J Neurosurg 77:832-841,1992

Linear accelerator radiosurgery for arteriovenous malformations WILLIAM A. FRIEDMAN, M.D., AND FRANK J. BOVA, PH.D.

Departments of Neurosurgery and Radiation Oncology, University oJ"Florida, Gainesville, Florida u~ Between May, 1988, and August, 1991, 80 patients with arteriovenous malformations (AVM's) were treated radiosurgically at the University of Florida. A mean dose of 1650 cGy was directed to the periphery of the lesion, which almost always corresponded to the 80% isodose line. The mean lesion diameter was 23 mm. Seventy-six patients were treated with one isocenter. Angiography, performed at 1 year after radiosurgery in 41 of the 48 eligible patients, revealed an overall complete thrombosis rate of 39%. The l-year thrombosis rate was highest in those patients with relatively small AVM's. Angiography was performed at 2 years posttreatment in 21 of the 25 eligible patients, demonstrating an overall complete thrombosis rate of 81%. This incidence did not correlate with lesion size: that is, large lesions (up to 35 mm in diameter) seemed just as likely to thrombose. Two patients (2.5%) experienced hemorrhage at some time after radiosurgical treatment, and both recovered. Two patients (2.5%) have sustained mild, but permanent, radiation-induced neurological complications. KEY WORDS 9 arteriovenous malformation stereotaxis 9 instrumentation

N 1985, the Departments of Neurosurgery and Radiation Oncology at the University of Florida decided to institute radiosurgery. After reviewing the other existing radiosurgical options, it was decided to develop a new linear accelerator (LINAC)-based radiosurgical system. Jo-~3Our goal was to build a system with the following design criteria: the highest possible accuracy, state-of-the-art computer hardware and software for dose planning, and a large number of collimators such that any lesion between 5 and 35 mm in diameter could be treated with a homogeneous field of radiation. A team that included neurosurgeons, radiation physicists, and computer programmers engaged in a 2year research, development, and testing process. In the current report, we present our experience with 80 consecutive patients with arteriovenous malformations (AVM's) treated with LINAC radiosurgery between May, 1988, and August, 1991.

I

Clinical Material and Methods

Patient Population Between May, 1988, and August, 1991, 134 patients were treated with the University of Florida radiosurgery system. Of these, 80 patients had AVM's which were graded according to the Spetzler and Martin 832

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radiosurgery

linear accelerator

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classification 32 (Table 1). There were 40 men and 40 women, with a mean age of 40 years (range 17 to 66 years). Presenting symptoms included hemorrhage (41 patients), seizure (21), headache/incidental (16), and progressive neurological deficit (two). The locations of the lesions are given in Fig. 1. Prior surgical attempts at A r M excision had been made in 18 patients, while 11 had undergone at least one embolization procedure. All patients referred for radiosurgery were first screened by a cerebrovascular surgery expert; radiosurgery was carried out only if he believed that the patient was a poor candidate for conventional microsurgery. The mean radiation dose to the periphery of the lesion was 1650 cGy (range 1000 to 2500 cGy). This treatment dose was almost always delivered to the 80% isodose line (range 70% to 90%). The mean lesion diameter was 23 mm (range 10 to 35 mm), and the diameter of the 80% isodose line almost always equaled the diameter of the lesion. Diameter, not lesion volume, was used for treatment planning in this series; however, equivalent spherical volumes were computed retrospectively using the lesion diameter, for approximate comparison with several other punished series. Seventy-six patients were treated with one isocenter, one with two isocenters, and three with three isocenters. Follow-up monitoring consisted of clinical exami-

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Linear accelerator radiosurgery for AVM's

Ft(;. 1. Diagrams depicting the approximate locations of the arleriovenous malformations treated in this series. Supratentorial non-midline lesions are shown on the axial view /left), and posterior fossa and midline lesions on the sagittal view (right).

TABLE 1 Spetzler-Martin classification of arteriovenous ma![brmations (A VM's) in 80 patients* Grade

No. of Cases 11 II 33 I11 30 IV 6 total 80 * The Spetzler-Martin32classificationfor AVM'sassignsa score(as shownbelowin brackets) to each of three features: nidus size (< 3 cm [1], 3 to 6 cm [2], > 6 cm [3]), venousdrainage (with [l] or without [0] a deep venous system component), and location of the AVM (eloquent [1] or non-eloquent [0] brain area). The scores are then added so that AVM'scan be classifiedinto five grades(with the grade equal to the score and Grade Vl given to inoperable malformations involvingdiffuselya vital brain area). 1

nation and magnetic resonance (MR) imaging every 3 to 6 months after treatment. 3~ If possible, follow-up review was performed in Gainesville; otherwise, MR images and examination results were forwarded by the patient's local physician. All patients were asked to undergo angiography at yearly intervals, regardless of the MR imaging results, until complete occlusion of the AVM was demonstrated.

Radiosurgical Treatment System The University of Florida radiosurgical system has been described in detail in other publications? '~~ Briefly, meeting the first goal of our program (to provide the highest possible accuracy of radiation beam delivery) required a mechanical system independent of the relatively inaccurate (1 to 2 mm) LINAC gantry and patient-support system (Fig. 2). The motions that required precise control were the arcing movements of the LINAC and the movements of the patient during repositioning for new arcs. To solve this problem, highJ. Neurosurg. / Volume 77 / December, 1992

precision bearings were assembled in-house. One of the bearings controls the isocentric accuracy of the collimator and a second controls the rotation of the patient. The two bearing systems are coupled mechanically so that the rotational axes coincide. However, this system alone cannot produce the desired accuracy when rigidly attached to the LINAC head. To avoid any torque transfer from the LINAC head to the collimator, a gimbal-type bearing with a sliding collimator mount was developed. This allows the collimator to tilt and slide in minute increments, remaining in precise alignment with the isocenter defined by the mechanical bearing system without being dragged off by the "sagging" LINAC gantry. In addition, all standard stereotactic pieces were remachined to provide the accuracy desired for radiosurgery. The accuracy of radiation beam delivery in this system is 0.2 -+ 0.1 mm, which is as high as that reported for any other radiosurgical device.~~ The second design goal was to use state-of-the-art computer hardware and software for dose planning. Because every lesion is different in location, size, shape, and other characteristics, each dose plan must be modified to optimize the treatment. An accurate and rapid dose planning system is, therefore, essential. We currently use a SUN microsystem, with an 80-megaflop array processor. The general approach is to create and evaluate a three-dimensional treatment plan through the use of interpolated, reformatted computerized tomography (CT) scans, a database with which neurosurgeons are quite familiar. The third design goal was to provide a sufficiently large number of collimators such that any lesion between 5 and 35 mm in diameter could be treated with a homogeneous field of radiation. Although its value in radiosurgery is currently debated, target dose-homogeneity has been a primary goal in radiation treatment planning for decades. Accordingly, a series of cerrobond 833

W. A. Friedman and F. J. Bova

FIG. 2. Drawings showing the modified linear accelerator (LINAC) radiosurgical system used at the University of Florida. The LINAC produces high-energy photons (called x-rays) by accelerating electrons to nearly the speed of light and colliding them with a heavy metal alloy. The resultant radiation is collimated and focused on the target that, in this application, is stereotactically positioned at the central point of the LINAC gantry rotation (left). The patient is rotated to new couch positions between LINAC arcs (right). Typically, between five and 11 separate arcs are performed. This paradigm produces a series of non-coplanar radiation arcs that only coincide at the target point. An unmodified LINAC has a tendency, because of its weight, to sag as it rotates from the vertical to the horizontal position. The modified system couples several high-precision bearings to the LINAC to produce a radiation beam accuracy of 0.2 + 0.1 mm.

collimators were constructed, 15 cm in length and ranging in diameter by 2-mm increments from 5 to 35 ram. Single-beam profiles were obtained for each collimator using standard dosimetric techniques.

Radiosurgical Treatment Paradigm With the exception of the first few cases, all radiosurgery has been performed on an outpatient basis. The patient reports to the neurosurgical clinic at 8:15 a.m., and a stereotactic headring is applied with the patient under local anesthesia. No skin shaving or preparation is required. The patient is transported to the angiography suite, where a stereotactic angiogram is performed. Subsequently, an intravenous bolus of contrast material is injected to maximize resolution and stereotactic CT is performed. Because the stereotactic anglogram is a relatively poor three-dimensional database, 4'29 we also rely on the appearance of the nidus on contrastenhanced CT scans for treatment planning. After CT, the patient is transported to the outpatient radiology area for postangiographic observation. The stereotactic angiogram and CT scan (now stored on magnetic tape) are taken to the radiation physics suite for dosimetry. The nidus of the AVM is outlined on the angiogram, which is then mounted on a digitizer board. A mouse-like device is used to identify the stereotactic fiduciai markers and to trace the nidus, which appears simultaneously on the computer screen. The computer then generates the anteropostefior, lateral, and vertical coordinates of the center of the lesion as well as its demagnified diameter and quickly determines the position of all of the CT images within the stereotactic coordinate system. The angiographic target 834

center point is displayed on the CT image. Dosimetry then begins and continues until the neurosurgeon, radiation therapist, and radiation physicist are satisfied that the optimum dose plan has been developed (Fig. 3). A final computer printout shows all of the treatment parameters in a checklist format. Patients rest comfortably until the end of the normal radiation therapy treatment day (around 4:30 p.m.). After the radiosurgical device has been connected to the LINAC, the patient is attached to the device and treated. The actual radiation treatment time averages approximately 15 minutes. Afterwards, the headring is removed and, following an observation period of a few minutes, the patient is discharged. The radiosurgical device is disconnected from the LINAC, which is then ready for conventional use.

Statistical Analysis Univariate and multivariate statistical analyses* were performed on the following variables: lesion volume, treatment dose, patient age, total occlusion at 1 year after treatment, total occlusion at 2 years after treatment, and incidence of complications. Results

One- Year Angiographic Occlusion Rate Follow-up information was obtained for 79 of the 80 patients in this series. The mean follow-up period was 19 months (range 3 to 42 months). Forty-eight patients * Statistical analysis software developed by SAS Institute, Inc., Cary, North Carolina.

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Linear accelerator r a d i o s u r g e ~ for A V M ' s

FIG. 3. A: Angiogram, anteroposterior view, in a 28-year-old man who presented in coma after a subarachnoid hemorrhage from a brain-stem arteriovenous malformation. He made a full recovery and was referred for radiosurgery. B and C: Contrast-enhanced. thin-section computerized tomography scans, axial (B) and sagittal (C) views, with the 80%, 40%, 16%, and 8% isodose lines superimposed. A dose of 1500 cGy was prescribed to the 80% isodose line, using a 14-ram collimator. D: Follow-up angiogram, anteroposterior view, obtained 1 year after treatment, revealing complete obliteration of the lesion.

TABLE 2

Incidence of complete thrombosis after radiosurgery,for arteriovenous malformation (AVM) AVM Volume < 1 cc 1.0 to 4.0 cc 4.0 to 10.0 cc > 10 cc total

Follow-UpThrombosis Findingsat: 1 Year 0/0 11/20 (55%) 4/14 (29%) 1/7 (14%) 16/41 (39%)

2 Years 0/0 7/9 (78%) 6/8 (75%) 4/4 (100%) 17/21 (81%)

have been followed for 1 year or longer; of these 41 underwent angiography at 1 year after treatment (Fig. 4). The other seven patients did not undergo angiography at that time for the following reasons: one patient was lost to follow-up study, two refused, and in four the study was delayed due to scheduling conflicts. The results of the 41 l-year follow-up angiograms are as follows: total occlusion was demonstrated in 16 patients (39%), greater than 90% occlusion in 10 (24.4%), 50% to 90% occlusion in 10 (24.4%), and less than 50% occlusion in five (12.2%). As suggested in Table 2, there was a statistically significant (p > 0.03) correlation between l-year angiographic occlusion rates and AVM size: occlusion was demonstrated in 55% of the AVM's with a volume of 1 to 4 cc, in 29% with a volume of 4 to 10 cc, and in 14% with a volume greater than 10 cc. Treatment dose also correlated with outcome at 1 year (p > 0.04).

Two- Year Angiographic Occlusion Rate A total of 25 patients were followed for 2 years or longer; of these, 21 underwent follow-up angiography (Fig. 5). In the other four patients, follow-up angiography was not performed for the following reasons: one patient refused and in three the study was delayed due

J. Neurosurg. / Volume 77/December, 1992

FIG. 4. Angiograms, lateral view, in a 49-year-old man who presented with a long history of seizures Left: Digital angiogram showing a left basofrontal arteriovenous malformation. He was treated with 1500 cGy of irradiation to the 80% isodose line, with a 28-mm collimator. Right: Followup angiogram obtained 1 year after treatment, showing complete thrombosis. to scheduling conflicts. The results in the 21 patients

who underwent follow-up angiography at 2 years after treatment are as follows: total occlusion was demonstrated in 17 (81%), greater than 90% occlusion in two (9.5%), and 50% to 90% occlusion in two (9.5%); none had less than 50% occlusion. As suggested in Table 2, there was no significant correlation between 2-year occlusion rates and AVM size. In addition, patient age and treatment dose did not correlate with outcome at

2 years. Complications Acute Morbidity. Two (2.5%) of the total 80 patients, both treated early in the series, experienced seizures within 48 hours after radiosurgery. Both had originally presented with a seizure disorder. In subsequent patients with a history of seizures, anticonvulsant drug levels were optimized in the high-normal range prior to radiosurgical therapy and no further posttreatment seizures have been observed. No other acute morbidity has been seen after radiosurgery. 835

W. A. Friedman and F. J. Bova

FIG. 5. Angiograms, lateral view, obtained in a 36-year-old man. L@. Angiogram obtained during a workup for minor head trauma demonstrating an incidental left parietal arteriovenous malformation. He received 2250 cGv of radiation to lhe 80% isodose line, through an 18-mm collimator. Center:Angiogram obtained l year after treatment, revealing substantial but incomplete thrombosis of the lesion. Note the decreased size of the draining veins. Ri~,,ht:Angiogram, obtained 2 years after treatment, revealing complete nidus thrombosis and disappearance of the draining veins.

Hemorrhage. Two patients (2.5%) experienced intracerebral hemorrhage after radiosurgical treatment; neither had originally presented with a hemorrhage. Since 80 patients have been followed for a mean of 19 months, the total patient follow-up period in the series is 126 years. The annualized hemorrhage rate for the series is, therefore, 1.6%. One patient, who had undergone partial surgical excision of a parietal AVM prior to radiosurgery (Fig. 6), experienced an intracerebral hemorrhage accompanied by hemiparesis and dysphasia 3 months after radiosurgery. After prolonged rehabilitation, the patient recovered to his preradiosurgical functional level. The second patient, who had undergone five attempts at embolization of a tbalamic AVM prior to radiosurgery, experienced a severe intraventrieular hemorrhage after radiosurgical treatment. This condition necessitated prolonged inpatient treatment, including placement of

a ventriculoperitoneal shunt. The patient made a substantial recovery and is currently undergoing further rehabilitation.

RadiaIion Edema~Necrosis. Four patients (5%) experienced delayed complications directly attributable to radiosurgery. The first patient had received 2500 cGy to the 80% isodose line of a 24-ram AVM (Fig, 7). An angiogram obtained at 1 year posttreatment showed complete thrombosis. One month later, the patient experienced a flurry of seizure activity and MR imaging revealed a 24-ram lesion consistent with radionecrosis, as well as considerable surrounding edema. She responded to large doses of dexamethasone, which were tapered off after a course of several months. She currently exhibits only a minor limp. In the second patient, a 30-ram brain-stem AVM was treated with 1750 cGy to the 80% isodose line.

FIG. 6. Left.' Stereotactic angiogram, lateral view, in a 61-year-old man who underwent clipping of a carotid artery aneurysm and partial resection of a right motor strip region arteriovenous malformation. He was referred for radiosurgical treatment of the residual nidus (outlined) and received 1500 cGy of irradiation to the 80% isodose line through a 22-mm collimator. Center. Computerized tomography scan, obtained 3 months after radiosurgery, demonstrating an intracerebral hemorrhage with significant hemiparesis. After prolonged rehabilitation, the patient recovered to his pretreatment level. Right: Angiogram, lateral view, obtained 1 year posttreatment, revealing substantial but incomplete thrombosis. A 2-year angiogram is pending. 836

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Linear accelerator radiosurgery for AVM's

FIG. 7. Magnetic resonance (MR) images in a 55-year-old woman who developed a grand mal seizure disorder and was discovered to have a fight mesial frontal arteriovenous malformation. She was treated with 2500 cGy of irradiation to the 80% isodose line, through a 24-ram collimator. Angiography at 1 year posttreatment showed complete thrombosis. One month later, she developed seizures and a left hemiparesis. Left and Center: Gadolinium-enhanced, Tl-weighted MR images, axial (left) and coronal (center) views, revealing probable radiation necrosis in the exact area treated with radiosurgery, surrounded by considerable edema. She was treated with steroids, which produced a prompt and dramatic clinical improvement. After months of therapy, the steroids were tapered. Right: Follow-up T2-weighted MR image, axial view, showing minimal evidence of abnormality in the treatment area.

Approximately 10 months after treatment, Parinaud's syndrome and obstructive hydrocephalus developed. An MR image showed edema throughout the mesencephalon. The patient was treated with placement of a ventriculoperitoneal shunt and steroid therapy, which was successfully tapered off after several months. He has recovered well, with only a residual Parinaud's syndrome. The third patient had a 16-mm AVM that was treated with 1750 cGy to the 80% isodose line. An angiogram performed at 1 year posttreatment showed complete thrombosis. Shortly thereafter, she reportedly developed dysphasia, which corresponded to edema on MR im-

aging. She responded to a short course (1 month) of steroid therapy and is now entirely well, with normal MR findings. The fourth patient underwent radiosurgical treatment with 1750 cGy to the 80% isodose line of a 16mm AVM in the motor strip area. Angiography at 1 year showed greater than 90% thrombosis. Two months later, she presented with complaints of headache. Subsequent MR imaging revealed a focus of gadolinium enhancement in the treatment area, surrounded by edema. The patient's headaches have responded to dexamethasone therapy, and she has remained neurologically asymptomatic. No AVM flow was visualized on her latest MR image, and she remains on a tapering steroid dose. In summary, two patients (2.5%) have experienced minor but permanent neurological deficits due to radiation and another two (2.5%) have experienced transient complications (one of these is currently undergoing treatment). Figure 8 shows the treatment dose and lesion size for all patients with radiation-induced complications. Lesion volume, treatment dose, and patient age did not significantly correlate with the occurrence of complications.

Discussion

FIG. 8. Graph showing the lesion size for all arteriovenous malformations in our series that were followed for at least 1 year and the prescribed irradiation dose (squares). Note that the diameter of the 80% isodose line is usually equal to the collimator diameter. The triangles represent the 1% risk for radionecrosis according to Kjellberg, et al. ~ The diamonds" indicate the two patients who experienced minor but permanent neurological deficits; these two patients received doses that were well above Kjellberg's line. The circles indicate the two patients who experienced transient difficulties; both received doses well below Kjellberg's line. J. Neurosurg. / Volume 77 / December, 1992

Several studies have demonstrated a substantial (3% to 4%/yr) risk of hemorrhage, often associated with morbidity or mortality, m patients harboring A V M ' s . 27"2s Refinements in microsurgical technique as well as the development of increasingly effective endovascular treatments render many of these lesions amenable to a successful and safe surgical cure.14'32 Those AVM's that are not suitable for surgical removal are often considered for radiosurgical management. Although radiosurgery is a relatively old concept, ~9'2~only in recent years has this technique proliferated. A num837

W. A. Friedman and F. J. Bova her of important questions remain regarding radiosurgical treatment of AVM's. In reviewing our results as well as other reports in the literature, we attempt to address the following questions: What is the expected complete thrombosis rate after radiosurgical treatment of AVM's? What is the expected complication rate after radiosurgical treatment of AVM's? How does this LINAC radiosurgical system compare with other radiosurgical methods? R a t e s ~ f Angiographic T h r o m b o s i s

Radiosurgery appears to produce AVM thrombosis by inducing a pathological process in the nidus, leading to gradual thickening of the vessels until thrombosis occurs. 27Several radiosurgical series have systematically evaluated this process by obtaining 1- and 2-year followup angiograms. Steiner and colleagues 2~'36-39 have reported on gamma knife radiosurgery for treating AVM's, with l-year occlusion rates ranging from 33.7% to 39.5% and 2-year occlusion rates ranging from 79% to 86.5%. However, these results were "optimized" by retrospectively selecting patients who received a minimum treatment dose. For example, in a recent report, 2~ these authors stated, "... a large majority of patients received at least 20-25 Gy of radiation . . . . Of the 248 patients treated before 1984, the treatment specification placed 188 in this group." The reported thrombosis rates in that report applied only to these 188 patients (76% of their total series)) ~ It may be important to note that, in our series, only 10 (21%) of 48 patients followed for at least 1 year received a dose that high, yet equally good 1- and 2-year thrombosis rates were achieved. Kemeny, et al., ~6 reported on 52 AVM patients treated with gamma knife radiosurgery: all received 2500 cGy of radiation to the 50% isodose line. At 1 year, 16 patients (31%) bad complete thrombosis and 10 (19%) had "almost complete" thrombosis. These authors found that the results were better in younger patients and in patients with a relatively lateral location of the AVM. There was no difference in outcome between small (< 2 cc), medium (2 to 3 cc), or large (> 3 cc) AVM's. Recently, Lunsford, et al., 24 analyzed results in 227 AVM patients treated with gamma knife radiosurgery with a mean dose of 21.2 Gy delivered to the AVM margin. The Pittsburgh gamma knife was the first to include an 18-ram secondary collimator, which was claimed to be " . . . invaluable for the treatment of larger AVM's." Multiple isocenters were used in 48% of the patients. Seventeen patients underwent angiography at 1 year posttreatment, which confirmed complete thrombosis in 76.5%. As indicated in their paper, "this rate may be spurious since many of these patients were selected for angiography because their MR image had suggested obliteration." Among 75 patients who were followed for at least 2 years, angiography at the 2-year follow-up examination was performed in only 46 (61%), and complete obliteration was confirmed in 37 (80%) 838

of these. This thrombosis rate strongly correlated with AVM size; thrombosis was demonstrated in all patients with an AVM less than 1 cc in size, in 85% of those with an AVM between 1 and 4 cc, and in 58% of those with an AVM between 4 and 10 cc. In a recent analysis of 86 AVM's treated with a particle-beam radiosurgical system, Steinberg, et al., 35 reported a 29% thrombosis rate at 1 year, a 70% thrombosis rate at 2 years, and a 92% thrombosis rate at 3 years. The best results were obtained in patients with smaller lesions who received higher doses. Initially, a treatment dose of 34.6 Gy was used but an incidence of neurological complications higher than expected (20% for the entire series) led to the currently used dose range of 7.7 to 19.2 Gy. ~5 No patients treated with radiosurgery at the lower dose range had complications. Betti and colleagues ~'2 reported on the results of 66 AVM's treated with a LINAC radiosurgical system. Doses of "no more than 40 Gy" were used in 80% of their patients. The 2-year thrombosis rate was 66%. The percentage of cured patients was highest when the entire malformation was included in the 75% isodose line (96%) or the maximum diameter of the lesion was less than 12 mm (81%). Colombo, et al., 5"6 reported on 97 AVM patients treated with a LINAC system at doses ranging from 18.7 to 40 Gy delivered in one or two sessions. Of 56 patients who were followed for longer than 1 year, 50 underwent 12-month follow-up angiography; complete thrombosis was demonstrated in 26 (52%) of these. Fifteen (75%) of the 20 patients who underwent angiography at 2 years posttreatment had complete thrombosis. A definite relationship between AVM size and thrombosis rate was reported: lesions less than 15 mm in diameter had a 1-year obliteration rate of 76% and a 2-year rate of 90%; lesions 15 to 25 mm in diameter had a 1-year thrombosis rate of 37.5% and a 2-year rate of 80%; and lesions greater than 25 mm in diameter had a 1-year thrombosis rate of 11% and a 2-year rate of 40%. A report by Souhami, et al., sL on 33 AVM's treated with a LINAC system at a prescribed dose at the isocenter varying from 50 to 55 Gy revealed complete obliteration in 38% of cases seen on 1-year follow-up angiography. For patients in whom the AVM nidus was covered by a minimum dose of 25 Gy, the total obliteration rate was 61.5%, whereas no patient who had received less than 25 Gy at the edge of the nidus experienced total obliteration. Loeffier, et al., 22 reported on 16 AVM patients treated with a LINAC system. The prescribed dose was from 15 to 25 Gy delivered typically to the 80% to 90% isodose line. The total obliteration rate was 45% (five of 11 patients) at 1 year and 73% (eight of 11 patients) at 2 years after treatment. We reported 80 patients treated with the University of Florida radiosurgery system. No retrospectively applied criteria were used to select patients for analysis. The vast majority of eligible patients underwent both J. Neurosurg. / Volume 77/December, 1992

L i n e a r a c c e l e r a t o r r a d i o s u r g e r y for A V M ' s l-year (85%) and 2-year (84%) follow-up angiography. Thrombosis rates of 39% at 1-year posttreatment and 81% at 2 years were identified. Although the 1-year thrombosis rate did correlate with AVM size, the 2-year rate did not. The AVM's treated in this series were larger (mean diameter 23 mm) and the treatment doses lower (mean 1650 cGy) than those previously reported, yet the thrombosis rates were at least as good. Complications Hemorrhage. The hemorrhage rate for AVM's

treated but not yet obliterated with radiosurgery has been reported to be the same as the rate for AVM's that have not been treated. 2s24'-7~7 On the other hand, no patient with documented angiographic obliteration of an AVM has yet been reported to have suffered a hemorrhage. In this series, two (2.5%) of 80 patients experienced a hemorrhage after radiosurgical treatment. The latent period (1 to 3 years) for angiographic obliteration, during which the patient remains at risk for hemorrhage, is the major drawback of radiosurgery as compared to microsurgical treatment. Radiation-Induced Complications. Several authors have previously reported that radiosurgery can acutely exacerbate seizure activity.24'27After observing this phenomenon in two of our patients treated early in the series, we systematically optimized anticonvulsant drug levels in patients with a history of seizures before radiosurgical treatment. Since adopting this policy, we have not observed any further treatment-related seizures. Other authors have reported nausea, vomiting, and headache occasionally occurring after radiosurgical treatment; 724 however, these complications were not observed in this series. Delayed radiation-induced complications have been reported by all authors performing radiosurgery to treat AVM's. Steiner36'37 found symptomatic radiation necrosis in approximately 3% of his patients. Statham, et al., 34 described one patient who developed radiation necrosis 13 months after gamma knife radiosurgery with 25 Gy to the margin of a 5.3-cc AVM. Lunsford, et al., TM reported that 10 patients (4.4%) in their series developed new neurological deficits thought to be secondary to radiation injury. Symptoms were dependent on the location and developed at 4 to 18 months after treatment. All patients were treated with steroids and all improved. Only two patients were reported to have residual deficits that appeared permanent. The radiation dose and isodose line treated did not correlate with this complication. As Lunsford, et al., noted, the failure of correlation between dose and complications may very well relate to the fact that the dose was selected to fall below the 3% risk line determined by Flickinger, et al. 8,9 This is a mathematically derived line which prescribes lower doses for larger lesions. Steinberg, et al., 35 reported a definite correlation between lesion size, radiation dose, and complications. The initial treatment close of 34.6 Gy led to a relatively J. Neurosurg. / Volume 77/December, 1992

high complication rate. '5 No patients treated subsequently with a lower dose range suffered complications. In an earlier report by Hosobuchi, etal., ~ on 75 AVM patients treated with helium particles at a dose of 45 Gy, seven (9%) of 75 patients experienced radiationinduced complications. Kjellberg, et at., 17'E8 using a compilation of animal and clinical data, constructed a series of log-log lines relating prescribed dose and lesion diameter. This 1% isorisk line is quite similar to Flickinger's mathematically derived 3% risk line. In a series of patients reported by Colombo, et al.,5 three (3 %) patients experienced symptomatic radiationinduced complications. Loeffier, et at., 23 reported that one of the 21 AVM patients in their series developed a similar problem, which responded well to steroid treatment. Souhami, etal., 3~ reported "severe side-effects" in two (6%) of 33 patients. Marks and Spencer25 recently reviewed six radiosurgical series and found a 9% incidence of clinically significant radiation reactions. Seven of the 23 patients in these series received doses below Kjellberg's 1% risk line. We report two patients with minor but permanent radiation-induced neurological deficits, another with a completely transient deficit, and a fourth who is currently asymptomatic while receiving tapering steroid doses. A graph correlating radiation dose with lesion diameter in our series shows that both patients with permanent deficits received doses above Kjellberg's 1% line and Flickinger's 3% line (Fig. 8). The doses received by patients with transient problems were well below those lines. Thus, in our series, it appears that radiation dose is an important predictor of permanent deficit and we currently use these lines as one criterion for dose selection, l'his deliberate process wherein lower doses are selected for larger lesions may well account for the fact that dose and volume did not correlate in a statistically significant fashion with the occurrence of complications. Others 24-26 have reported that asymptomatic radiation-induced changes appear frequently on MR images; the incidence rate reported by Lunsford, et al., 24 was 24%. We have also observed this phenomenon, which will be the subject of another report. These changes tend to be asymptomatic if the lesion is located in a relatively "silent" brain area and symptomatic if the lesion is located in an "eloquent" brain area. Thus, lesion location may be another important consideration in radiosurgical treatment planning and dose selection. Most radiosurgical series report their radiation-induced complications as a percentage of the total patient population treated. Since most radiation-induced complications do not appear until 12 to 18 months after treatment, a systematic underestimate of the true complication rate is reported. Comparative Features o f This Radiosurgery Series

In our series of 80 AVM patients, the lesions were larger and the radiation doses lower than in many 839

W. A. F r i e d m a n a n d F. J. B o v a previous reports. Despite this, we obtained high 1- and 2-year thrombosis rates and a low radiation-induced complication rate. The complex multifactorial nature of AVM radiosurgery makes it impossible to fully explain these results. Yet it may be useful to speculate regarding the major differences between methods employed in this series and those described in previous reports. These differences include the use of larger collimators, increased reliance on stereotactic CT for nidus localization, lower radiation doses, and increased accuracy. Larger Collimators. This LINAC radiosurgical system has cerrobond collimators ranging in diameter from 5 to 35 mm (by 2-mm increments). This range in collimator size makes it possible to treat any AVM in that size range with a homogeneous dose of radiation. It is also possible to treat larger AVM's with one isocenter, as opposed to multiple isocenters. Although Lunsford, eta[., 24 found no correlation between the isodose line treated and the results of AVM radiosurgery, they did comment that the addition of the 18-mm secondary collimator to the Pittsburgh gamma knife was "invaluable for the treatment of larger AVM's." We also found the larger collimators (from 19 to 35 mm) to be invaluable. Table 2 allows easy comparison of our results with the Pittsburgh experience. It is possible that the larger collimators at our disposal, which made it possible to treat this group of larger lesions homogeneously and with one isocenter, made a difference. Contrary to this argument, it should be noted that one group of patients treated with gamma knife radiosurgery ~6 showed no correlation between thrombosis rate and lesion size and that several groups treated with LINAC or particle-beam radiosurgery 2'5'35 exhibited such a correlation, despite the availability of larger collimators. Further follow-up studies of larger groups of patients will be needed to definitively address the question of expected results versus lesion size. Increased Reliance on Stereotactic C T for Lesion Localization. Radiosurgical treatment planning for cerebral AVM's requires accurate definition of the true three-dimensional size and shape of the nidus. Over- or underestimation of these parameters may result in undue irradiation of normal brain tissue or in suboptimum irradiation coverage of the malformation, leading to treatment failure. As addressed in several previous publications, 4'-~9'33angiography is not an ideal database for radiosurgery of AVM's. Its shortcomings include planar representation of a three-dimensional volume and simultaneous visualization of feeding arteries and draining veins, overlapping with the nidus and obscuring its outline. Stereotactic, contrast-enhanced CT may provide, in selected cases, better spatial definition of the nidus and superior anatomical detail for final design of the radiosurgical isodose distribution. We not infrequently adjust the target center and collimator size selected from stereotactic angiography after we have studied the appearance of the nidus on stereotactic CT. 840

Thus, we have systematically treated a target "different" from that reported in most previous gamma knife and LINAC radiosurgery series. Lower Radialion Doses. Many series, 2'5'~5'24'3~with patients treated via particle-beam, gamma knife, or LINAC radiosurgical systems, have advocated treatment of the periphery of the AVM with a minimum dose of 20 Gy whenever possible. Perhaps because AVM's treated in this series were larger, we have had the opportunity to observe many successful results with markedly lower radiation doses. Relatively few patients (21%) in this series received a dose of 20 Gy or greater, yet thrombosis rates were high. In accord with Steinberg, et al., we have found that doses ranging from 15 to 18 Gy are quite effective. Most radiosurgeons agree that lower doses are necessary if larger lesions are to be treated without an undue incidence of radiation-induced complications. The knowledge that these lower doses will frequently produce complete thrombosis, coupled with the availability of larger collimators, may make it possible to treat generally larger AVM's than have been reported previously. lncreasedAccuracy. As outlined in the Clinical Material and Methods section, this radiosurgical system is unique in that it incorporates a stereotactic add-on that increases the accuracy of radiation beam delivery when compared to an unmodified LINAC radiosurgical system. The measured accuracy of this system is 0.2 _+ 0.1 mm. ~2 Unmodified LINAC radiosurgical systems are subject to the inherent inaccuracy of the LINAC, which may be as great as 1 to 2 mm.~~ Conclusions

A series of 80 consecutive AVM patients were treated with a modified LINAC radiosurgical system. The vast majority of eligible patients underwent l- and 2-year angiography, and only one patient was lost to followup study. The 1-year angiographic thrombosis rate was 39%, with the rate being highest in patients with small lesions. The 2-year thrombosis rate was 81%, and there was no correlation between lesion size and thrombosis rate at 2 years posttreatment. Two patients (2.5%) sustained minor, but permanent, radiation-induced neurological deficits. Systematic treatment differences between this LINAC and other reported radiosurgical series include: larger collimators than are available for the gamma knife, increased reliance on stereotactic CT for AVM treatment planning, lower radiation doses, and higher accuracy than possible with other LINAC radiosurgical systems. References

1. Betti OO: Treatment of arteriovenous malformations with the linear accelerator. Appl Neurophysiol 50:262, 1987 2. Betti OO, Munari C, Rosier R: Stereotactic radiosurgery with the linear accelerator: treatment of arteriovenous malformations. Neurosurgery 24:311-321, 1989 J. Neurosurg. / Volume 77/December, 1992

Linear accelerator radiosurgery for AVM's 3. Bova FJ: Radiation physics. Neurosurg Clin North Am !: 909-931, 1990 4. Bova FJ, Friedman WA: Stcreotactic angiography: an inadequate database for radiosurge~'? Int J Radiat Oncol Biol Phys 20:891-895, 1991 5. Colombo F, Benedetti A, Pozza F, el al: External stereotactic irradiation by linear accelerator. Neurosurgery 16: 154-160, 1985 6. Colombo F, Benedetti A, Pozza F, et al: Linear accelerator radiosurgery of cerebral arteriovenous malformations. Neurosurgery 24:833-840, 1989 7. Colombo F, Benedetti A, Pozza F, et al: Linear accelerator radiosurgery of three-dimensional irregular targets. Stereotact Funct Neurosurg 54/55: 541-546, 1990 8. Flickinger JC: An integrated logistic formula for prediction of complications from radiosurgery. Inl J Radiat Oncol Biol Phys 17:879-885, 1989 9. Flickinger JC, Schel[ MC, Larson DA: Estimation of complications for linear accelerator radiosurgery with the integrated logistic formula. Int J Radiat Oncol Biol Phys 19:143-148, 1990 10. Friedman WA: LINAC radiosurger3'. Neurosurgery Clin North Am 1:991-1008, 1990 11. Friedman WA, Bova FJ: Stereotactic radiosurgery. Contemp Neurosurg 11(12):1-7, 1989 12. Friedman WA, Bova FJ: The University of Florida radiosurgery system. Surg Neurol 32:334-342, 1989 13. Friedman WA, Spiegelmann R: LINAC radiosurgery. Neurosurg Clin North Am 3:141-166, 1992 14. Heros RC, Korosue K, Diebold PM: Surgical excision of cerebral arteriovenous malformations: late results. Neurosargery 26:570-578, 1990 15. Hosobuehi Y, Fabricant J, Lyman J: Stereotactic heavyparticle irradiation of intracranial arteriovenous malformations. Appl Neurnphysiol 50:248-252, 1987 16. Kemeny AA, Dias PS, Forster DMC: Results of stereotactic radiosurgery of arteriovenous malformations: an analysis of 52 cases. J Neurol Neurosurg Psychiatry 52: 554-558, 1989 17. Kjellberg RN, Abbe M: Stereotactic Bragg peak proton beam therapy, in Lunsford LD (ed): Modern Stereotactic Neurosurgery. Boston: Martinus Nijhoff, 1988, pp 463-470 18. Kjellberg RN, Hanamura T, Davis KR, et al: Bragg-peak proton-beam therapy for arteriovenous malformations of the brain. N Engl J Med 309:269-274, 1983 19. Leksell L: The stereotaxic method and radiosurgery of the brain. Acta Chir Scand 102:316-319, 1951 20. Leksell L: Stereotaxis and Radiosurgery. Springfield, II1: Charles C Thomas, 1971 21. Lindquist C, Steiner L: Stereotactic radiosurgical treatmerit of malformations of the brain, in Lunsford LD (ed): Modern Stereotactic Neurosnrgery. Boston: Martinus Nijhoff, 1988, pp 491-506 22. Loeffier JS, Alexander E III, Siddon RL, et al: Stereotactic radiosurgery for intracranial arteriovenous malformations using a standard linear accelerator. Int J Rudiat Oncol Biol Phys 17:673-677, 1989 23. Loeffier JS, Siddon RL, Wen PY, et al: Stereotactic radiosurgery of the brain using a standard linear accelerator: a study of early and [ate effects. Radiolher Oncol 17: 311-321, 1990

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24. Lunsford LD, Kondziolka D, Flickinger JC, ct al: Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurnsurg 75:512-524, 1991 25. Marks LB, Spencer DP: The influence of volume on the tolerance of the brain to radiosurgery. J Neurosurg 75: 177-180, 1991 26. Marks MP, Delapaz RL, Fabrikant JI, et al: Intracranial vascular malformations: imaging of charged-particle radiosurgery. Part II. Complications. Radiology 168: 457-462, 1988 27. Ogilvy CS: Radiation therapy for arteriovenous malformations: a review. Neurosurgery 26:725-735, 1990 28. Ondra SL, Troupp H, George ED, et al: The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg 73:387-391, 1991 29. Phillips MH, Kessler M, Chuang FY, et al: Image correlation of MRI and CT in treatment planning for radiosurgery of intracranial vascular malformations. Int J Radiat Oncol Biol Phys 20:881-889, 1991 30. Quisling RG, Peters KR, Friedman WA, et al: Persistent nidus blood flow in cerebral arteriovenous malformation after stereotactic radiosurgery: MR imaging assessment. Radiology 180:785-791, 1991 31. Souhami L, Oliver A, Podgorsak EB, et al: Radiosurgery of cerebral arteriovenous malformations with the dynamic stereotactic irradiation. Int J Radiat Oncol Biol Phys 19:775-782, 1990 32. Spetzler RF, Martin NA: A proposed grading system of arteriovenous malformations. J Neorosurg 65:476-483, 1986 33. Spiegelmann R, Friedman WA, Bova FJ: Limitations of angiographic target localization in planning radiosurgical treatment. Neurosurgery 30:61%624, 1992 34. Statham P, Macpherson P, Johnston R, et al: Cerebral radiation necrosis complicating stereotactic radiosurgery for arteriovenous malformation. J Neurol NeurosurgPsychiatry 53:476-479, 1990 35. Steinberg GK, Fabrikant JI, Marks MP, et al: Stereotactic heavy-charged Bragg-peak radiation for intraeranial arteriovenous malformations. N Engl J Med 323:96-101, 1990 36. Sleiner L: Radiosurgery in cerebral arteriovenous malformations, in Fein JM, Flamm ES (eds): Cerebrovascular Surgery. New York: Springer-Verlag, 1985 VoI 4, pp 1161-1251 37. Steiner L: Treatment of arteriovenous malformations by radiosurgery, in Wilson CB, Stein BM (eds): Intracranial Arteriovenous Malformations. Baltimore: Williams & Wilkins, 1984, pp 295-313 38, Steiner L, Leksell L, Forster DMC et al: Stereotactic radiosurgery in intracranial arterio-venous malformations. Acta Neuroehir Suppl 21:195-209, 1974 39 Steiner L, LekseU L, Greitz T, et ah Stereotaxic radiosurgery for cerebral artefiovenous malformations. Report of a case. Acta Chir Scand 138:459-464, 1972 Manuscript received November 6, 1991. Accepted in final form May 18, 1992. Address reprint requests to. William A. Friedman, M.D., Department of Neurosurgery, Box J-265, JHMHC, University of Florida, Gainesville, Florida 326;0.

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