission rates were 20.3% at 4 years, 49.9% at 8 years, and 76.3% at 8 years. Absence of cavernous sinus invasion and lower baseline IGF-1 were significant predictor of remission. Authors had shown low-dose SRS took longer biochemical remission periods despite of reasonable biochemical remission rates. Thus, the results of this study suggest that low-dose SRS may offer comparable biochemical remission and new hormone deficiency rates compared to standard radiosurgery dose. Future studies to compare directly low- and standard-dose SRS may clarify differences in efficacy and safety between both method. Hideyuki Kano Pittsburgh, Pennsylvania Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

NeurosurgeryOxford University Press

Published: Jul 1, 2019

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