Stereotactic Radiosurgery for Pituitary Tumors

Neurosurg Focus 14 (5):Article 10, 2003, Click here to return to Table of Contents

Stereotactic radiosurgery for pituitary tumors

THOMAS C. WITT, M.D. Department of Neurosurgery, Indiana University Medical Center, Indianapolis, Indiana

Pituitary adenomas frequently pose challenging clinical problems. Stereotactic radiosurgery (SRS) is one treatment option in selected patients. The purpose of this report is to identify the advantages and disadvantages of radiosurgery in cases of pituitary tumors to assess better its role in relation to other treatment. Methods for optimizing outcome are described. The author reviews several recent series to determine rates of growth control, endocrine response, and complications. In general, growth control is excellent, complications are very low, and reduction of excessive hormone secretion is fair. Depending on the clinical situation, SRS may be the treatment of choice in selected patients.

KEY WORDS • stereotactic radiosurgery • pituitary tumor • acromegaly • prolactinoma • adrenocorticotropic hormone

Although pituitary adenomas are histologically benign, structures must not occur. The purpose of this report is to the unrelated neurological and physiological conse- analyze the current status of SRS for pituitary tumors and quences can be devastating. Compression of the optic ap- to examine its utility compared with other treatment mo- paratus (nerves, chiasm, tracts) may lead to blindness or dalities. loss of peripheral vision. Interference with the function of nerves traversing the cavernous sinus can result in diplo- pia and/or facial paresthesias. Further expansion of the tu- RADIOSURGICAL TECHNIQUES mor laterally into the temporal lobes or posteriorly into the hypothalamus can lead to significant cognitive problems. Stereotactic radiosurgery is performed using three general types of devices: a cyclotron that generates heavy Excessive GH production associated with acromegaly 50,51 can lead to life-threatening cardiovascular and respiratory particles such as protons and helium ions; a linear accelerator that generates x-ray beams;19 and a GK that gen- conditions, diabetes mellitus, and possibly an increased 60 risk of colon cancer. Prolonged hypersecretion of ACTH erates gamma rays from 201 sources of Co. The majority in Cushing disease can lead to severe problems with hy- of studies published in the last 15 years regarding radio- pertension and osteoporosis. In patients with prolactino- surgery for pituitary adenomas are from centers at which mas, galactorrhea and infertility may occur.87 the GK is used. Because the author’s experience is also Successful management of these tumors can be chal- primarily with the GK, its use in cases of pituitary adeno- lenging. Treatment options include microresection, medi- ma radiosurgery will be described in more detail. cal therapy, fractionated radiotherapy, and SRS. Stereotac- Once the decision has been made to treat a patient with SRS, preparation may begin several months prior to the tic radiosurgery was defined in 1951 by Lars Leksell as 40 the “closed skull destruction of an intracranial target using procedure. In 2000, Landolt, et al., first reported a signi- ionizing radiation.”49 Applied to pituitary adenomas, de- ficantly lower incidence of GH and IGF-I normalization struction of the target means prevention of the tumor’s in patients with acromegaly in whom antisecretory med- growth and normalization of hormone production. De- ications were administered at the time of radiosurgery. In struction of surrounding neural, endocrine, and vascular a separate report on patients with prolactinomas, Landolt and Lomax42 found that patients not receiving dopamine agonists at the time of radiosurgery have a significantly better chance of experiencing endocrinological cure than Abbreviations used in this paper: ACTH = adrenocorticotropic those who continue to take these medicines. Since then, hormone; CA = carotid artery; CT = computerized tomography; GH = growth hormone; GK = gamma knife; GKS = GK radio- others have also documented a negative effect of antise- surgery; ICA = internal carotid artery; IGF-I = insulin-like growth cretory medications administered at the time of radiosur- 72 factor–I; LINAC = linear accelerator; MR = magnetic resonance; gery on the reduction of excessive hormone secretion. PRL = prolactin; SRS = stereotactic radiosurgery; UFC = urinary- Landolt, et al.,40 speculated that these drugs lower the met- free cortisol. abolic rate of the tumor and consequently make the tumor

Neurosurg. Focus / Volume 14 / May, 2003 1

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC T. C. Witt less susceptible to radiation. The optimal length of time For identification of the tumor, MR imaging is far supe- for these medications to be withheld is not clear. For pa- rior to CT scanning. The latter may be used in cases in tients with prolactinomas, Landolt and Lomax42 recom- which a non–MR imaging–compatible metallic implant mended that dopamine agonists be withheld for 2 months exists or if the patient is too large to fit into a closed MR prior to radiosurgery. For patients with acromegaly receiv- imaging unit (the latter scenario is not unusual in patients ing the long-acting form of octreotide, the last injection with Cushing disease). When MR imaging is used, a post- should occur 4 months before the GK. Six weeks later, the Gd thin-slice (1-mm) volume-acquisition sequence is rec- medication should be switched to the immediate-release ommended. Depending on the patient’s history of treat- form, which should be maintained until 2 weeks before ra- ment and findings on preradiosurgery images, acquisition diosurgery. In these last 2 weeks before the procedure, no of precontrast studies or use of fat-suppression techniques antisecretory medications should be taken.40 Because the may help in identification of the tumor. If there is signifi- tumor may enlarge once these medications are stopped cant flow artifact across the sella from the CAs, the phase/ (Fig. 1), the potential benefits of these medication adjust- frequency-encoding direction can be flipped so that this ments must be weighed against the potential risks. A larg- artifact extends in an anteroposterior direction and does er tumor may mean a lower prescription dose and a high- not obscure the sella. er risk for surrounding structures. One relatively common problem in patients with Cush- On the day of the treatment, the stereotactic head frame ing disease is the inability to detect the tumor on the imag- is applied in the standard fashion. Mild intravenous seda- ing study,79 which may occur if the tumor is extremely tion is administered for adults, and general anesthesia is small or because neoplastic cells invaded the dura or have induced for children. The scalp is prepared with alcohol, diffusely infiltrated the gland.6,61,79 As long as pre-GKS and the areas of the pin placements are infiltrated with a tests strongly suggest that the tumor does reside in the long-lasting local anesthetic. It may be helpful to angle the sella, radiosurgery may still be successfully performed. frame parallel to the axis of the optic apparatus.26 In the Semple, et al.,79 Sheehan, et al.,81 and Shimon, et al.,84 author’s experience, this angle approximates a line joining have reported successful outcomes in microsurgical series the lateral canthus and the top of the pinna. One purpose when the tumor cannot be identified on a preoperative MR of this maneuver is to make identification of the optic images. Inferior petrosal sinus sampling can successfully nerves, chiasm, and tracts easier by having an MR or CT predict lateralization of the tumor 81% of the time.79 With- image that demonstrates the entire optic apparatus in a sin- out the aid of direct visualization and histological analysis gle slice. at the time of surgery, however, the predictive value of inferior petrosal sinus sampling may not be accurate enough to allow the radiosurgeon to target just one half of the gland. It is probably more reasonable to select the entire sella as the radiosurgical target in cases in which the tumor cannot be visualized to minimize chances of failure to normalize excessive hormone production. After stereotactic images have been acquired and trans- ferred into a computer workstation, multiple isocenter dose planning is performed to enclose the borders of the tumor within the prescription isodose line.16 The 50% isodose is the most common prescription isodose line in GKS series because this line is where the slope of the radiation falloff is the steepest.99 Beam blocking plug patterns are often used to distort the peripheral isodose curves away from the optic apparatus because of the radiosensitivity of this structure17 (Fig. 2). The need to use plug patterns can be reduced by adjusting the gamma angle so that the anteroposterior axis of the peripheral isodose curves is parallel to the optic apparatus in the sagittal plane. If the frame is placed parallel to the course of the optic apparatus, then a gamma angle of 90° may be used. This maneuver takes advantage of the extremely steep falloff of radiation dorsal to the isocenter. Selection of the prescription dose is based partially on the integrated logistic for- mula13,15 as well as specific strategies for protecting the optic apparatus, controlling tumor growth, and establishing and maintaining normal endocrinological function.

Fig. 1. Images obtained in a patient with a recurrent prolactin- EXPECTATIONS IN RADIOSURGERY oma. Upper: Coronal MR image obtained just prior to stopping cabergoline. Lower: Reconstructed CT scan acquired at the time There are two therapeutic goals when performing SRS of radiosurgery 2 months later. Note the expansion of the tumor for pituitary tumors. One goal is the arrest of tumor dorsally and laterally. growth and the prevention of future problems from mass

2 Neurosurg. Focus / Volume 14 / May, 2003

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC Review of SRS for pituitary adenomas

expanding literature on radiosurgery for growth control of other benign tumors.38,48 Another growth control concept that can be extrapolat- ed from Tables 1 through 5 is that radiosurgeons tend to use a lower margin dose for an endocrine-inactive tumor than for a secretory adenoma. This point becomes more obvious after examining the data from series that only include patients with endocrine-inactive tumors.83,98 In the other series, many authors reported one mean or median margin dose for the entire group of tumors, endocrine- active and -inactive lesions alike. The fact that their lower margin and maximum doses have been sufficient for achieving growth control is not surprising, because these doses have been reported to control other benign tumors.38,48 One unanswered question, however, is whether a higher dose is helpful in normalizing excessive hormone production. This issue will be subsequently addressed. Acromegaly in Radiosurgery A significant problem with the interpretation of the results of radiosurgically treated secretory adenomas is the lack of consistency in reporting “normal” results. This problem is most apparent in the series of patients with GH-producing tumors (Table 2). Endocrine cure rates vary from 0 to 96% with improvement shown in an additional 0 to 67% of patients. Out of the 20 series reported, however, six groups did not cite their criteria for a cure. Of Fig. 2. Upper: Multiple isocenter dose plan with plug pattern the 14 other studies, there are 11 different criteria used to to shift the 25% isodose curve away from the optic chiasm in a define cure. Endocrinologists have developed a consensus patient with recurrent endocrine-inactive adenoma. Lower: Fol- for what they consider a cure: GH less than 1 ng/ml in low-up image obtained 2 years later. The patient’s vision remains normal. response to a glucose challenge and normal serum IGF-I matched for age and sex.22,95 Of these two parameters, the IGF-I level is probably more significant.74 A random GH level is not considered reliable for assessment of cure.74,95 lesion-induced effect. The second is normalization of ex- There have been reports of persistent and progressive ac- cessive hormone production. The results obtained in 29 romegaly in patients with normal GH levels but elevated series published within the last 5 years will be discussed IGF-I levels.7 As long as these levels remain elevated, the in terms of these goals. The reports contain information on acromegaly-related morbidity also remains elevated.74 If 1255 patients. Their data are presented in Tables 1 through one examines the series in Table 2 in which the authors 5 for endocrine-inactive adenomas, GH-secreting adeno- followed criteria closest to the endocrinologists’ consen- mas, prolactin-secreting adenomas, Cushing disease, and sus, a fairly wide variation in results persists (20–82%). Nelson syndrome, respectively. One possible explanation for these variations may be differences in the number of patients in each series receiving Growth Control somatostatin analogs at the time of radiosurgery, because these medications appear to affect the impact of radiation One common interseries feature for almost all types of 40 tumor is the excellent growth control rate (92–100%). The on hormone secretion. one exception is the series of patients with Nelson syndrome reported by Pollock and Young73 in which tumor Prolactinoma in Radiosurgery growth occurred in two of 11 patients. The ACTH-pro- The endocrine cure rates for prolactinomas after radio- ducing tumors in patients who have undergone adrenalec- surgery are less than 30% in 13 of the 16 studies listed in tomy, however, tend to be more biologically aggressive Table 3. In a substantial number of patients (range 29– neoplasms.60 Because most pituitary adenomas are slow- 100%) significant reductions in PRL levels did occur. growing benign tumors, some skepticism concerning the Fortunately, variations in the definition of a normal PRL value of short-term follow-up studies is warranted, al- level are not as extreme as those in the assessment of GH though the follow-up duration in seven of these 29 studies function. The upper limits of normal values only vary includes periods longer than 8 years,28,29,72,82,83,85,96 and in between 15 and 29 ng/ml (Table 3). Analysis of the results one study by Hoybye, et al.,28 the mean follow-up period of prolactinoma-related results, however, may be signifi- was 17 years (range 12–22 years). In this latter study, cantly confounded by variations in the number of patients three patients needed surgery for persistent endocrinopa- receiving antisecretory dopamine agonists at the time of thy; no patient has required surgery or irradiation because radiosurgery.42 Additionally, because patients with non- of uncontrolled tumor growth. Therefore, the present data PRL-secreting adenomas may experience a slight hyper- on growth control for pituitary tumors augments the ever- prolactinemia after radiosurgery secondary to mild radia-

Neurosurg. Focus / Volume 14 / May, 2003 3

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC T. C. Witt

TABLE 1 Effects of SRS on tumor volume in patients with endocrine-inactive pituitary adenomas*

Radiosurgery No. of Follow Up Margin Max Growth Authors & Year Device Patients (mos)† Dose (Gy)† Dose (Gy)† Control (%)‡

Martinez, et al., 1997 GK 14 36 16 28 100 Lim, et al., 1998 GK 22 26 25 48 92 Mitsumori, et al., 1998 LINAC 7 47 15 19 100 Witt, et al., 1998 GK 24 32 19 38 94 Yoon, et al., 1998 LINAC 8 49 17 21 96 Hayashi, et al., 1999 GK 18 16 20 NR 92 Inoue, et al., 1999 GK 18 24 20 43 94 Mokry, et al., 1999 GK 31 21 14 28 98 Izawa, et al., 2000 GK 23 28 22 NR 94 Shin, et al., 2000 GK 3 19 16 NR 100 Feigl, et al., 2002 GK 61 55 15 NR 94 Sheehan, et al., 2002 GK 42 31 16 32 98 Wowra & Stummer, 2002 GK 30 58 16 29 93 * NR = Not recorded. † Expressed as either mean or median. ‡ Absence of tumor growth. tion-induced stalk effect,28 it may be that persistent post- hormone production is important. In the series examined radiosurgery elevation of PRL in a patient with a pro- in this paper, a decrease in hormone hypersecretion could lactinoma is due to a similar stalk effect and not hyper- be seen as early as 3 months after radiosurgery;82 on the secretion by residual tumor. other hand, normalization could take up to 8 years.85 If normalization is going to occur, it frequently does so Cushing Disease within the first 2 years.43,46,72,82,102 Some investigators have Endocrinologists continue to debate the criteria that found that the latency interval between radiosurgery and endocrine normalization is not dependent on margin should be used to define the endocrine cure of a patient 10 35 with Cushing disease.10,67 Most authors prefer to use the dose. In addition, Kim, et al., found that dose and level of UFC in a 24-hour urine collection to measure re- treatment volume do not affect the extent of hormonal response to treatment because, unlike serum ACTH and sponse. These same investigators demonstrated that max- serum cortisol levels, it is not susceptible to hourly physi- imum dose and the volume of tumor within the prescrip- ological fluctuations. Nevertheless, Newell-Price67 recent- tion isodose have a significant influence on the latency ly argued that the 9 a.m. serum cortisol level should be the interval to normalization. They recommended a maximum standard by which to define cure. Of the 18 studies listed dose of at least 55 Gy for secretory adenomas. Other investigators have observed a correlation between dose and in Table 4, eight groups did not report their criteria for 89 72 establishing cure. Although some of the differences in the hormonal response. Pollock, et al., found that in multi- reported criteria from the other centers are subtle, there re- variate analysis the only factors influencing extent of hor- main seven different definitions of cure among the 10 re- monal response were the absence of hormone-suppressive porting investigators. With this in mind, rates of endocrine therapy at the time of radiosurgery and a maximum dose cure vary from 10 to 100%. Two of the centers reporting greater than 40 Gy. In fact, none of the patients in this 100% success rates only treated three patients in each of series experienced an endocrine cure if receiving antisecretory medications at the time of radiosurgery. Pan, et their studies, and the 83% success rate reported by Hoy- 71 bye, et al.,28 was achieved by treating patients up to four al., also found a positive correlation between dose and times in the pre–CT/MR imaging era. If these three series hormonal response and have recommended a margin are not considered, the best result is the 78% cure rate dose of greater than 30 Gy for secretory adenomas. There obtained by Pollock, et al.72 seems to be no correlation between the volume response of the tumor and the endocrine response of the tumor.11,40,82 Nelson Syndrome Even though a high margin or maximum dose may not be conclusively proven to reduce excessive hormone produc- The limited data on SRS for ACTH-producing tumors tion, because the results of radiosurgery for normalizing in patients who have undergone bilateral adrenalectomy hormone production are less than excellent, it seems rea- are presented in Table 5. Based on this information, it sonable to continue to administer high doses for secretory appears that radiosurgery can be used successfully to con- tumors until a more effective strategy becomes apparent. trol this tumor type. Perhaps because of its potential to be relatively biologically aggressive, however, growth con- Cranial Neuropathy trol rates and endocrine cure rates may be lower than for 73 In the 1255 patients evaluated in the studies reviewed in other pituitary adenomas. this paper, there were 11 cases (0.9%) of new optic neuropathy; one of these deficits was transient.25,31,53,66,72,73,82, Rate of Endocrine Response 83,96,102 The severity of these deficits varied from homony- The speed at which a treatment causes normalization of mous quadrantanopsia to nonspecifically decreased visual

4 Neurosurg. Focus / Volume 14 / May, 2003

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC Review of SRS for pituitary adenomas acuity to blindness. The estimated doses at which these As reported in series in which meningiomas were deficits occurred varied from 0.7 to 12 Gy to the optic treated radiosurgically, the nerves of the cavernous sinus apparatus. Interestingly, one case of blindness was report- (oculomotor, trochlear, abducent, trigeminal) appear to be ed by Pollock, et al.,72 to have occurred at an estimated quite tolerant of high single-session radiation doses.8 In dose of 8 to 10 Gy, whereas four other patients in the same the 29 series reviewed in this paper, there were 13 new series remained asymptomatic despite treatment with deficits in 10 patients involving the third, fourth, or sixth greater than 12 Gy to the optic apparatus. Other investiga- cranial nerves.3,57,66,70,73,85,96,102 Seven of these deficits in tors have subjected the optic apparatus to doses as high as five patients were transient; thus, the permanent compli- 14.1 and 12 Gy without evidence of optic neuropathy.3,70 cation rate was 0.4% (five of 1255) patients regarding Most investigators have chosen an upper limit of 8 to 12 these nerves. New trigeminal neuropathy was reported in Gy as an acceptably safe radiation dose for the optic only (0.2%) two patients.96 nerve. The more conservative upper limit of 8 Gy is based Although radiosurgery is not usually performed with on data reported by investigators from the University of the expectation of improving neurological function, post- Pittsburgh and the Joint Center for Radiation Therapy in radiosurgery improvement in cranial nerve function in- Boston.90 From both a clinical and a theoretical radiobio- cluding vision has been reported in a small number of pa- logical standpoint, authors of more recent reports have tients.1,3,25,31,83,100 suggested that a small volume of the optic apparatus may be exposed to doses as high as 10 Gy without a signifi- Vascular Injury cantly increased risk of optic neuropathy.47,70 Both the ab- There has been one case of infarction due to ICA occlu- solute dose and the volume of exposed tissue appear to be sion after radiosurgery for a pituitary adenoma. Lim, et important in the probability of new visual deficits due to al.,52 reported on a 35-year-old man who underwent SRS radiosurgery. with a maximum dose of 40 Gy to a residual pituitary ade- An important criterion for deciding whether a tumor is noma that encased both CAs. The dose to the right ICA a candidate for SRS is its proximity to the optic apparatus. was estimated to be less than 20 Gy. Four years after GKS A clearance of at least 23,96 to 553,82 mm is desired. The radiosurgery, he developed left hemiparesis and a small absolute distance between these structures is not the limit- right internal capsule lacunar infarct was found. Imag- ing factor by itself. This distance defines how steeply the ing studies at that time also revealed that the tumor had radiation gradient must be constructed so that a tolerable significantly decreased in size. Doppler ultrasonography dose is delivered to the optic apparatus and an effective revealed total right ICA occlusion. The patient had no dose is still delivered to the tumor. If an acceptable gra- other known vascular risk factors. Pollock, et al.,72 report- dient cannot be constructed, then alternative treatments ed two cases of asymptomatic ICA stenosis and recom- should be performed. mended that the prescription dose coverage of the ICA

TABLE 2 Effects of SRS on endocrinopathy and tumor volume in patients with acromegaly

Endo- No. Follow Margin Max crine Endocrine Growth of Pa- Up Dose Dose Cure Improve- Controls Authors & Year Device tients (mos)* (Gy)* (Gy)* (%)† Criteria for Cure ment (%)‡ (%)§

Martinez, et al., 1997 GK 7 36 25 39 71 normal IGF-I 0 100 Landolt, et al., 1998 GK 16 NR 25 50 81 GH 10 mIU/L IGF-I 50 mIU/L NR NR Lim, et al., 1998 GK 20 26 25 48 38 GH 2 ng/ml 62 92 Mitsumori, et al., 1998 LINAC 1 47 15 19 0 NR NR 100 Morange-Ramos, et al., 1998 GK 15 20 28 NR 20 GH 5 ng/ml; normal IGF-I 67 NR Witt, et al., 1998 GK 20 32 19 38 20 normal IGF-I 13 94 Yoon, et al., 1998 LINAC 2 49 17 21 50 GH 5 ng/ml 0 96 Hayashi, et al., 1999 GK 22 16 24 NR 41 NR 49 92 Inoue, et al., 1999 GK 12 24 20 43 58 NR 42 94 MS Kim, et al., 1999 GK 2 12 22 36 0 NR 0 100 SH Kim, et al., 1999 GK 11 27 29 55 46 GH 5 ng/ml 36 68** Laws, et al., 1999 GK 56 NR NR NR 25 normal IGF-I for age & sex NR NR Mokry, et al., 1999 GK 16 46 16 33 31 GH 7 ng/ml; IGF-I 380 IU/ml 62 98 Izawa, et al., 2000 GK 29 28 22 NR 41 NR 52 94 Shin, et al., 2000 GK 6 43 34 NR 67 GH 10 mIU/L; IGF-I 450 ng/ml 33 100 Zhang, et al., 2000 GK 68 34 31 NR 96 GH 12 ng/ml 0 100 Fukuoka, et al., 2001 GK 9 42 20 41 50 GH 5 ng/ml; normal IGF-I NR 100 Ikeda, et al., 2001 GK 17 48 25 NR 82 normal age-adjusted IGF-I NR 100 Feigl, et al., 2002 GK 9 55 15 NR NR NR NR 94 Pollock, et al., 2002 GK 26 42 20 40 42 GH 2 ng/ml; normal age-adjusted IGF-I 19 100 * Expressed as either mean or median. † Normal values off medication. ‡ Either normal values on medication or improved values, still not normal. § Absence of growth. ** Expressed as percentage of tumors that decreased in size.

Neurosurg. Focus / Volume 14 / May, 2003 5

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC T. C. Witt

TABLE 3 Effects of SRS on endocrinopathy and tumor volume in patients with prolactinomas

Endocrine Growth No. of Follow Up Margin Max Endocrine Criteria for Cure Improvement Control Authors & Year Device Patients (mos)* Dose (Gy)* Dose (Gy)* Cure† (PRL level) (%)‡ (%)§

Martinez, et al., 1997 GK 5 36 33 43 0 20 ng/ml 100 100 Lim, et al., 1998 GK 19 26 25 48 56 25 ng/ml 33 92 Mitsumori, et al., 1998 LINAC 4 47 15 19 0 NR NR 100 Witt, et al., 1998 GK 12 32 19 38 0 NR 86 94 Yoon, et al., 1998 LINAC 11 49 17 21 84 25 ng/ml NR 96 Hayashi, et al., 1999 GK 13 16 24 NR 15 NR 54 92 Inoue, et al., 1999 GK 2 24 20 43 50 NR 50 94 MS Kim, et al., 1999 GK 20 12 22 36 19 NR 69 100 SH Kim, et al., 1999 GK 18 27 29 55 17 20 ng/ml 67 68†† Laws, et al., 1999 GK 19 NR NR NR 7 20 ng/ml NR NR Mokry, et al., 1999 GK 21 31 14 30 21 25 ng/ml 32 98 Morange-Ramos, et al., 1999 GK 4 20 28 NR 0 25 ng/ml (F); 100 NR 20 ng/ml (M)** Izawa, et al., 2000 GK 15 28 22 NR 20 NR 53 94 Landolt, et al., 2000 GK 20 29 25 50 25 19 ng/ml (F); 55 NR 16 ng/ml (M)** Pan, et al., 2000 GK 128 33 32 45 15 30 ng/ml 55 98 Feigl, et al., 2002 GK 18 55 15 NR NR NR NR 94 Pollock, et al., 2002 GK 7 42 20 40 29 23 ng/ml 29 100 * Expressed as either mean or median. † Normal values off medication. ‡ Either normal values on medication or improved values still not normal. § Absence of growth. ** Different values for females (F) and males (M). †† Expressed as percentage of tumors that decreased in size. should be limited to less than 50% of the vessel diameter. nomas. Some groups reported no patients requiring new Shin, et al.,85 recommended keeping the ICA dose to less hormone replacement.25,29,31,35,41,83,85,96 Others reported a than 30 Gy. relatively low incidence (1.5–29%) of some degree of anterior pituitary insufficiency.53,57,64,66,72,73,82,98,102 The Brain Injury authors of studies dedicated to the examination of this question11 or with a very long ( mean 17 years) follow-up In the 1255 patients reviewed in these 29 series, there 28 were 10 cases (0.8%) of irritation or radiation necrosis of period have revealed a moderately high (49 and 72%, re- the surrounding brain tissue. In two of these cases, the spectively) degree of hypopituitarism. It should be noted hypothalamus was affected. Kalapurakal, et al.,33 reported that the long-term report from the Karolinska Institute, in a patient suffering acute hyperthermia (105°) 5 hours after which the incidence of hypopituitarism was 72%, included patients treated without CT or MR imaging–based radiosurgery for a pituitary adenoma. The hypothalamus 28 11 was estimated to have received 16 Gy in this CT scan– plans, with doses up to 240 Gy. Feigl, et al., found that based plan. Within 20 hours, the patient’s temperature the only factor positively associated with the eventual normalized and no other explanation for the elevated tem- development of hypopituitarism was the radiation dose to perature could be found. Witt, et al.,96 reported a patient in the pituitary stalk. Factors not significant included sex, whom the hypothalamus enhanced 11 months after CT age, integral dose to tumor, preradiosurgery endocrine sta- scan–based radiosurgery for a pituitary tumor that had tus, target volume, dose to hypothalamus, normal pituitary been surgically treated and subjected to fractionated radio- gland, or median eminence. The authors suggested that therapy as well. Five months after the onset of this en- the higher incidence of hypopituitarism may have been hancement, the patient suffered a seizure and died. The due to the longer follow-up period, more detailed testing, relatively large tumor volume, and the fact that all 92 pa- remaining eight patients suffered temporal lobe injury fol- 11 14 lowing radiosurgery for pituitary adenomas.25,31,63,72,73 Four tients had undergone prior microsurgery. Pollock, et al., suggested a correlation between prescription treatment of these eight patients had also undergone prior fraction- 72 ated radiotherapy. Two of the eight patients developed volume and the risk of anterior pituitary insufficiency. seizure disorders, and one patient required a temporal lobectomy for radiation necrosis. A relatively lower dose Secondary Neoplasms should be considered in patients who have previously 14 There were no reports of new intracranial neoplasms in undergone fractionated radiotherapy. the 1255 patients reviewed in this paper. Of approximately 200,000 patients who have undergone GKS worldwide, Pituitary Insuffiency there are eight patients who have been treated with stere- There is wide variation in the reported incidence of otatic GKS and in whom a malignant brain tumor has la- hypopituitarism following radiosurgery for pituitary ade- ter been diagnosed.5,24,32,80,86,101 The possibility of a link

6 Neurosurg. Focus / Volume 14 / May, 2003

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC Review of SRS for pituitary adenomas

TABLE 4 Effects of SRS on endocrinopathy and tumor volume in patients with Cushing disease

Margin Max Endocrine Growth No. of Follow Dose Dose Endocrine Improve- Control Author & Year Device Patients Up (mos)* (Gy)* (Gy)* Cure (%)† Criteria for Cure ment (%) ‡ (%)§

Martinez, et al., 1997 GK 3 36 24 40 100 ACTH 10 µg/L; 0 100 UFC 650 nmol/24 hr Lim, et al., 1998 GK 4 26 25 48 25 NR 50 92 Mitsumori, et al., 1998 LINAC 5 47 15 19 40 NR NR 100 Morange-Ramos, et al., 1998 GK 6 20 28 NR 67 UFC 90 µg/24 hr; 0 NR normal ACTH; normal cortisol Witt, et al., 1998 GK 25 32 19 38 28 normal 24 hr UFC 14 94 Yoon, et al., 1998 LINAC 1 49 17 21 NR NR NR 96 Hayashi, et al., 1999 GK 10 16 24 NR 10 NR 40 92 Inoue, et al., 1999 GK 3 24 20 43 100 NR 0 94 SH Kim, et al., 1999 GK 8 27 29 55 62 UFC 100 µg/24 hr 12 68†† Laws, et al., 1999 GK 50 NR NR NR 58 normal 24 hr UFC NR NR Mokry, et al., 1999 GK 5 56 17 35 33 NR 33 98 Izawa, et al., 2000 GK 12 28 22 NR 17 NR 42 94 Sheehan, Vance, et al., 2000 GK 43 44 20 47 63 normal 24 hr UFC NR 100 Shin, et al., 2000 GK 7 88 32 NR 50 UFC 90 µg/24 hr NR 100 Hoybye, et al., 2001 GK 18 204 NR 60–240 83 normal 24 hr UFC; 0 83** 8 a.m. ACTH; 11 pmol/L Feigl, et al., 2002 GK 4 55 15 NR# NR NR NR 94 Kobayashi, et al., 2002 GK 20 64 29 49 35 ACTH 50 pg/ml; 50 100 cortisol 10 µg/dl Pollock, et al., 2002 GK 9 42 20 40 78 UFC 90 µg/24 hr 0 100 * Expressed as either mean or median. † Normal values off medication. ‡ Either normal values on medication or improved values, still not normal. § Absence of growth. ** Expressed as percentage of patients who did not need further surgery. †† Expressed as percentage of tumors that decreased in size. between radiosurgery and the malignant tumor is stronger 16 to 28–Gy margin doses (median 24 Gy). Dose plans in some cases, weaker in others, and conclusively proven were constructed to attempt to keep the dose to the optic in none. apparatus less than 8 Gy; in two patients a small volume of optic tissue received 9 Gy. Six of the patients in our series were treated within 6 ALTERNATIVE TREATMENT OPTIONS months of submission of this paper and will not be included in follow-up analysis. The follow-up interval in the Stereotactic Radiosurgery at Indiana University other 16 patients varied from 6 to 48 months (median 24 At the author’s institution, 22 patients have undergone months). No MR imaging evidence of tumor growth has stereotactic GKS for pituitary adenomas since September been demonstrated. Five tumors (31%) have decreased in 1997: three patients with endocrine-inactive tumors; two size. No patient has developed a new neurological deficit. with prolactinomas; eight with Cushing disease; two with One patient with an ACTH-producing tumor in the cav- Nelson syndrome; six with GH-secreting tumors; and one ernous sinus experienced marked improvement in third with a mixed GH–PRL secreting tumor. Age at the time and sixth cranial nerve palsies as well as post-GKS shrink- of radiosurgery ranged from 17 to 86 years (median 49 age of the tumor. years). Eleven men and 11 women were treated. Nineteen Of the four patients with GH-secreting tumors, normal- patients (86%) had undergone at least one resection prior ization of the IGF-I level has occurred in only one patient. to radiosurgery. Five patients had undergone two resec- This patient harbors a mixed GH-PRL–producing tumor tions and two had received fractionated radiotherapy be- and was receiving bromocriptine at the time of radiosur- fore GKS. The three patients with secretory adenomas gery. His IGF-I level was 409 ng/ml before radiosurgery who did not undergo resection were very poor medical and was 76 ng/ml 36 months after the procedure. He candidates for general anesthesia and/or had tumor in- continues to receive bromocriptine (at a lower dose [2.5 volvement of the cavernous sinus. mg/day]), and his PRL level is normal. In the other three In all patients, multiple isocenter dose planning was patients, the IGF-I level remains unchanged at 31 months, conducted to enclose the borders of the tumor within the 78% of the pretreatment level at 12 months, and 66% of 50% isodose curve. The three endocrine-inactive tumors the pretreatment level at 6 months. None of these patients were treated with margin doses of 13, 16, and 20 Gy, re- was taking a somatostatin analog at the time of radio- spectively. The 19 secretory adenomas were treated with surgery.

Neurosurg. Focus / Volume 14 / May, 2003 7

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC T. C. Witt

A more encouraging endocrine response has been tations. These benefits and risks will be placed in per- demonstrated in the two patients with prolactinomas. Nei- spective relative to those associated with radiosurgery. ther was receiving dopamine agonists at the time of radiosurgery. In one patient the PRL level dropped by 80% Microresection of the Lesion within the first 6 months after treatment and is normal, off If a patient is neurologically compromised as a result of medication, at 48 months. The second patient was placed pituitary adenoma–induced mass effect, microresection is back on cabergoline after radiosurgery. Twelve months usually the procedure of choice. Microsurgery also allows after her procedure, her PRL level on medication is 36% for the most rapid reduction in excessive hormone levels. of the pretreatment on medication level. Endocrine remission may be achieved in 56 to 91% of Both patients with Nelson syndrome had a significant patients with Cushing disease,45,75,84 28 to 72% of those decrease in ACTH level as well as a significant decrease with acromegaly,29,45 and 24 to 87% of patients with pro- in tumor volume after radiosurgery. the ACTH decreased lactinomas.45,55,65,69 Long-term tumor control rates for pa- by 90% at 34 months in one patient and by 68% at 25 tients with endocrine-inactive tumors vary from 50 to months in the other. The level, however, has not normal- 90%.83 Remission and control rates are significantly lower ized in either case. for patients with invasive extrasellar tumors. Current com- Only one of our eight patients with Cushing disease has plication rates in the most experienced hands are less than had a radiographically identifiable tumor. In this patient 0.5% mortality, 1.5% major morbidity, and less than 3% an 84% reduction in ACTH level was demonstrated at 35 iatrogenic hypopituitarism.45 A survey in 1997 of neuro- months but remission has not occurred. Our strategy for surgeons in the US, however, showed that transsphenoidal treating patients in whom a discrete tumor cannot be iden- surgery for pituitary tumors is associated with a 3.9% risk tified has changed over the years. At first, we used infor- of CSF leak, a 1.8% risk of new visual deficit, a 19.4% mation derived from examination of the patient’s prior risk of pituitary insufficiency, and a 0.9% risk of death.4 In transsphenoidal resection specimen as well as postopera- cases in which surgery for residual or recurrent tumors is tive inferior petrosal sinus sampling to select one half of performed after prior therapy, significantly lower success the pituitary gland as the target. We then conformed our rates and significantly higher complication rates have prescription isodose to this half of the sella, from the level been reported.44 of the pituitary stalk as the medial margin to the medial border of the ICA as the lateral margin. We have treated three patients in this fashion. In two patients the 24-hour Medical Therapy UFC values were normal at 10 and 24 months, respec- Administration of dopamine agonists such as bromo- tively; in the third patient severe clinical signs of Cushing criptine, cabergoline, quinagolide, metergoline, and li- disease exist, and the patient requires ketoconazole. De- suride inhibits PRL production, causes individual cell spite the somewhat promising results in two of these pa- volume to decrease, and subsequently induces tumor tients, we now select the entire gland for the radiosurgical shrinkage. Normalization of PRL levels resulting from target in patients without a radiographically visible tumor. dopaminergic therapy has been reported to be as high as The morbidity attendant on failing to treat tumor cells in 70 to 100%. The tumor mass decreases by 80 to 90%. The the other half of the gland seems greater than that associ- time course of these responses, however, can vary from ated with of treating the entire gland. The two patients in days to months, and the degree of reduction is variable whom we have targeted the entire gland have experienced and unpredictable as well. Side effects may limit the only modest improvement in urinary free cortisol and length of time that a patient is able to tolerate a certain ACTH levels at 13 months. medication dose. These side effects include nausea, vom- Additional treatment options for patients with pituitary iting, dizziness, postural hypotension, headaches, and be- adenomas include microresection, medical therapy, and havioral disturbances. Another drawback of dopaminergic fractionated irradiation. These treatments are not neces- therapy is that it is a lifelong treatment regimen; if drug sarily exclusive of each other or SRS. For some patients therapy is stopped, tumor expansion and PRL hypersecre- with particularly challenging tumors, a combination of tion will resume.69 two or more modalities may be required. As with radio- Patients with acromegaly can undergo medical manage- surgery, each treatment methods has advantages and limi- ment involving somatostatin analogs such as octreotide as

TABLE 5 Effects of SRS on endocrinopathy and tumor volume in patients with Nelson syndrome

Margin Max Endocrine Growth No. of Follow Up Dose Dose Endocrine Criteria Improve- Control Authors & Year Device Patients (mos)* (Gy)* (Gy)* Cure (%)† for Cure ment (%)‡ (%)§

Wolffenbuttel, et al., 1998 GK 1 33 12 40 0 NR 100 100 Laws, et al., 1999 GK 9 NR NR NR 11 NR NR NR Pollock, et al., 2002 GK 11 37 20 40 36 NR 54 82 * Expressed as either mean or median. † Normal values off medication. ‡ Either normal values on medication or improved values still not normal. § Absence of growth.

8 Neurosurg. Focus / Volume 14 / May, 2003

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC Review of SRS for pituitary adenomas well as the aforementioned dopamine agonists. Somato- pected to have a greater impact on hormone production statin analogs normalize GH and IGF-I levels in 50 to than radiotherapy. Comparison of results of hormone nor- 79% of treated patients.2,62,68 These medications also cause malization in radiosurgery series to radiotherapy series is a modest (30–50%) reduction in tumor volume in 40 to made difficult by the inconsistent standards of normal 73% of patients.2,62,68 Some endocrinologists advocate so- values used by different investigators. In series in which matostatin analog therapy as the second-line treatment the data are examined by the same authors, radiosurgery after microsurgery and the first-line therapy if the patient appears to lead to hormone level normalization signifi- is not a good candidate for surgery.62 Dopamine agonists cantly faster than radiotherapy.41 The use of stereotactic will help lower GH levels in only approximately 10% of methods in the delivery of fractionated irradiation may be patients.62 There are some significant disadvantages of expected to decrease some of the complications of con- long-term somatostatin analog therapy for patients with ventional fractionated radiotherapy because less normal acromegaly. The drug may take several months to have an tissue is irradiated, but the radiobiological effect on the impact on GH levels and tumor volume.62 Gastrointestinal target tumor should not be any different than the effects side effects are common.62,68 The drug must be admin- of conventional radiotherapy. The results of fractionated istered by injection; this has become less of a limitation, stereotactic radiotherapy are currently too limited in num- however, because of the development of long-acting forms bers of patients and follow-up duration to allow adequate that can be administered once every 4 weeks.2 Normali- comparison to radiosurgery or conventional radiotherapy zation of GH and IGF-I levels and reduction of tumor vol- series. ume do not always occur concomitantly. In one study by There are some situations in which fractionated radio- Bevan, et al.,2 only 29% of patients achieved all three therapy may be preferable to radiosurgery. One involves a parameters of normal GH, normal IGF-I, and a greater tumor volume that is so large that an effective radiation than 30% reduction in tumor volume. The drug is very ex- dose cannot be safely delivered in a single session. The pensive, and if it is to be used as the sole treatment modal- minimally effective dose to control a benign tumor has not ity, it needs to be continued for the rest of the patient’s been established, but doses as low as 12 Gy have been life.62 administered to achieve successfully long-term growth Cushing disease is less commonly treated medically control in vestibular schwannomas.38 Extrapolating from than acromegaly or hyperprolactinemia. The most com- the integrated logistical formula, the maximum volume mon drug used in Cushing disease is ketoconazole, an an- that can be treated at this dose with a less than 3% risk tifungal drug that inhibits steroid biosynthesis in the adre- of complications is approximately 23 cm3.13 A spherical nal gland. Other less frequently used inhibitors of steroid structure of this volume would have a mean diameter of synthesis at the adrenal level include aminoglutethimide, 35 mm. Fractionated radiotherapy may also be preferable metyrapone, and mitotane. The peripheral receptor sites to radiosurgery if the tumor is too close to the optic appa- for glucocorticoid drugs can be blocked by mifepristone. ratus to achieve an acceptable falloff gradient with single- The production of ACTH can be inhibited by serotonin session irradiation. antagonists (cyproheptadine), dopamine agonists (bromocriptine), GABA agonist (depakote), and somatostatin analogs such as octreotide.88 CONCLUSIONS Stereotactic radiosurgery can be a relatively safe, effec- Fractionated Radiotherapy tive procedure for patients with pituitary adenomas. There are certainly cases in which radiosurgery is not the most Fractionated radiotherapy has been used for decades to appropriate treatment. In a patient harboring a relatively treat patients with unresectable pituitary adenomas. Rates small, medically refractory tumor in a surgically inacces- of tumor growth control vary from 76 to 97%.58,59,76,78, sible location, however, radiosurgery may provide the best 92,93,103 Fractionated radiotherapy has been less successful opportunity for long-term preservation of neurological (30–83%) in reducing hypersecretion of hormones by function and for the restoration as well as preservation of tumors.9,23,27,69,74,77,93,103 Complications related to fraction- normal endocrine function. ated irradiation include a relatively high rate (12–100%) There are several challenging issues that stereotactic of hypopituitarism12,23,37,54,58,59,76,77,78,91,92,103 and a low but neurosurgeons and radiation oncologists should address to still significant risk (1–3%) of optic neuropathy12,18,37,58, improve the outcomes of patients undergoing pituitary 59,77,103 and induction of a secondary tumor (2.7% actuari- adenoma radiosurgery. The optimal timing of administra- al incidence at 15 years).94 Fractionated irradiation also tion of antisecretory medications with respect to the date contributes to the development of cognitive function in of radiosurgery needs to be clarified. Attempts should be patients who have already undergone surgery for pituitary made to identify other factors that can improve the re- tumors.59 sponse of secretory adenomas to radiosurgery. The opti- Although the risks of hypopituitarism, brain radione- mal target in a patient with an “invisible” tumor needs to crosis, and radiation-induced neoplasia may not be non- be determined. The function of the normal pituitary gland existent with radiosurgery, they risks to be significantly following radiosurgery for a pituitary adenoma should be higher in patients in whom have radiotherapy for pituitary studied more thoroughly. Along with physicians in other adenomas. Radiobiologically, the doses currently deliv- specialties who care for these patients, a consistent defin- ered in single-session radiosurgery are equivalent to those ition of endocrine cure needs to be established and fol- that would be too toxic to be given by multiple-fraction lowed to determine the optimal treatment for individual radiotherapy.20,39,56 Therefore, radiosurgery would be ex- patients.

Neurosurg. Focus / Volume 14 / May, 2003 9

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC T. C. Witt

References 22. Giustina A, Barkan A, Casanueva FF, et al: Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 1. Abe T, Yamamoto M, Taniyama M, et al: Early palliation of oc- 85:526–529, 2000 ulomotor nerve palsy following gamma knife radiosurgery for 23. Goffman TE, Dewan R, Arakaki R, et al: Persistent or recurrent pituitary adenoma. Eur Neurol 47:61–63, 2002 acromegaly: Long-term endrocrinologic efficacy and neurolog- 2. Bevan JS, Atkin SL, Atkinson AB, et al: Primary medical ther- ic safety of postsurgical radiation therapy. Cancer 69:271–275, apy for acromegaly: an open, prospective, multicenter study of 1992 the effects of subcutaneous and intramuscular slow-release oc- 24. Hanabusa K, Morikawa A, Murata T, et al: Acoustic neuroma treotide on growth hormone, insulin-like growth factor-1, and with malignant transformation. Case report. J Neurosurg 95: tumor size. J Clin Endocrinol Metab 87:4554–4563, 2002 518–521, 2001 3. Chen JC, Giannotta SL, Yu C, et al: Radiosurgical management 25. Hayashi M, Izawa M, Hiyama H, et al: Gamma Knife radiosur- of benign cavernous sinus tumors: dose profiles and acute com- gery for pituitary adenomas. Stereotact Funct Neurosurg 72 plications. Neurosurgery 48:1022–1032, 2001 (Suppl 1):111–118, 1999 4. Ciric I, Ragin A, Baumgartner C, et al: Complications of 26. Hayashi M, Taira T, Chernov M, et al: Gamma knife surgery for transsphenoidal surgery: results of a national survey, review cancer pain-pituitary gland-stalk ablation: a multicenter pro- of the literature, and personal experience. Neurosurgery 40: spective protocol since 2002. J Neurosurg (Suppl 5) 97: 225–237, 1997 433–437, 2002 5. Comey CH, McLaughlin MR, Jho HD, et al: Death from a ma- 27. Howlett TA, Plowman PN, Wass JA, et al: Megavoltage pitu- lignant cerebellopontine angle triton tumor despite stereotactic itary irradiation in the management of Cushing’s disease and radiosurgery. Case report. J Neurosurg 89:653–658, 1998 Nelson’s syndrome: long-term follow-up. Clin Endocrinol 31: 6. Dickerman RD, Oldfield EH: Basis of persistent and recurrent 309–323, 1989 Cushing disease: an analysis of findings at repeated pituitary surgery. J Neurosurg 97:1343–1349, 2002 28. Hoybye C, Grenback E, Rahn T, et al: Adrenocorticotrophic 7. Dimaraki EV, Jaffe CA, DeMott-Friberg R, et al: Acromegaly hormone-producing pituitary tumors: 12- to 22-year follow up with apparently normal GH secretion: implications for diagno- after treatment with stereotactic radiosurgery. Neurosurgery sis and follow-up. J Clin Endocrinol Metab 87:3537–3542, 49:284–292, 2001 2002 29. Ikeda H, Jokura H, Yoshimoto T: Transsphenoidal surgery and 8. Duma CM, Lunsford LD, Kondziolka D, et al: Stereotactic adjuvant gamma knife treatment for growth hormone-secreting radiosurgery of cavernous sinus meningiomas as an addition or pituitary adenoma. J Neurosurg 95:285–291, 2001 alternative to microsurgery. Neurosurgery 32:699–705, 1993 30. Inoue HK, Kohga H, Hirato M, et al: Pituitary adenomas treat- 9. Estrada J, Boronat M, Mielgo M, et al: The long-term outcome ed by microsurgery with or without Gamma Knife surgery: ex- of pituitary irradiation after unsuccessful transsphenoidal sur- perience in 122 cases. Stereotact Funct Neurosurg 72 (Suppl gery in Cushing’s disease. N Engl J Med 336:172–177, 1997 1):125–131, 1999 10. Estrada J, Garcia-Uria J, Lamas C, et al: The complete normal- 31. Izawa M, Hayashi M, Nakaya K, et al: Gamma knife radiosur- ization of the adrenocortical function as the criterion of cure gery for pituitary adenomas. J Neurosurg (Suppl 3) 93:19–22, after transsphenoidal surgery for Cushing’s disease. J Clin En- 2000 docrinol Metab 86:5695–5699, 2001 32. Kaido T, Hoshida T, Uranishi R, et al: Radiosurgery-induced 11. Feigl GC, Bonelli CM, Berghold A, et al: Effects of gamma brain tumor. Case report. J Neurosurg 95:710–713, 2001 knife radiosurgery of pituitary adenomas on pituitary function. 33. Kalapurakal JA, Silverman CL, Akhtar N, et al: Acute hyper- J Neurosurg (Suppl 5) 97:415–421, 2002 thermia following stereotactic radiosurgery for pituitary adeno- 12. Fisher BJ, Gaspar LE, Noone B, et al: Radiation therapy of pi- ma. Br J Radiol 72:1218–1221, 1999 tuitary adenoma: delayed sequelae. Radiology 187:843–846, 34. Kim MS, Lee SI, Sim JH: Gamma knife radiosurgery for func- 1993 tioning pituitary microadenoma. Stereotact Funct Neurosurg 13. Flickinger JC: An integrated logistic formula for prediction of 72 (Suppl 1): 119–124, 1999 complications from radiosurgery. Int J Radiat Oncol Biol 35. Kim SH, Huh R, Chang JW, et al: Gamma knife radiosurgery Phys 17:879–885, 1989 for functioning pituitary adenomas. Stereotact Funct Neuro- 14. Flickinger JC, Deutsch M, Lunsford LD, et al: Repeat mega- surg 72 (Suppl 1):101–110, 1999 voltage irradiation of pituitary and suprasellar tumors. Int J 36. Kobayashi T, Kida Y, Mori Y, et al: Gamma knife radiosurgery Radiat Oncol Biol Phys 17:171–175, 1989 in the treatment of Cushing disease: long-term results. J Neu- 15. Flickinger JC, Lunsford LD, Kondziolka D: Dose prescription rosurg (Suppl 5) 97:422–428, 2002 and dose-volume effects in radiosurgery. Neurosurg Clin N 37. Kokubo M, Sasai K, Shibamoto Y, et al: Long-term results Am 3:51–59, 1992 of radiation therapy for pituitary adenoma. J Neurooncol 47: 16. Flickinger JC, Lunsford LD, Wu A, et al: Treatment planning 79–84, 2000 for gamma knife radiosurgery with multiple isocenters. Int J 38. Kondziolka D, Lunsford LD, Flickinger JC: Gamma knife ra- Radiat Oncol Biol Phys 18:1495–1501, 1990 diosurgery for vestibular schwannomas. Neurosurg Clin N 17. Flickinger JC, Maitz A, Kalend A, et al: Treatment volume Am 11:651–658, 2000 shaping with selective beam blocking using the Leksell gamma 39. Kondziolka D, Somaza S, Comey C, et al: Radiosurgery and unit. Int J Radiat Oncol Biol Phys 19:783–789, 1990 fractionated radiation therapy: comparison of different tech- 18. Flickinger JC, Nelson PB, Martinez AJ, et al: Radiotherapy of niques in an in vivo rat glioma model. J Neurosurg 84: nonfunctional adenomas of the pituitary gland. Results with 1033–1038, 1996 long-term follow-up. Cancer 63:2409–2414, 1989 40. Landolt AM, Haller D, Lomax N, et al: Octreotide may act as a 19. Foote KD, Friedman WA, Buatti JM, et al: Linear accelerator radioprotective agent in acromegaly. J Clin Endocrinol Metab radiosurgery in brain tumor management. Neurosurg Clin N 85:1287–1289, 2000 Am 10:203–242, 1999 41. Landolt AM, Haller D, Lomax N, et al: Stereotactic radiosur- 20. Fowler JF: Radiation-induced lung damage: dose-time fraction- gery for recurrent surgically treated acromegaly: comparison ation considerations. Radiother Oncol 18:184–187, 1990 with fractionated radiotherapy. J Neurosurg 88:1002–1008, 21. Fukuoka S, Ito T, Takanashi M, et al: Gamma knife radiosur- 1998 gery for growth hormone-secreting pituitary adenomas in- 42. Landolt AM, Lomax N: Gamma knife radiosurgery for pro- vading the cavernous sinus. Stereotact Funct Neurosurg 76: lactinomas. J Neurosurg (Suppl 3) 93:14–18, 2000 213–217, 2001 43. Laws ER, Vance ML, Thapar K: Pituitary surgery for the

10 Neurosurg. Focus / Volume 14 / May, 2003

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC Review of SRS for pituitary adenomas

management of acromegaly. Horm Res 53 (Suppl 3):71–75, ment of pituitary adenomas. Stereotact Funct Neurosurg 72 2000 (Suppl 1):88–100, 1999 44. Laws ER Jr, Fode NC, Redmond MJ: Transsphenoidal surgery 65. Molitch ME: Disorders of prolactin secretion. Endocrinol Me- following unsuccessful prior therapy. An assessment of benefits tab Clin North Am 30:585–610, 2001 and risks in 158 patients. J Neurosurg 63:823–829, 1985 66. Morange-Ramos I, Regis J, Dufour H, et al: Gamma-knife sur- 45. Laws ER Jr, Thapar K: Pituitary surgery. Endocrinol Metab gery for secreting pituitary adenomas. Acta Neurochir 140: Clin North Am 28:119–131, 1999 437–443, 1998 46. Laws ER Jr, Vance ML: Radiosurgery for pituitary tumors 67. Newell-Price J: Transsphenoidal surgery for Cushing’s Disease: and craniopharyngiomas. Neurosurg Clin N Am 10:327–336, defining cure and following outcome. Clin Endocrinol 56: 1999 19–21, 2002 47. Leber KA, Bergloff J, Pendl G, et al: Dose-response tolerance 68. Newman CB: Medical therapy for acromegaly. Endocrinol of the visual pathways and cranial nerves of the cavernous sinus Metab Clin North Am 28:171–190, 1999 to stereotactic radiosurgery. J Neurosurg 88:43–50, 1998 69. Nomikos P, Buchfelder M, Fahlbusch R: Current management 48. Lee JY, Niranjan A, McInerney J, et al: Stereotactic radio- of prolactinomas. J Neurooncol 54:139–150, 2001 surgery providing long-term tumor control of cavernous sinus 70. Ove R, Kelman S, Amin PP, et al: Preservation of visual fields meningiomas. J Neurosurg 97:65–72, 2002 after peri-sellar gamma-knife radiosurgery. Int J Cancer 90: 49. Leksell L: The stereotaxic method and radiosurgery of the 343–350, 2000 brain. Acta Chir Scand 102:316–319, 1951 71. Pan L, Zhang N, Wang EM, et al: Gamma knife radiosurgery as 50. Levy RP, Fabrikant JI, Frankel KA, et al: Heavy-charged-parti- a primary treatment for prolactinomas. J Neurosurg (Suppl 3) cle radiosurgery of the pituitary gland: clinical results of 840 93:10–13, 2000 patients. Stereotact Funct Neurosurg 57:22–35, 1991 72. Pollock BE, Nippoldt TB, Stafford SL, et al: Results of stereo- 51. Levy RP, Fabrikant JI, Frankel KA, et al: Particle-beam irradi- tactic radiosurgery in patients with hormone-producing pitu- ation of the pituitary gland, in Alexander E 3rd, Loeffler JS, itary adenomas: factors associated with endocrine normaliza- Lunsford LD (eds): Stereotactic Radiosurgery. New York: tion. J Neurosurg 97:525–530, 2002 McGraw-Hill, 157–165, 1993 73. Pollock BE, Young WF Jr: Stereotactic radiosurgery for pa- 52. Lim YJ, Leem W, Park JT, et al: Cerebral infarction with ICA tients with ACTH-producing pituitary adenomas after prior occlusion after Gamma Knife radiosurgery for pituitary adeno- adrenalectomy. Int J Radiat Oncol Biol Phys 54:839–841, ma: a case report. Stereotac Funct Neurosurg 72 (Suppl 1): 2002 132–139, 1999 74. Powell JS, Wardlaw SL, Post KD, et al: Outcome of radiother- 53. Lim YL, Leem W, Kim TS, et al: Four years’ experiences in the apy for acromegaly using normalization of insulin-like growth treatment of pituitary adenomas with gamma knife radiosur- factor I to define cure. J Clin Endocrinol Metab 85: gery. Stereotact Funct Neurosurg 70 (Suppl 1):95–109, 1998 2068–2071, 2000 54. Littley MD, Shalet SM, Beardwell CG, et al: Hypopituitarism 75. Rees DA, Hanna FW, Davies JS, et al: Long-term follow-up following external radiotherapy for pituitary tumours in adults. results of transsphenoidal surgery for Cushing’s disease in a Q J Med 70:145–160, 1989 single centre using strict criteria for remission. Clin Endo- 55. Losa M, Mortini P, Barzaghi R, et al: Surgical treatment of pro- crinol 56:541–551, 2002 lactin-secreting pituitary adenomas: early results and long-term 76. Rush S, Cooper PR: Symptom resolution, tumor control, and outcome. J Clin Endocrinol Metab 87:3180–3186, 2002 side effects following postoperative radiotherapy for pituitary 56. Marks LB: Conventional fractionated radiation therapy vs. ra- macroadenomas. Int J Radiat Oncol Biol Phys 37: diosurgery for selected benign intracranial lesions (arteriove- 1031–1034, 1997 nous malformations, pituitary adenomas, and acoustic neurino- 77. Rush SC, Newall J: Pituitary adenomas: the efficacy of radio- mas). J Neurooncol 17:223–230, 1993 therapy as the sole treatment. Int J Radiat Oncol Biol Phys 57. Martinez R, Bravo, G, Burzaco, et al: Pituitary tumors and 17:165–169, 1989 gamma knife surgery. Clinical experience with more than two 78. Salinger DJ, Brady LW, Miyamoto CT: Radiation therapy in years of follow-up. Stereotact Funct Neurosurg 70 (Suppl the treatment of pituitary adenomas. Am J Clin Oncol 15: 1):110–118, 1997 467–473, 1992 58. McCollough WM, Marcus RB Jr, Rhoton AL Jr, et al: Long- 79. Semple, PL, Vance, ML, Findling J, et al: Transsphenoidal sur- term follow-up of radiotherapy for pituitary adenoma: The ab- gery for Cushing’s disease: Outcome in patients with a normal sence of late recurrence after ≥ 4,500 cGY. Int J Radiat Oncol magnetic resonance imaging scan. Neurosurgery 46:553–559, Biol Phys 21:607–614, 1991 2000 59. McCord MW, Buatti JM, Fennell EM, et al: Radiotherapy for 80. Shamisa A, Bance M, Nag S, et al: Glioblastoma multiforme pituitary adenoma: long-term outcome and sequelae. Int J Ra- occurring in a patient treated with gamma knife surgery. Case diat Oncol Biol Phys 39:437–444, 1997 report and review of the literature. J Neurosurg 94:816–821, 60. McCutcheon IE: Stereotactic radiosurgery for patients with 2001 ACTH-producing pituitary adenomas after prior adrenalecto- 81. Sheehan JM, Lopes MB, Sheehan JP, et al: Results of trans- my. Int J Radiat Oncol Biol Phys 54:640–641, 2002 sphenoidal surgery for Cushing’s disease in patients with no 61. Meij BP, Lopes MB, Ellegala DB, et al: The long-term signifi- histologically confirmed tumor. Neurosurgery 47:33–36, 2000 cance of microscopic dural invasion in 354 patients with pitu- 82. Sheehan JM, Vance ML, Sheehan JP, et al: Radiosurgery for itary adenomas treated with transsphenoidal surgery. J Neuro- Cushing’s disease after failed transsphenoidal surgery. J Neu- surg 96:195–208, 2002 rosurg 93:738–742, 2000 62. Melmed S, Casanueva F, Cavagnini F, et al: Guidelines for 83. Sheehan JP, Kondziolka D, Flickinger J, et al: Radiosurgery for acromegaly management. J Clin Endocrinol Metab, 87: residual or recurrent nonfunctioning pituitary adenoma. J Neu- 4054–4058, 2002 rosurg (Suppl 5) 97:408–414, 2002 63. Mitsumori M, Shrieve DC, Alexander E 3rd, et al: Initial clini- 84. Shimon I, Ram Z, Cohen ZR, et al: Transsphenoidal surgery for cal results of LINAC-based stereotactic radiosurgery and ste- Cushing’s disease: endocrinological follow-up monitoring of reotactic radiotherapy for pituitary adenomas. Int J Radiat 82 patients. Neurosurgery 51:57–62, 2002 Oncol Biol Phys 42:573–580, 1998 85. Shin M, Kurita H, Sasaki T, et al: Stereotactic radiosurgery for 64. Mokry M, Ramschak-Schwarzer S, Simbrunner J, et al: A six pituitary adenoma invading the cavernous sinus. J Neurosurg year experience with the postoperative radiosurgical manage- (Suppl 3) 93:2–5, 2000

Neurosurg. Focus / Volume 14 / May, 2003 11

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC T. C. Witt

86. Shin M, Ueki K, Kurita H, et al: Malignant transformation of a gress in Neurological Surgery. Basel: Karger, 1998, Vol 14, vestibular schwannoma after gamma knife radiosurgery. Lan- pp 114–127 cet 360:309–310, 2002 97. Wolffenbuttel BH, Kitz K, Beuls EM, et al: Beneficial gamma- 87. Simard MF: Pituitary tumor endocrinopathies and their en- knife radiosurgery in a patient with Nelson’s syndrome. Clin docrine evaluation. Neurosurg Clin N Am 14:41–54, 2003 Neurol Neurosurg 100:60–63, 1998 88. Sonino N, Boscaro M: Medical therapy for Cushing’s disease. 98. Wowra B, Stummer W: Efficacy of gamma knife radiosurgery Endocrinol Metab Clin North Am 28:211–222, 1999 for nonfunctioning pituitary adenomas: a quantitative follow 89. Thoren M, Hoybye C, Grenback E, et al: The role of gamma up with magnetic resonance imaging-based volumetric analy- knife radiosurgery in the management of pituitary adenomas. sis. J Neurosurg (Suppl 5) 97:429–432, 2002 J Neurooncol 54:197–203, 2001 99. Wu A, Lindner G, Maitz AH, et al: Physics of gamma knife 90. Tishler RB, Loeffler JS, Lunsford LD, et al: Tolerance of cra- approach on convergent beams in stereotactic radiosurgery. nial nerves of the cavernous sinus to radiosurgery. Int J Int J Radiat Oncol Biol Phys 18:941–949, 1990 Radiat Oncol Biol Phys 27:215–221, 1993 100. Yoon SC, Suh TS, Jang HS, et al: Clinical results of 24 pitu- 91. Tominaga A, Uozumi T, Arita K, et al: Anterior pituitary func- itary macroadenomas with linac-based stereotactic radiosur- tion in patients with nonfunctioning pituitary adenoma: results gery. Int J Radiat Oncol Biol Phys 41:849–853, 1998 of longitudinal follow-up. Endocr J 42:421–427, 1995 101. Yu JS, Yong WH, Wilson D, et al: Glioblastoma induction af- 92. Tsang RW, Brierley JD, Panzarella T, et al: Radiation therapy ter radiosurgery for meningioma. Lancet 356:1576–1577, for pituitary adenoma: treatment outcome and prognostic fac- 2000 tors. Int J Radiat Oncol Biol Phys 30:557–565, 1994 102. Zhang N, Pan L, Wang EM, et al: Radiosurgery for growth hor- 93. Tsang RW, Brierley JD, Panzarella T, et al: Role of radiation mone-producing pituitary adenomas. J Neurosurgery (Suppl therapy in clinical hormonally-active pituitary adenomas. Ra- 3) 93:6–9, 2000 diother Oncol 41:45–53, 1996 103. Zierhut D, Flentje M, Adolph J, et al: External radiothera- 94. Tsang RW, Laperriere NJ, Simpson WJ, et al: Glioma arising py of pituitary adenomas. Int J Radiat Oncol Biol Phys 33: after radiation therapy for pituitary adenoma. A report of four 307–314, 1995 patients and estimation of risk. Cancer 72:2227–2233, 1993 95. Vance ML: Endocrinological evaluation of acromegaly. J Neu- Manuscript received March 24, 2003. rosurg 89:499–500, 1998 Accepted in final form April 14, 2003. 96. Witt TC, Kondziolka D, Flickinger JC, et al: Gamma knife ra- Address reprint requests to: Thomas C. Witt, M.D., Indiana Uni- diosurgery for pituitary tumors, in Lunsford LD, Kondziolka versity Medical Center, 535 Barnhill Drive RT 447, Indianapolis, D, Flickinger JC (eds): Gamma Knife Brain Surgery. Pro- Indiana 46202. email: [email protected].

12 Neurosurg. Focus / Volume 14 / May, 2003

Unauthenticated | Downloaded 09/24/21 07:07 PM UTC