Linear Accelerator Radiosurgery for Pituitary Macroadenomas. BACKGROUND. A prospective study was conducted to assess the efficacy and side

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1 1355 Linear Accelerator Radiosurgery for Pituitary Macroadenomas A 7-Year Follow-Up Study Juergen Voges, MD 1 Martin Kocher, MD 2 Matthias Runge, MD 1 Jorg Poggenborg, MD 3 Ralph Lehrke, MD 1 Doris Lenartz, MD 1 Mohammad Maarouf, MD 1 Ioanna Gouni-Berthold, MD 4 Wilhelm Krone, MD 4 Rolf-Peter Muller, MD 2 Volker Sturm, MD 1 1 Department of Stereotaxy and Functional Neurosurgery, University of Cologne, Cologne, Germany. 2 Deparment of Radiation Oncology, University of Cologne, Cologne, Germany. 3 Department of Radiology, University of Cologne, Cologne, Germany. 4 Department of Internal Medicine II, University of Cologne, Cologne, Germany. BACKGROUND. A prospective study was conducted to assess the efficacy and side effects of linear accelerator (LINAC)-based radiosurgery (RS) performed with a reduced dose of therapeutic radiation for patients with surgically inaccessible pituitary macroadenomas. METHODS. From August 1990 through January 2004, 175 patients with pituitary macroadenomas were treated with LINAC-RS according to a prospective protocol. To minimize the risk for radiation-induced damage of the pituitary function, the therapeutic dose to be applied was limited to 20 grays. RESULTS. Among 175 patients, 142 patients who had a minimum follow-up of 12 months (mean 6 standard deviation, months) were included in the current study. The local tumor control rate was 96.5%, and the tumor response rate was 32.4%. The mean time (6 standard deviation) from LINAC-RS to normalization of pathologic hormone secretion was months. The probability for normalization was 34.3% at 3 years and 51.1% at 5 years. The frequency of endocrine cure (defined as the normalization of hormone secretion without specific medication intake) was 35.2% (mean 6 standard deviation time to cure, months). Patients with Cushing disease had a statistically significant greater chance of achieving a cure (P ¼.001). Side effects of LINAC-RS were deterioration of anterior pituitary function (12.3%), radiation-induced tissue damage (2.8%), and radiation-induced neuropathy (1.4%). CONCLUSIONS. LINAC-RS using a lower therapeutic radiation dose achieved local tumor control and normalization or cure of hormone secretion comparable to the results achieved with g-knife RS. Compared with the latter, the time to normalization or endocrine cure was delayed, most probably as a result of dose reduction. However, the lower therapeutic radiation dose did not prevent radiation-induced damage of pituitary function completely. Cancer 2006;107: Ó 2006 American Cancer Society. Address for reprints: Jurgen Voges, MD, Department of Stereotaxy and Functional Neurosurgery, University of Cologne, Kerpener Strasse 62, D Cologne, Germany. Fax: (011) ; j.voges@uni-koeln.de Received March 6, 2006; revision received May 25, 2006; accepted June 12, KEYWORDS: pituitary adenoma, stereotactic radiosurgery, linear accelerator, hormone-secreting adenoma, nonsecreting adenoma, efficacy, toxicity. Although the vast majority of pituitary adenomas are benign histopathologically, these tumors can cause severe medical problems. Surgery is the treatment of choice for patients with pituitary adenomas, but the degree of resection often is limited by tumor extension, mainly by invasion into the cavernous sinus. In the literature, long-term tumor control rates after surgery vary from 50% to 80% of patients. 1 4 In the early 1990s, when the current clinical study was initiated, in the vast majority of patients with pituitary adenoma, externalbeam radiotherapy (XRT) was used as adjuvant treatment for surgi- ª 2006 American Cancer Society DOI /cncr Published online 7 August 2006 in Wiley InterScience (

2 1356 CANCER September 15, 2006 / Volume 107 / Number 6 cally inaccessible tumor parts. Radiosurgery (RS), which was applied at that time with high therapeutic radiation doses ( grays [Gy]) using a g-knife or proton beams, also was very effective. Local tumor control was observed in >90% of patients, 5 7 and the probability of improving hormone hypersecretion ranged from 50% to 70% of patients. 5 8 The most frequent side effects from RS were impairment of visual function (17% of patients 5,6 ) and hypothalamopituitary dysfunction (up to 55% of patients 7,9 ). In those early studies, radiation damage of the pituitary gland could be attributed mainly to 1) the limited visualization of the target region and surrounding structures at risk in an era before the introduction of high-resolution, 3-dimensional imaging; and 2) the high radiation dose, which was delivered to the target region. The objective of the current study was to examine whether reducing the radiation dose could 1) achieve therapeutic rates comparable to the currently used higher doses and 2) prevent or limit the aforementioned radiationinduced side effects. The data presented in this report encompass an analysis of all consecutive patients who were treated prospectively over >10 years with linear accelerator (LINAC)-based RS (LINAC-RS) for pituitary macroadenomas and who had a mean follow-up of 6.8 years. MATERIALS AND METHODS This study was performed at the University Hospital of Cologne (Departments of Stereotaxy and Functional Neurosurgery, Radiation Oncology, and Internal Medicine II). It started in August 1990 and closed in January Informed consent was obtained from each patient. Objectives and Endpoints The objective of this study was to investigate the effect of a moderate therapeutic dose of LINAC-RS on tumor growth, hypothalamopituitary function, cranial nerve function, and normal brain tissue in patients with pituitary macroadenoma. Endpoints of the study were 1) worsening of hypothalamopituitary function; 2) radiologic tumor recurrence; 3) date of surgery, fractionated radiotherapy, or RS after LINAC- RS; and 4) normalization or cure of hormone hypersecretion. Eligibility Criteria Inclusion criteria for the study were 1) pituitary adenoma with radiologically confirmed progression and/ or medically intractable hormone secretion, 2) surgically inaccessible adenoma, 3) clear-cut tumor borders on computed tomographic (CT) images and on magnetic resonance imaging (MRI) scans, 4) a greatest tumor dimension that did not exceed 35 mm, 5) a minimum distance of 1 mm to 2 mm between tumor and optic nerves and/or chiasm and/or optic tract, and 6) no compression of normal brain tissue by the tumor. Baseline and Follow-Up Investigations In addition to routine examinations, the following variables were assessed at baseline: 1) growth hormone (GH), insulin-like-growth-factor 1 (IGF-1), thyroid-stimulating hormone (TSH), corticotropin, and folliclestimulating hormone (FSH)/luteinizing hormone (LH), and adenoma-induced hormone hypersecretion; 2) CT studies (before 1994) or MRI studies (after 1994; T1- weighted and T2-weighted sequences); and 3) neurologic examination together with assessment of visual fields and visual acuity. During the first 3 years after LINAC-RS, we recommended regular follow-up visits every 6 months and yearly afterward. Data for the current analysis were taken from medical records and CT and/or MRI studies from our archives. If necessary, we completed this information by telephone interview by using a standardized questionnaire. Tumor size Tumor size was determined on CT and/or MRI studies by measuring the greatest tumor dimension and the corresponding greatest rectangular dimension. We defined a response as a reduction >25% in the greatest tumor dimension compared with baseline measurements in at least 2 reconstruction planes, stabilization was defined as a reduction or increase 25%, and progression was defined as an increase >25%. A complete response was documented when CT and/or MRI studies displayed no signal specific for tumor tissue. Endocrinology Criteria for normalization of hormone-secretion were 1) for GH-secreting adenomas, fasting GH <2 ng/ ml 10 or mean GH <2 ng/ml 11 together with normal IGF-1 corrected for age and gender; 2) for adrenocorticotropic (ACTH)-secreting adenomas, either serum cortisol <25 mg/dl or normal 24-hour urinary free cortisol level 12,13 ; 3) for Nelson tumors, normal serum ACTH; 4) for TSH-secreting adenomas, normal free 3,5,3 0 -triiodothyrone, free thyroxine, and TSH levels and a normal thyrotropin-releasing hormone test 14 ; and 5) for prolactin-secreting adenomas, normal serum prolactin levels. Endocrine cure was defined as

3 LINAC-RS for Pituitary Macroadenomas/Voges et al normalization of hormone secretion without specific medication intake. Hypopituitarism was classified as partial if the function of 1 or 2 of the hormones TSH, corticotropin, and FSH/LH axes had to be substituted and was complete when all aforementioned axes required substitution. Radiation-induced hypothalamopituitary dysfunction was diagnosed if the patient presented after LINAC-RS with a new deficit of a previously normal hormone function. Treatment Planning and Dose Application The hardware and software components of our treatment-planning and irradiation system are described elsewhere in detail. 15 Briefly, from 1990 to 1996, the tumor contour and the organs at risk (pituitary, pituitary stalk, optic nerve, and chiasm) were outlined on stereotactic CT images. Starting in 1996, all patients underwent high-resolution MRI from 1 to 3 days before RS. Since then, we have used MRI studies for computer-assisted (DecWorkstation; Digital Equipment) treatment planning (software: STP 3.3 and 3.5, Stryker-Leibinger, Freiburg, Germany) that are integrated into the stereotactic CT images with landmark-based image fusion. 16 The upper limit for the therapeutic dose, defined as the radiation dose that covered the tumor surface, was prescribed as 20 Gy. The dose delivered to the anterior visual pathways was kept below 9 Gy. Since 1994, the volume of healthy brain tissue exposed to a minimum dose of 10 Gy has been calculated regularly on dose-volume-histograms and was restricted to <10 cc. 15 Dose application was performed in 137 of 142 patients with cylindrical collimators. The standard radiation field was applied with 10 table positions and a gantry rotation from 208 to 1608 using a standard linear accelerator (8-MeV or 6-MeV photons; Philips SL20 or Elekta Sli25; Philips, Best, the Netherlands). To adjust dose distribution individually, we modified 1 or several of the following parameters: number and size of the radiation fields, number of table positions, gantry rotation angle, and maximum field dose. In 5 of 142 patients we used a motor-driven micromultileaf collimator (40 lamellae, 1.5-mm thickness each; MRC-Systems, Heidelberg, Germany). Data Analysis and Statistics Data are given as mean values 6 standard deviations. To analyze variances of variables among subgroups we used a 1-way analysis of variance procedure to compare mean values. Values for hormone normalization, hormone cure, or radiation-induced hypothalamopituitary dysfunction are given as frequencies (the number of patients in the total series) and as probabilities, which were calculated with the Kaplan Meier method. Univariate analyses of classified variables were performed using the Kaplan Meier method and the log-rank test. The prescribed level of statistical significance (P value) was 5%. RESULTS Study Population From August 1990 through January 2004, 175 patients (53 patients with nonfunctioning adenomas and 122 patients with hormone-secreting adenomas) were included in the study. Preliminary results from 32 patients were published in For the current analysis, we excluded 33 of 175 patients who had an actual follow-up of <12 months. The mean follow-up for the 142 patients who were included was months (range, months). Fifty percent of those patients had a minimum follow-up of 77 months. Intrasellar tumor extension in combination with extrasellar and/or parasellar tumor extension was documented in 80 of 142 patients (56.3%). Fifteen of 142 patients (10.6%) had an intrasellar adenoma. In 47 of 142 patients (33.1%), we documented isolated extrasellar/parasellar tumor growth. In 127 of 142 patients (89.4%), the adenoma had infiltrated the cavernous sinus, and that infiltration was bilateral in 23 of 127 patients. Therapy Prior to RS Seventy-three of 137 patients who underwent surgery prior to LINAC-RS underwent 1 operation, and 64 of 137 patients underwent from 2 to 4 operations. In 4 patients, iodine-125 seeds were placed into the sella turcica for local irradiation after adenoma resection. XRT was applied adjuvant to surgery in 4 patients and was the only treatment in 5 patients. Epidemiologic and treatment data for the evaluated patients are listed in Table 1. Tumor Volume At baseline, the mean 6 standard deviation tumor volumes of the different adenoma subtypes were as follows: nonsecreting adenomas, cc; GHsecreting adenomas, cc, ACTH-secreting adenomas, cc; Nelson tumors, cc; and prolactin-secreting adenomas, cc. In the 2 TSH-secreting tumors, the volumes were 3.1 cc and 5.7 cc. Patients who had prolactin-secreting adenomas had statistically significantly larger tumors compared with patients who had ACTH-secreting or GH-secreting adenomas (P <.05).

4 1358 CANCER September 15, 2006 / Volume 107 / Number 6 TABLE 1 Characteristics and Treatment Data from 142 Evaluated Patients Characteristic Value Gender (no. of patients) Male 57 Female 85 Age, y Mean 6 SD Range Tumor volume, ml Mean 6 SD Range Therapeutic dose, Gy Mean 6 SD Range Maximum dose, Gy Mean 6 SD Range Isocenter level, % Mean 6 SD Range No. of isocenters Mean 6 SD Range 1 9 Adenoma type, no. of patients Nonsecreting 37 GH-secreting 64 ACTH-secreting 17 Nelson tumor 9 Prolactin-secreting 13 TSH-secreting 2 SD indicates standard deviation; Gy, grays; GH, growth hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone. The applied therapeutic dose had an inverse relation to the tumor volume. The dose was significantly lower in the larger, nonsecreting adenomas (dose, Gy) and prolactin-secreting tumors (dose, Gy) compared with the smaller, ACTH-secreting adenomas (dose, Gy) and the GH-secreting adenomas (dose, Gy; P <.001). In contrast to the therapeutic dose, the maximum target dose did not differ significantly among adenoma subgroups (P ¼.09). LINAC-RS produced a complete response in 5 of 142 patients (3.5%) and a partial response in 41 of 142 patients (28.9%). The tumor volume was unchanged in 91 of 142 adenomas (64.1%). The local tumor control rate was 96.5% (137 of 142 patients), and the tumor response rate was 32.4% (46 of 142 patients). Table 2 summarizes the tumor response rates for adenoma subgroups. Five of 142 patients (3.5%) developed an ipsilateral, out-of-field recurrence. Three of those patients had ACTH-secreting adenomas, and 2 patients had GH-secreting tumors. Two other patients with GHsecreting adenomas presented with a new tumor contralateral to the originally treated side. Hormone Hypersecretion Hormone normalization was documented in 30 of 64 patients (46.9%) with GH-secreting adenomas, in 11 of 17 patients (64.7%) with Cushing disease, in 2 of 9 patients (22.2%) with Nelson tumors, and in 5 of 13 patients (38.5%) with prolactin-secreting tumors. The time from LINAC-RS to normalization was months (range, months). The probability of achieving normalized hormone secretion after therapy for the whole group was 34.3% at 3 years and 51.1% at 5 years. An endocrine cure was achieved in 37 of 105 patients (35.2%) with all types of hormone-secreting adenomas. The mean time from LINAC-RS to cure was months (range, months). The probability for a cure was 19.3% at 3 years and 36.6.% at 5 years. Cure rates with respect to different adenoma types were 37.5% for GH-secreting adenomas (24 of 64 patients), 52.9% for ACTH-secreting adenomas (9 of 17 patients), and 15.4% for prolactinsecreting adenomas (2 of 13 patients). One of 9 patients with a Nelson tumor (11.1%) fulfilled the criteria for a cure 46 months after LINAC-RS, and 1 of 2 patients with a TSH-secreting tumor fulfilled the criteria for a cure 17 months after therapy. The times to normalization or endocrine cure are listed in detail in Table 3 and are displayed graphically in Figures 1 and 2. According to univariate analysis, patients who had a diagnosis of an ACTH-secreting adenoma had a statistically significantly greater chance of achieving a cure (P ¼.001). The factors therapeutic dose (0 16 Gy vs. >16 Gy), maximum dose (0 35 Gy vs. >35 Gy), tumor extension into cavernous sinus (yes vs. no), and prescribed target volume (0 3.5 cc vs. >3.5 cc) had no impact on endocrine normalization or cure. Cranial Nerves At baseline, 49 of 142 patients (34.5%) presented with cranial nerve deficits. In 39 of 49 patients only 1 nerve was affected; and, in 10 of 49 patients, >1 nerve was affected. Prior to LINAC-RS, we registered reduced visual acuity in 9 patients, visual field deficits in 15 patients, and both symptoms in 18 patients. Sixteen patients had impaired function of cranial nerves III, IV, V, or VI. After LINAC-RS, we observed improvement of cranial nerve function (in cranial nerves: III, IV, or VI) in 4 of 142 patients (2.8%). One patient (0.7%) developed quadrant anop-

5 LINAC-RS for Pituitary Macroadenomas/Voges et al TABLE 2 Follow-Up and Tumor Response Rates as Assessed on Computed Tomographic/Magnetic Resonance Images after Linear Accelerator Radiosurgery in 142 Patients with Pituitary Macroadenoma No. of patients (%)* Adenoma type Actuarial FU: Mean 6 SD (Range), months Complete response Partial response Stable disease Progressive disease Total Nonsecreting ( ) 15 (40.5) 22 (59.5) 37 GH-secreting ( ) 2 (3.1) 13 (20.3) 47 (73.5) 2 (3.1) 64 ACTH-secreting ( ) 3 (17.7) 2 (11.8) 10 (58.7) 2 (11.8) 17 Nelson tumor ( ) 0 4 (44.4) 4 (44.4) 1 (11.2) 9 Prolactin-secreting ( ) 0 5 (38.5) 8 (61.5) 0 13 TSH-secreting 42.5 (Patient 1), 57.6 (Patient 2) 0 2 (0) Total 5 (3.5) 41 (28.9) 91 (64.1) 5 (3.5) 142 FU indicates follow-up; SD, standard deviation; GH, growth hormone; ACTH, adrenocorticotropic hormone; TSH, stimulating-stimulating hormone. * For definitions, see Materials and Methods. Months are given as single values. TABLE 3 Probabilities for Normalization and Cure in 105 Patients who Underwent Linear Accelerator Radiosurgery for Hormone- Secreting Adenomas Adenoma type Months (Mean 6 SD)* Probability (%) At 2 years At 3 years At 5 years GH-secreting Normalization Cure ACTH-secreting Normalization Cure Nelson tumor Normalization Cure Prolactin-secreting Normalization Cure SD indicates standard deviation; GH, growth hormone; ACTH, adrenocorticotropic hormone. * The time in months was measured from treatment to the first documentation of normalization or cure (for definitions, see Materials and Methods). sia, and another patient (0.7%) developed decreased visual acuity 3 years after therapy. FIGURE 1. Cumulative probabilities and the time to normalization of endocrine disorders are illustrated for 103 patients who underwent linear accelerator radiosurgery (RS) for hormone-secreting adenomas. Ticks represent censored patients. ACTH indicates adrenocorticotropic hormone; GH, growth hormone. Normal Brain Tissue Seven to 12 months after LINAC-RS, 4 of 142 patients (2.8%) presented with CT images that displayed ringlike contrast enhancement and edema in the temporal lobe next to the treated site. These patients were treated between the years 1990 and Two of them became symptomatic with a single seizure episode, which was treated with steroids for several weeks until CT images and clinical status had normalized. The third patient had repeated seizure activities, transient memory disturbances, and transient motor aphasia. This patient had to be treated with anticonvulsive medication for 2 years. The fourth patient developed a permanent deficit syndrome that was characterized by memory disturbances and imperative sleeping attacks. Hypothalamopituitary Function At baseline, 60 of 142 patients (42.3%) had normal pituitary function, and 82 of 142 patients (57.7%) had

6 1360 CANCER September 15, 2006 / Volume 107 / Number 6 FIGURE 2. Cumulative probabilities and the time to endocrine disorder cures are illustrated for 103 patients who underwent linear accelerated radiosurgery (RS) for hormone-secreting adenomas. Ticks represent censored patients. ACTH indicates adrenocorticotropic hormone; GH, growth hormone. hypothalamopituitary dysfunction. Specifically, we found partial hypopituitarism in 55 of 142 patients (38.7%), complete hypopituitarism in 17 of 142 patients (12.0%), diabetes insipidus (DI) in 1 of 142 patients (0.7%), and DI plus hypopituitarism in 9 of 142 patients (6.3%). To analyze the effect of LINAC-RS on pituitary function, all patients with preexisting complete hypopituitarism and/or DI (27 patients) or who had previous exposure to ionizing radiation (1 patient) were excluded. The 114 patients at risk had a mean ( 6 standard deviation) follow-up of months. At baseline, anterior pituitary function was intact in 60 of 114 patients, 1 axis was affected in 30 of 114 patients, and 2 axes were affected in 24 of 114 patients. After LINAC-RS, pituitary function improved in 2 patients (1.7%), and the status remained unchanged in 98 of 114 patients (86.0%). The frequency of treatment-related hypothalamopituitary dysfunction was 12.3% (14 of 114 patients). Twelve of those 14 events occurred within the first 5 years after therapy. Two patients presented with hypopituitarism 86 months and 92 months after LINAC-RS. The cumulative risk for developing hypopituitarism after LINAC-RS of a macroadenoma was 13.2% at 3 years and 18.3% at 5 years (Fig. 3). No patients were observed who had RS-related DI. According to the univariate analysis, neither tumor margin dose (0 16 Gy vs. >16 Gy; P ¼.41), maximum dose (0 35 Gy vs. >35 Gy; P ¼.22), tumor volume (0 3.5 cc vs. >3.5 cc; P ¼.43), nor FIGURE 3. Cumulative probabilities and the time course of radiationinduced hypothalamopituitary dysfunction are illustrated after linear accelerate radiosurgery (LINAC-RS). One hundred fourteen of 142 patients who had either intact baseline anterior pituitary function or only partially insufficient baseline anterior pituitary function and who had not received radiation therapy prior to LINAC-RS were selected for analysis. Ticks represent censored patients. bilateral invasion of the cavernous sinus (yes vs. no; P ¼.92) showed a significant association with treatment-related hypopituitarism. Additional Therapy after LINAC-RS Five patients with recurrent GH-secreting adenomas received a second treatment with LINAC-RS (mean 6 standard deviation time from first to second treatment, months; range, months), which was tolerated without side effects. One patient responded partially (60% decrease in the elevated IGF-1 serum level), and 1 patient had normalized hormone levels. Three patients did not respond. Two patients with recurrent ACTH-secreting adenomas received XRT. In another 5 patients, intrasellar/parasellar tumor recurrences were removed surgically. One of those patients died postoperatively from an intracranial hemorrhage.

7 LINAC-RS for Pituitary Macroadenomas/Voges et al DISCUSSION During the last 10 to 15 years, RS has emerged as an important treatment modality in the management of nonresectable pituitary adenomas. The majority of these patients has been treated with the g-knife technique. 3,18 39 Until now, to our knowledge, only 3 groups have reported regarding the treatment of patients with hormone-secreting (48 patients) and nonsecreting adenomas (30 patients) with LINAC-RS The follow-up periods in those studies were 12 to 18 months, months, 40 and 49.2 months. 42 With 142 patients evaluated and a mean follow-up of months, the current analysis, to our knowledge, represents the largest data base of patients with pituitary macroadenomas who were treated prospectively in a single center with LINAC-RS. Because approximately 40% of those patients had an actual follow-up that exceeded 5 years, we were able to assess long-term effects in a significant number of patients. RS Tumor growth LINAC-RS with a mean therapeutic dose of 15.3 Gy (range, 8 20 Gy) produced local tumor control in 96.5% of patients and tumor response in 34.4% of patients. This tumor control rate is comparable to the data reported by others, which varied from 92% to 100%. 10,20 22,24 26,29 33,35 38,40,42 According to the literature, local tumor control does not depend on the prescribed therapeutic dose and the type of adenoma. There was no difference between patients with hormone-inactive adenomas who received an average therapeutic dose of Gy (range, Gy) 10,20,22,25,29 31,35,36,38,40,42,43 and patients with hormone-secreting adenomas who, on average, received a radiation dose of Gy (range, Gy). 10,20 22,24 26,29 33,35 38,40,42 In contrast to tumor control, the prescribed therapeutic dose seems to determine tumor regression. When the prescribed therapeutic dose was kept below 20 Gy, according to the literature, tumor regression rates ranged from 17% to 46%, 31,35 37,40,41 rates that are comparable to the findings of the current study (tumor regression rate, 32.4%). In most series in which patients received a mean therapeutic dose that exceeded 20 Gy, tumor regression rates tended to be higher (range, %). 10,24,27 29,33,34,43 Hormone hypersecretion In the current study, 48 of 105 patients (45.7%) who were treated for a hormone-active adenoma experienced hormone normalization within a mean of 36 months after RS. The cure rate was 35.2% (37 of 105 patients), and the mean 6 standard deviation time from LINAC-RS to a cure was months. ACTH-secreting adenomas (cure rate, 52.9%) and TSH-secreting adenomas (a cure was achieved in 1 of 2 patients) were the most responsive adenoma types followed by GH-secreting adenomas (cure rate, 37.5%), prolactin-secreting adenomas (cure rate, 15.4%), and Nelson tumors (cure rate, 11.1%). According to the univariate analysis, the diagnosis of Cushing disease was associated significantly with a high cure rate (P ¼.001). Considering studies that used definitions and cut-off levels comparable to those used in our protocol, the cure rates varied considerably. Specifically, the cure rate for patients with GH-secreting adenomas ranged from 17% to 82%. 10,18,19,24,32 With almost identical follow-up intervals, however, in 2 of those studies, the cure rates were lower (17% 18 and 23% 19 ) than that in the current study (37.5%); and, in 1 study, the cure rate was comparable (42% 10 ). In patients with Cushing disease, the cure rate ranged from 10% to 83% 3,10,22,23,27,34,36 (current study, 52.9%); and in patients with prolactin-secreting tumors, the cure rate ranged from 15% to 84% 3,10,27 29,31,33,42 (current study, 15.4%). Data from the literature support the findings of the current study, i.e., that the type of adenoma determines the degree of hormone response after RS. The best results were reported for patients who had ACTH-secreting tumors (average cure rate, 54.7%), 3,10,22,23,27,34,36 followed by GH-secreting adenomas (average cure rate, 40%), 3,10,21,24,32,37 and prolactin-secreting tumors (average cure rate, 24.3%). 3,10,27 29,31,33,42 In the majority of patients who received treatment with the g-knife, remission or cure occurred within 2 years after RS. 3,10,23,27,33,34,37 Pollock et al. calculated cure rates at 1 year, 2 years, and 4 years on the order of 20%, 32%, and 61%, respectively. 10 In the current analysis, the overall time from RS to cure was longer (mean 6 standard deviation, months). The probability of achieving a cure was 19.3% at 3 years and 36.6% at 5 years. Taking into consideration both the comparably higher therapeutic dose and the higher maximum dose applied in g-knife treatments, these parameters may have influenced the time lag of hormone response. This conclusion is in line with the results from Pollock and coworkers, who reported that, in addition to the absence of hormone-suppressive medication, a maximum radiation dose >40 Gy was correlated significantly with a cure. 10 Neurotoxicity Four patients who received treatment before 1993 presented with radiation-induced brain damage. Intensified dose confirmation according to a risk-prediction

8 1362 CANCER September 15, 2006 / Volume 107 / Number 6 paradigm, 15 however, could prevent this side effect of RS completely during the following years. Brain damage also was reported after g-knife RS of pituitary adenomas with a frequency that ranged from 1.6% to 4.7%. 10,22,25,37 In the series by Witt and coworkers, 1 of 58 patients (1.7%) presented with contrast enhancement in the hypothalamus, suggesting a radiationinduced blood-brain barrier breakdown 12 months after therapy, and the patient died after an epileptic attack 4 months later. 37 Even though, in our protocol, the maximum tolerated dose prescribed to the optic system was set at 9 Gy, we observed radiation-induced neuropathy (RON) in 2 patients (1.4%). Because these patients were treated prior to the integration of MRI into our treatment-planning analyses, RON most probably was caused by the limited anatomic information from CT images. Only 1 group that used LINAC-RS observed RON with a significantly higher incidence of 38.7%. 41 However, in the series by Rocher and coworkers, 10 of 36 tumors were treated with a therapeutic dose of 20 Gy, even though there was close contact with the chiasm. Consequently, many of their patients were at risk a priori for radiation-induced damage of the anterior optic pathway, which significantly exceeded the risk for patients who had a sufficient distance between tumor and these structures. In an extensive review of the literature on g- knife-based RS for 1255 patients with pituitary adenomas, the frequency of RON was 0.9%, 44 which is comparable the frequency of RON in our population. In the same review, the reported rate of permanent damage to cranial nerves III, IV, and VI was 0.4% (5 patients), and the reported rate of injury to the trigeminal nerve was 0.2% (2 patients). 44 However, those structures were not affected in our patients. Hypothalamopituitary function In the current study, the total rate of developing hypopituitarism after LINAC-RS was 12.3% (14 of 114 analyzed patients), and the cumulative risk was 18.3% at 5 years. The reports after g-knife RS have yielded wide variation in the incidence of radiationinduced hypopituitarism. Although, in some series, patients did not require new hormone replacement, 25,27,36 others have reported that the incidence of requiring new hormone replacement varied from 1.5% to 29%. 10,29 32,34,38,39 Feigl et al. observed the highest incidence reported to date of 49%. 20 Other study groups that used LINAC-RS for pituitary adenomas reported shorter follow-up (12 49 months) than the current study but a higher incidence of radiogenic pituitary insufficiency (range, %) In contrast to the current study, which included a median of 3 isocenters per treatment, the radiation dose was applied in those other studies with only 1 isocenter. Because using more isocenters improves dose conformality, which, again reduces the dose delivered to the pituitary gland and/or pituitary stalk, the different outcomes between the current study and other LINAC series may be explained in part by the different irradiation strategies. This hypothesis is in accordance with factor analyses, which revealed a significant, direct relation between the radiation dose delivered to the pituitary gland 45 or pituitary stalk 20 and the occurrence of pituitary dysfunction after g-knife RS. Fractionated Radiotherapy According to a recently published review, local tumor control after XRT of pituitary adenomas varies from 67% to 98%, 46 which is comparable to the control achieved with RS. On average, GH was controlled in 77.3% of patients (143 of 185 patients; range, %), and ACTH was controlled in 40.7% of patients with Cushing disease (109 of 268 patients; range, 0 100%). Although the endocrine response to XRT is comparable to the results gained with RS, the time to remission is significantly longer. In the series by Zierhut et al., 47 normalization of GH occurred within a mean of 53 months (range, months), pathologically increased ACTH levels responded within 16 to 104 months, and 3 of 11 patients with a prolactinsecreting adenomas had normalized hormone values 37 months, 75 months, and 131 months after therapy. 47 In another study, Epaminonda et al. also demonstrated that the time from XRT to normalization of IGF-1 (mean 6 standard deviation, years) was considerably longer than after RS. 48 When XRT is performed according to modern treatment guidelines (single dose, 2Gy; total dose, 50 Gy), the risk for RON ranges from 1% to 3%. In contrast to RS, however, XRT carries a higher risk for the development of hypopituitarism (range, 13 56%). 46 During the last 5 years, the results from 2 larger studies (total, 172 treated patients) using stereotactic fractionated RT (SRT) have been published. Local tumor control rates from those studies were 95% 49 and 98.7%. 50 In the series by Milker-Zabel et al., 4 of 20 patients (25%) who had hormone-secreting adenomas had normalization of hormone hypersecretion within a median of 13.5 months. 49 Colin et al. reported a cure rate after SRT of 42% (median time to cure, 80 months). 50 Comparable to XRT, the time to cure is longer than after RS, but final cure rates obviously are in the same range. The risk for developing hypopituitarism after SRT was 40.7% at 4 years

9 LINAC-RS for Pituitary Macroadenomas/Voges et al and 50.1% at 8 years, 50 which similar to the data evaluated for XRT and, thus, higher than the risk after RS. Radiation damage of the anterior optic apparatus was reported differently for the 2 SRT series: Whereas Colin et al. observed no vision impairment caused by SRT, 50 Milker-Zabel et al. 49 reported an incidence of reduced visual acuity of 7%. In conclusion, LINAC-RS performed with a therapeutic radiation dose of 20 Gy is safe and highly effective in patients with small and surgically inaccessible pituitary macroadenomas. Compared with RS studies that used higher radiation doses, local tumor control rates and cure rates of hormone hypersecretion were similar. Although, in the current study, the reduced therapeutic dose delayed the time from RS to a cure, it still was significantly shorter than the time from XRT or SRT to a cure. 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