Intracranial arteriovenous malformations treated with linear accelerator–based conformal radiosurgery: clinical outcome and prediction of obliteration

Surgical Neurology 67 (2007) 487 – 492 www.surgicalneurology-online.com

Radiosurgery

Intracranial arteriovenous malformations treated with linear accelerator–based conformal radiosurgery: clinical outcome and prediction of obliteration Sergio Moreno-Jime´nez, MDa,4, Miguel Angel Celis, MDa, Jose´ Manuel La´rraga-Gutie´rrez, MScb, Jose´ de Jesu´s Sua´rez-Campos, MDc, Amanda Garcı´a-Gardun˜o, MScb, Mariana Herna´ndez-Bojo´rquez, MScb a

Neurosurgery, bMedical Physicist, and cRadiation-oncology, National Institute of Neurology and Neurosurgery, Mexico City, C.P. 14269, Me´xico D.F. Received 5 July 2006; accepted 16 August 2006

Abstract

Background: Little is written about the clinical outcome and predictor factors of obliteration and treatment success in patients with intracranial AVMs treated with LINAC-based conformal radiosurgery in Mexican institutions. Methods: We analyzed 40 patients with intracranial AVMs with a mean follow-up of 29 (range, 23-34) months. Seven AVMs (17.5%) had a volume b 1 cm3; 10 (25%), 1 to 4 cm3; 13 (32.5%), 4.1 to 10 cm3; and 10 (25%), N 10 cm3. The mean prescription dose was 15.4 Gy. Twenty-six patients (68%) presented hemorrhage before treatment; 4 (10%), chronic headache; 14 (35%), seizures; and 3(8%), neurologic deficit. Results: Seven patients (17.5%) underwent objective clinical improvement. Thirty patients (75%) remained without clinical changes. Three patients (7.5%) developed edema and 1 (2.5%) had a rebleeding after treatment. Twenty-five patients (63%) presented complete obliteration of the AVM. A successful treatment (obliteration without a new deficit) was obtained in 23 (58%) of the cases. The percentage of obliteration was in b 1 cm3 (86%), 1 to 4 cm3 (80%), 4.1 to 10 cm3 (54%), and N 10 cm3 (40%), without a significant difference between groups ( P = .1). Patients with RBAS of V 1.9 had an obliteration of 79% and, those with N 1.9, 48%; the successful treatment in the former resulted in 79% and, in the latter, 38% ( P = .08 and P = .02, respectively). Conclusions: The clinical outcome was similar to other series. The RBAS seems to be a good predictor of obliteration and successful treatment in patients with AVMs treated with LINAC-based conformal radiosurgery. D 2007 Elsevier Inc. All rights reserved.

Keywords:

Arteriovenous malformations; Conformal radiosurgery; LINAC; Clinical outcome; Obliteration

Abbreviations: AVM, Arteriovenous malformation; CT, Computed tomography; DICOM, Digital imaging and communications in medicine; HBO, Hyperbaric oxygen; LINAC, Linear accelerator; MRI, Magnetic resonance imaging; RBAS, Radiosurgery-based arteriovenous malformation score. 4 Corresponding author. Instituto Nacional de Neurologı´a y Neurocirugı´a MVS, Unidad de Radioneurocirugı´a, C.P. 14269, Me´xico D.F. Tel.: +52 56063822x4473, 4472. E-mail address: [email protected] (S. Moreno-Jime´nez). 0090-3019/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2006.08.076

1. Introduction Intracranial AVMs are congenital anomalies developing between the fourth and eighth week of intrauterine life. They consist of the persistence of connections between an artery and a vein without the interposition of a capillary bed. AVMs can become apparent with an intracerebral hemorrhage, epilepsy, focal neurologic deficit, or headache, or can be incidental. The risk of hemorrhage from AVMs without a

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Table 1 Clinical features of 40 patients with AVMs treated with LINAC-based conformal radiosurgery AVM volume (cm3)

n

Age mean

Range

Sex (F/M)

Hemorrhage

Headache

Epilepsy

Neurologic deficit

b1 1-4 4.1-10 N 10 Total

7 10 13 10 40

29.1 26.7 30.6 29.1 29.0

20-49 11-40 18-42 21-40 11-49

5/2 3/7 6/7 4/6 18/22

6 8 7 5 26

0 1 2 1 4

0 3 5 6 14

1 0 1 1 3

(86%) (80%) (54%) (50%) (68%)

(0%) (10%) (15%) (10%) (10%)

(0%) (30%) (38%) (60%) (35%)

(14%) (0%) (8%) (10%) (8%)

n = number.

previous event is about 3% per year [1-4]. The current treatment of AVMs comes with 3 basic tools: microsurgical resection, embolization, and radiosurgery [5,6]. The adequate use of each of these tools as a single treatment modality or in combination is necessary to complete the treatment with success [7]. The radiosurgery is, nowadays, an attractive treatment alternative in patients with AVMs. There are some reports of patients treated with c units (gamma knife) [8-17], with heavy particles (cyclotrons) [18,19], and with high-energy x-rays (linear accelerators) [20-26]. The overall obliteration index with LINAC based radiosurgery is about 80% and is dose-, volume-, and time of follow-up–dependent. There exists a latency period with risk of hemorrhage. The mean dose reported in the literature is between 15 and 25 Gy, and the isodose curve used to conform de nidus is usually the 80% [20-24]. There are some reports about complications or treatment failure after radiosurgery [27-32]. The purpose of this study was to analyze the clinical outcome, as to the obliteration and successful treatment predictor factors, in patients with diagnosis of AVMs treated with LINAC-based conformal radiosurgery. 2. Clinical material and methods 2.1. Patient clinical data and AVM characteristics Between January and December 2003, we treated 47 consecutive patients with diagnosis of intracranial AVMs in the National Institute of Neurology and Neurosurgery of Mexico City with a dedicated linear accelerator (BrainLAB Novalis Heimstetten, Germany). We included patients with complete charts. Six patients were excluded because of incomplete clinical charts or insufficient follow-up, and one more for being treated with hypofractionation. The mean follow-up was 29 months (range, 23-34 months).The clinical data from the patients are shown in Table 1. From the 40 patients in our series, 22 (55%) were males and 18 (45%) were females. Three patients (7.5%) underwent one attempt of surgical removal, 10 (25%) underwent incomplete embolization, 2 (5%) received both treatments, and 1 (2.5%) was treated with gamma knife–based radiosurgery. The latter patient had a residual nidus evidenced angiographicaly 3 years after the procedure. Twenty-four (60%) patients received no treatment before radiosurgery. The location and volumes from the AVMs are shown in

Tables 2 and 3. The nidus maximum diameter had a mean of 30.7 mm (range, 7-80 mm). One patient (2.5%) pertained to Spetzler-Martin grade I, 11 (27.5%) patients to grade II, 19 (47.5%) to grade III, 8 (20%) to grade IV, and 1 (2.5%) to grade V. Seven (17.5%) AVMs had a volume b 1 cm3, 10 (25%) from 1 to 4 cm3, 13 (32.5%) from 4.1 to 10 cm3, and 10 (25%) N10 cm3. Patients in the 4 volume categories were not different in relation to hemorrhage, epilepsy, or headache or focal neurologic deficit ( P = .2, .08, .7, and .7, respectively), or relative to age. 2.2. Technique, planning, and dosimetry Before the frame was placed, a 3-T MRI and magnetic resonance angiography were realized. Patients underwent placement of a BrainLab (BrainLAB) frame while receiving a local anesthetic. The fiducial localizing box was attached to the frame for the angiography. Patients also underwent angio-CT imaging. All images were fused for treatment planning. The CT and T2-weighted MRI fusion and biplanar angiography were used for contouring the nidus. In some cases in which the AVMs had a very compact and welldefined nidus and without previous treatment, stereotactic angiography was not performed. Magnetic resonance and CT images were processed in DICOM and transferred to the planning workstation via internal network. The nidus contour and the plan were executed according to the BrainScan 5.31 (BrainLAB). A radiation prescription dose from 10.5 to 20 Gy (mean, 15.4 Gy) was delivered in a single session. The choice of the radiation dose was influenced by the target volume and location. The isodose prescription curve used to conform to the target was from 63% to 95% (mean, 84%). The radiation dose at the center of the target was from 13 to 22 Gy (mean, 18.5 Gy). In all cases, a single isocenter and the micromultileaf collimator were used. A summary of the dosimetric parameters is shown in Table 4. The technique used was dynamic conformal arcs in 27 (68%) patients, conformal Table 2 Volume of the 40 AVMs treated with radiosurgery AVM volume (cm3)

b1 1-4 4.1-10 N 10 n = number.

Case n

%

7 10 13 10

18 25 32 25

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489

Table 3 AVM location by volume categories AVM location

Total series

1* 2* 3* Total

n 13 12 15 40

AVM

Volume

A % 32 30 38

B

n 2 2 3 7

% 29 29 42

n 3 3 4 10

C % 30 30 40

n 2 6 5 13

D % 15 46 39

n 6 1 3 10

% 60 10 30

A= b 1 cm3, B = 1-4 cm3, C = 4.1-10 cm3, D = N 10 cm3. 1* = frontal/temporal, 2* = parietal/occipital/intraventricular/corpus callosum/cerebelum, 3* = basal ganglia/thalamus/brain stem. n = number.

beam in 11 (27%), and intensity-modulated radiation surgery in 2 (5%). Dose homogeneity within the target volume was determined as the maximum dose divided by the prescription dose. The conformity index was determined as the ratio of prescription isodose volume to the target volume [33].

developing edema was 18 Gy, whereas the one within the patients without complications was 15.1 Gy (Mann-Whitney U test, P = .05). We did not find any difference in the incidence of complications with regard to location (Fisher exact test, P = .5). 3.2. Obliteration index

3. Results 3.1. Clinical and neurologic outcome The follow-up from the 40 patients ranged from 23 to 34 months (mean, 29 months; median, 30 months). Seven patients (17.5%) improved objectively from the pretreatment clinical status developing good seizure results or disappearance of the vascular headache. Thirty (75%) patients remained without changes during the follow-up after radiosurgery. Three patients (7.5%) developed perilesional edema with clinical manifestations, with only 2 of them (5%) resulting in a permanent focal neurologic deficit. One patient with a mesencephalic AVM developed edema and presented ocular movement anomalies. She did not improve initially with corticosteroids treatment and was referred to receive HBO therapy with finally incomplete resolution of the symptoms. Other patients with a thalamic AVM developed an increment of the hemiparesis after a hemorrhage and also required HBO therapy with only partial resolution. Another patient with an occipital AVM suffered perilesional edema with augmentation of the campimetric defect and with complete resolution with corticosteroids therapy. We observed 1 patient (2.5%) with a hemorrhage 6 months after the radiosurgical treatment without a new permanent neurologic deficit. No relationship between complication incidence and the volume group could be established (Fisher exact test, P = .34). The mean prescription dose within the patients Table 4 Dosimetry used in 40 patients with AVMs treated with radiosurgery Variable

Mean/SD

Range

Prescription Dose (Gy) Isodose curve prescription (%) Maximal dose (Gy) Arcs number AVM volume (cm3) Conformity index Homogeneity index

15.4 83.9 18.5 7.4 7.7 2.3 0.7

10.5-20 63-95 13-22.2 3-19 0.17-30 1.7-3.5 0.2-0.9

SD = standard deviation.

F F F F F F F

2.2 6.0 2.4 4.3 6.8 0.5 0.1

Twenty-five patients (63%) showed complete obliteration during the follow-up after radiosurgery. Total obliteration means the nidus is no longer visible angiographically and the circulation time and the afferent and efferent vessels that had supplied the malformation have returned to normal. Twenty-two cases were confirmed with angiography, whereas the other 3 cases were supposed to be obliterated because no flow voids were discernible in MRI and rejected the angiography. Fifteen patients (37%) underwent partial reduction of the nidus size but without complete obliteration. We defined success as the complete nidus obliteration without any new neurologic deficit after radiosurgery and were achieved in 23 (58%) patients. The percentage of obliteration in patients with AVM volume of b 1 cm3 was 86%; in 1 to 4 cm3, 80%; in 4.1 to 10 cm3, 54%; and in N 10 cm3, 40%. We analyzed the obliteration index and successful outcome in all 4 volume groups without finding a significant difference between the groups (Fisher exact test, P = .1 and P = .06). Recently, a radiosurgical grading system was developed by the Mayo Clinic/University of Pittsburgh to predict outcomes for gamma knife radiosurgery [34]. We calculated the RBAS (Table 5), finding a mean of 1.3 in the group of b1 cm3, 1.4 in the group from 1 to 4 cm3, 2.1 in the group from 4.1 to 10 cm3, and 3.0 in the group of N 10 cm3. The overall mean was 2.0. We analyzed different cutoff points in the RBAS, finding a significant difference in predicting a successful outcome, comparing the groups from V 1.9 and N 1.9. In the first one, we obtained obliteration in 15 (79%) of 19 patients, whereas in the second group, it resulted in 10 of Table 5 Radiosurgery-based arteriovenous malformations score RBAS = (0.1)* (volume, mL) + (0.02)* (age, y) + (0.3)* (location, frontal/temporal = 0, parietal/occipital/corpus callosum/ cerebelum = 1, basal ganglia/thalamus/brain stem = 2)

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21 patients (48%) (Fisher exact test, P = .08). The success was obtained in 15 (79%) of 19 and in 8 (38%) of 21 patients, respectively (Fisher exact test, P = .01). We analyzed the results of obliteration and success between patients with and without previous treatment before radiosurgery. Both groups were homogenous with regard of age, volume, and prescription dose. We did not find any significant differences in the obliteration index and the final outcome between groups (v 2 test, P = .2 and P = .2 respectively). 4. Discussion Yamamoto et al [35]reported 121 patients with AVMs treated with radiosurgery with gamma knife with a clinical improvement in 22 patients (18%), a stable evolution in 83 patients (69%), and a permanent neurologic deficit in 6 patients (5%), fatal hemorrhage in 3 patients (2.5%), nonfatal hemorrhage in 4 patients (3%), and 3 patients (2.5%) dying by other cause [9]. We found similar results: clinical improvement in 7 patients (17.5%), a stable evolution in 30 patients (75%), permanent neurologic deficit in 2 patients (5%) and a nonfatal hemorrhage in 1 patient (2.5%). We did not have patients with fatal hemorrhage. Friedman et al [9] reported 2% incidence of radiationinduced late complications. One presented headache and 2 more a mild dysphasia. All of them presented MRI changes attributable to radiation and with complete resolution with corticosteroids treatment. They found only 1.3% incidence of radiation-induced permanent neurologic deficit [22]. Ramı´rez-Castan˜eda et al [26] reported 12.5% of patients continuing with headache after the radiosurgical treatment, 29.2% remained with seizures and 29.5% with a focal neurologic deficit [35]. Betti et al [2] reported an improvement in frequency and intensity of seizures in 6 of 10 patients presenting with epilepsy. Two patients underwent a permanent neurologic deficit [20]. In the series of Colombo et al [4], there was a 2.7% incidence of temporal neurologic deficit after radiosurgery, and 2.2% of permanent deficit [21]. Steiner et al [33] reported 247 patients with AVMs treated with gamma knife–based radiosurgey. The headache resolved in 65 (66.3%) of 98 patients presenting with this symptom and improved in another 9 (9.2%). From 59 patients with epilepsy, 11 (18.6%) became seizure-free without taking anticonvulsants, and 30 more (50.8%) became seizure-free but taking anticonvulsants. The preexisting neurologic deficit improved or completely disappeared after radiosurgery in 56.7% of the affected patients [8]. In our series, we found only 1 patient with rebleeding. The percentage of obliteration in our series was in b1 cm3 (86%), in 1 to 4 cm3 (80%), in 4.1 to 10 cm3 (54%), and in N10 cm3 (40%). The mean prescription dose in each category was 17.3 ( b1 cm3), 15.7 (between 1 and 4 cm3), 15.3 (between 4.1 and 10 cm3), and 13.8 (N 10 cm3). Yamamoto et al [35] divided the patients according to AVM volume in V 10 cm3 and N 10 cm3 without finding any significant difference in the obliteration index at 12, 24, 36,

and N 36 months. Friedman et al [9] analyzed, with great detail, the relationship between the outcome and the AVM size. They found the following percentage of obliteration in each group: 1 to 4 cm3 (81%), 4.1 to 10 cm3 (89%), and N 10 cm3 (69%). The overall obliteration was 80%. The mean follow-up was 33 months [22]. Ramı´rez-Castan˜eda et al [26] reported an overall obliteration of 62.9% at 12 months [35]. In the series of Betti et al [2], 27 (65.8%) of 41 patients underwent obliteration after a follow-up of 24 months [20]. Colombo et al [4] reported 46% obliteration after 1 year and 80% after 2 years, whereas Steiner et al [33] reported 81% [8,21]. The mean volume of the nidus in our series was 7.7 cm3 (range, 0.17-30 cm3). Divided in categories, we found 7 (18%) in the group of b 1 cm3, 10 (25%) between 1 and 4 cm3, 13 (32%) between 4.1 and 10 cm3, and 10 (25%) in the group of N 10 cm3. Pollock [23] reported a group of patients with a mean volume lesion of 4.1 cm3 (range, 0.118). Most of the series mention the maximal diameter instead of the AVM volume. In our study, we have a mean maximal diameter of 31 mm (range, 7-80 mm). Yamamoto et al [35]reported a mean maximal diameter of 27 mm (range, 6-62 mm) [9]. Betti et al [2] divided the patients in 3 groups regarding the size of the AVM in b 12, 12 to 25, and 25 to 60 mm (18, 40, and 8 patients, respectively) [20]. Overall, we treated a greater proportion of AVMs with bigger volumes than other series, with a mean of 7.7 cm3 with similar outcomes. We analyzed the usefulness of the RBAS as a prognostic factor of obliteration and final treatment success [34]. The better cutoff point we found after analyzing some of them was 1.9. The patients with an RBAS V 1.9 had a percentage of complete obliteration of 79%, whereas those with an RBAS N 1.9 was 48% (v 2 test, P = .08). The percentage of success in the former was 79% and, in the latter, 38% (v 2 test, P = .01). Pollock and Flickinger [24] reported an excellent result in 100% of the patients with an RBAS of V 1.0 and 39% in those with an RBAS N 2.0 ( P = .0001). They analyzed the correlation between the Sptezler-Martin grade ( P = .13), the K index ( P = .26), and the obliteration prediction index ( P = .21) [34]. In our series, we found an excellent result of 75% in patients with an RBAS of V 1.0 and 44% in N2.0 (Fisher exact test, P = .6), but we had only 3 patients in the first group and 18 in the second, making evident, one more time, that we treated bigger AVMs. We did not find significant differences in the percentage of obliteration between the different grades from the Spetzler-Martin classification (Fisher exact test, P = .7). The results we obtained are similar to those written in other works with the difference that we treated bigger AVMs. 5. Conclusions It seems to be safe to treat patients with bigger AVMs than those reported in other series with LINAC-based conformal radiosurgery. The RBAS seems to be a good

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predictor index of obliteration and treatment success in patients with AVMs treated with LINAC-based conformal radiosurgery.

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Commentary Moreno et al present their initial experience with a small series, using a technique different from that described in the literature. They are treating patients with a more homogeneous dose distribution and not using the multiple isocenter approach common to gamma knives and the work of Dr William Friedman superbly done over the years, setting the standards for multiple isocenter radiosurgery using linear