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 Table of Contents  
Year : 2021  |  Volume : 54  |  Issue : 2  |  Page : 45-51

Fractionated stereotactic radiosurgery in treating the complex intracranial arteriovenous malformations

Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou; Department of Medicine, Chang Gung University, Taoyuan, Taiwan

Date of Submission01-Jun-2020
Date of Decision28-Jul-2020
Date of Acceptance27-Oct-2020
Date of Web Publication20-Mar-2021

Correspondence Address:
Peng-Wei Hsu
Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, No. 5, Fuxing Street, Guishan District, Taoyuan 33305
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/fjs.fjs_88_20

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Background: The aim of this study was to examine the efficacy and safety of treating large or eloquently located intracranial arteriovenous malformations (AVMs) with fractionated stereotactic radiosurgery (FSRS).
Materials and Methods: Eighteen patients with AVM treated with FSRS between March 2006 and August 2018 were retrospectively evaluated. The nidus obliteration, volume reduction, rate of rebleeding, newly onset neurological deficit, and signal change in magnetic resonance imaging (MRI) were evaluated.
Results: With a median follow-up of 88 months (range: 24–154), 6 of the 18 lesions (33.3%) had a complete obliteration. All obliteration occurred in patients received the total treatment dose of 21 Gy (6 of 9 patients, 66.7%). The median time to complete obliteration was 38 months (range: 12–53). The mean volume reduction after FSRS in the 25 Gy group was 30.2% ± 20.9% and that in the 21 Gy group was 87.7% ± 24.2%. During the follow-up period, 4 of 18 (22.2%) lesions revealed T2 signal change in the MRI. No FSRS-related complication was noted clinically or radiologically.
Conclusion: According to the present results, FSRS could be an effective and safe treatment alternative for complicated AVMs. Delayed toxicity after treatment is not noticed in the current study, but long-term follow-up is required. A higher dose in total and each fraction is likely needed when treating larger lesions.

Keywords: Arteriovenous malformation, eloquently located, fractionated, large, radiosurgery

How to cite this article:
Hsu PW. Fractionated stereotactic radiosurgery in treating the complex intracranial arteriovenous malformations. Formos J Surg 2021;54:45-51

How to cite this URL:
Hsu PW. Fractionated stereotactic radiosurgery in treating the complex intracranial arteriovenous malformations. Formos J Surg [serial online] 2021 [cited 2021 Sep 24];54:45-51. Available from: https://www.e-fjs.org/text.asp?2021/54/2/45/311592

  Introduction Top

Intracranial arteriovenous malformations (AVMs) are congenital vascular lesions composed of an abnormal vessel tangle named nidus with a direct arterial blood input and drainage into the venous system. The most common presentation is intracranial hemorrhage with an estimated risk of 2%–4% annually if untreated. Each bleeding leads to around 30%–50% morbidity and 10% mortality.[1] Other associated complications include seizure, mass effect caused by the AVM itself, ischemia induced by steal phenomena, and vascular headache.

The ultimate goal of treating cerebral AVMs is total obliteration to avoid further hemorrhage. Various methods, including microsurgical resection, endovascular embolization, stereotactic radiosurgery (SRS), or a combination of the above are used to eliminate AVMs. SRS, one of the effective alternatives, has been widely applied to treat AVMs since the 1970s. A margin dose of >18 Gy could achieve an obliteration rate around 80%–90% in small AVMs with a diameter of ≦2.5 cm.[2] Although SRS can yield a favorable outcome, there are still limitations in treating specific groups of lesions, such as large AVMs (diameter of >3 cm) and AVMs located in eloquent areas (brainstem, thalamus, basal ganglia, and motor cortex). A previous study reported a lower obliteration rate and higher morbidity and mortality rates in this group of AVMs.[3]

With the progress of image resolutions, planning software, and treatment machines, volume-based or dose-based fractionated stereotactic radiosurgery (FSRS) has been used to treat large or critically located AVMs. Favorable outcomes were achieved after volume-staged treatment with gamma knife radiosurgery.[4] In this study, we report our institutional experience in treating a specific group of AVMs with the dose-based fractionation technique. We also attempted to analyze the effects and treatment outcomes when different radiation doses, in total and in each fraction, were applied to the lesions.

  Methods Top

Patient population

We conducted this retrospective analysis at a single institution, and the study was approved by the institutional review board (IRB) of Chang Gung Memorial Hospital, Taoyuan, Taiwan (IRB No. 201700082B0 obtained on February 8, 2017). The IRB agrees to waive the informed consent.

From March 2006 to August 2018, 72 patients harbored intracranial AVMs underwent linear accelerator-based FSRS with the Novalis system. Twenty-three patients accepted FSRS after meeting the following inclusion criteria: (1) maximum AVM diameter of >3 cm or (2) AVMs located in eloquent areas with a maximum AVM diameter of ≦3 cm. All the AVMs were confirmed by cerebral angiography after initial evaluation with computed tomography (CT) or magnetic resonance imaging (MRI). Five patients with a follow-up time <24 months were excluded. There were 12 men and 6 women, and the median age was 32 years (range: 6–48). No patients had been treated with other modalities, such as microsurgical resection or endovascular embolization before undergoing FSRS.

Two treatment protocols were used: 5 Gy/fraction/day and 7 Gy/fraction/day for 5 and 3 consecutive days to reach a total dose of 25 Gy and 21 Gy. The AVMs with a maximal diameter of >3 cm were treated with the 25 Gy protocol and the other lesions were treated with the 21 Gy protocol.

Radiosurgery technique

The image preparation for FSRS, including thin-sliced CT, MRI, and bi-planar angiogram was used to define the treatment target and to design the treatment plan as presented in a previous study.[5]

The Novalis system (Brainlab, Heimstetten, Germany) was used for FSRS. The software Brainscan, version 5.31 (Brainlab, Germany) was used to design the treatment plan. A 100% isodose line was employed to cover the target. The target volume was calculated using the iPlan Radiotherapy Planning Software (iPlan RT Image 3.0.1, Brainlab, Germany).

Oral dexamethasone (0.5 mg 4 times per day for 7 consecutive days) was administered to the patients from the first treatment day to prevent the acute toxic effects induced by FSRS.

Follow-up evaluation

After FSRS, an annual magnetic resonance angiography (MRA) was used to evaluate the obliteration of the AVMs. Cerebral angiography was used to confirm a complete obliteration if no abnormal blood flow was detected on the follow-up MRA images.

During the outpatient clinic follow-up, any new-onset neurological deficits, clinical symptoms, and imaging findings such as hemorrhage, cerebral edema, radionecrosis, cyst formation, and signal changes on the T2-weighted images induced by radiation were recorded.

The last follow-up images were used to analyze the remained volume of the nidus. It was calculated using the same software as in the treatment planning system.

Statistical analysis

The association between patient characteristics and dose/fraction groups was examined by Fisher's exact test, Student's t-test, and Wilcoxon rank-sum test. For AVM reduction percentage, the Wilcoxon rank-sum test and the simple linear regression were used in the univariate analysis. The generalization linear model was adopted in multivariate analyses. For the presence of T2 signal change in MRI, the Fisher's exact test and the unconditional logistic model were used in univariate and multivariate analyses. A probability value of <0.05 was considered statistically significant.

  Results Top

Among the 18 patients, 9 (50%) and 9 (50%) patients received the 25 Gy and 21 Gy protocols. The mean nidus volume was 29.22 ± 28.64 cm3. The overall median follow-up time was 88 months (range: 24–154) [Table 1]. Six lesions (33.3%) had a complete obliteration during the follow-up period.
Table 1: General information of the patients had arteriovenous malformation treated with fractionated stereotactic radiosurgery

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After multivariate analysis, the factors associated with the outcome are the therapeutic dose and lesion volume. Six AVMs with a complete obliteration received a total treatment dose of 21 Gy [Figure 1]. The median time to complete obliteration was 38 months (12, 12, 36, 40, 41, and 53 months for each patient). The mean volume reduction after FSRS in 18 patients was 58.9% ± 36.8%. Whether in group 25 Gy or group 21 Gy, the lesion volume was significantly reduced after treatment (P = 0.0391 in group 25 Gy and 0.0078 in group 21 Gy). The data details are shown in [Table 2].
Figure 1: The figures demonstrated the treatment plan and result of the patient number 9. Two years after the fractionated stereotactic radiosurgery, the nidus located in the left thalamus (a) obliterated totally (b). (c and d) Showed the dose planning with the integration of bi-planar angiogram, computed tomography, and magnetic resonance images

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Table 2: Summary of patients and treatment characteristics in the present study

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During the follow-up period, neither new-onset neurological deficits nor worse seizure attacks were noted clinically. Increased signal changes were observed on the T2-weighted MRI in 4 of the 18 (22.2%) patients. No new-onset hemorrhage, brain edema, necrosis, or cyst formation induced by FSRS occurred.

  Discussion Top

Dose and volume limitation in single-fraction stereotactic radiosurgery

The treatment dose and the target volume are the important factors in the success of treatment with SRS. According to the previous studies, dose above 18 Gy in a single fraction treatment could provide a better obliteration rate.[6] However, there are limitations on the therapeutic dose in some important functional areas, such as 16 Gy to the basal ganglions and motor cortex, 12 Gy to the brainstem, and 8 Gy to the optic apparatus. A lower radiation dose may reduce the permanent symptomatic sequelae when treating eloquently located AVMs even with a nidus diameter of <3 cm. However, this strategy has a negative effect on the treatment outcome.

In consideration of nidus volume, Miyawaki et al. reported a lower obliteration rate and a higher complication rate in AVMs >14 cm3 in volume (estimated diameter >3 cm).[7] Observation is recommended for large volume AVMs in patients without prior bleeding.[6] Therefore, we try to use the FSRS to improve the treatment outcome.

Treatment outcomes for complex arteriovenous malformation

According to the literature, large- and deep-seated AVMs bear a higher rupture risk.[8] However, it is still a challenge to treat large or eloquently located AVMs. High morbidity and mortality rates were reported in treating large, Spetzler-Martin Grades IV and V AVMs using the microsurgical or multimodality approach.[3],[9] In general, it is difficult to achieve a complete obliteration by treating large AVMs with endovascular embolization. It also harbors an increased risk of hemorrhage after partial embolization.[9]

Consideration for fractionated stereotactic radiosurgery dose-fraction formula

When considering the radiation dose, the α/β ratio is an important determinant. It is accepted that the α/β ratio of AVMs is estimated to be 2.2 ± 1.6 Gy, which is similar to that of the brain parenchyma, a late-responding tissue.[10] This low ratio makes the conventional fractionated radiotherapy less effective. Thus, FSRS using a higher dose in each fraction will preserve the advantage of radiosurgery and provide a better radiobiological sparing of the late-responding tissue. In our study, we chose the dose-fraction formula in accordance with the linear-quadratic formalism presented previously.[11]

Applying a higher total dose or dose in each fraction to the nidus, Chang et al. presented a result with a 71% obliteration rate 6 years after FSRS using a dose of ≥28 Gy, which was delivered in 4 daily fractions.[12] Lindvall et al. also reported an overall obliteration rate of 92.5% using a dose of >30 Gy in 5 fractions.[13] Regarding the dose per fraction, Xiao et al. pointed out that 6 Gy was correlated with a good response.[14] Veznedaroglu et al. reported that 5 Gy in each fraction resulted in a lower obliteration rate than 7 Gy.[15] Compared with a per-fraction dose of <7 Gy, some studies also report a better outcome when using 7 Gy.[12] The risks of complications were higher when each fraction SRS with a higher dose was used, so we apply the formula with 25 Gy in 5 fractions to treat the large AVM.

The effect of nidus volume on treatment outcomes

The nidus volume is another important factor influencing the obliteration rate after radiosurgery.[2] The larger the volume, the worse the effect of the treatment and the greater the risk of complication are.[16] In the present study, a higher obliteration rate was observed in the 21 Gy group, which had a significantly smaller volume (P = 0.0026) [Figure 2]. All the 6 AVMs had a complete obliteration with a median volume of 1.87 cm3 (range: 0.52–5.49). Lindvall et al. and Boström et al. also demonstrated a higher complete obliteration rate when the nidus volume was smaller.[17],[18] In our series, there was no complete obliteration shown in the AVMs of the 25 Gy group. There may be two reasons for such poorer results: the first is the larger lesion volume, and the second is the lower dose per fraction. A similar result was also presented by Zabel-du Bois et al.[19] The previous studies reviewed are listed in [Table 3].
Figure 2: Statistical analysis using simple linear regression was performed with the nidus volume as a single variable. A better volume reduction rate was noted when the nidus volume being smaller

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Table 3: Summary of treatment characteristics in using fractionated stereotactic radiosurgery for large or eloquently located arteriovenous malformations

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Preradiosurgery embolization

Pre-FSRS embolization remains controversial in treating large AVMs. Some authors suggested that pre-FSRS embolization to reduce the nidus volume will increase the obliteration rate and decrease the incidence of posttreatment hemorrhage.[15],[20] However, some studies suggested that an increase in the rate of posttreatment hemorrhage was observed in patients undergoing pre-SRS embolization.[21] Embolization also made it more difficult to define the real margin of the nidus owing to the artifacts induced by the embolization materials, which would result in a worse response. Some suggested that pre-FSRS embolization should be reserved for AVMs with fistulas or aneurysms that are radioresistant or prone to bleeding.[14]

Radiosurgery-related complications

Regarding the complications, there were neither new-onset symptomatic neurological deficits nor asymptomatic rebleeding, radiation-induced cerebral necrosis, or edema noted during the follow-up period in this study. Transient, mild symptoms rather than permanent, severe complications were reported in the AVMs treated with FSRS when compared with SRS.[22] Aoyama et al. supposed that a lower dose than that used in single session radiosurgery provides a protective effect to the surrounding, low-response tissues.[23] Four lesions using the 21 Gy protocol presented here demonstrated an increased signal in the peri-nidus area on the T2-weighted MRI. The phenomenon is believed to correlate to the higher per-fraction dose. A number of previous studies noted that radionecrosis occurred more often when a higher total dose was applied.[13],[15],[22]

Some studies indicated that FSRS does not increase the subsequent bleeding risk.[14],[24] In contrast, some studies revealed a higher bleeding risk when only a partial obliteration was achieved after FSRS.[8],[25] However, some studies indicate that the incidence of this event will decrease over time after a transient higher bleeding rate because thickening of the vascular wall following radiation makes the nidi more resistant to fluctuating blood pressures.[26] No rebleeding was observed after the treatment in our study, probably because of the small sample size.

  Conclusion Top

While large- or deep-seated AVMs remain difficult lesions to manage, dose-based FSRS can be considered as the sole treatment option or adjunct to other treatment modalities in the treatment centers without a gamma knife system for volume-staged radiosurgery. Although limited cases were included and bias in patient selection may have occurred in this study, FSRS with a 21 Gy dose in 3 fractions is a relatively safe and effective method of treating the smaller, eloquently located AVMs. Even only partial obliteration achieved, FSRS makes it possible to further treat the larger AVMs with surgical resection or repeat SRS. A higher dose in total and in each fraction (such as 28 Gy in 4 fractions) could be considered to improve the treatment outcome, especially in those large AVMs. Risks of radiation-related complications are expected to be higher and need to be closely monitored. Prospective randomized trials with larger populations and longer follow-up are needed to better understand the real effects and complications.

Financial support and sponsorship

The Chang Gung Memorial Hospital provided financial support (grant numbers CIRPG3D0011, CIRPG3D0012, and CIRPG3D0013). The sponsor had no role in the design or conduct of this research.

Conflicts of interest

There are no conflicts of interest.

  References Top

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Wang YC, Huang YC, Chen HC, Wei KC, Chang CN, Lee ST, et al. Linear accelerator stereotactic radiosurgery in the management of intracranial arteriovenous malformations: long-term outcome. Cerebrovasc Dis 2014;37:342-9.  Back to cited text no. 2
Chang SD, Marcellus ML, Marks MP, Levy RP, Do HM, Steinberg GK. Multimodality treatment of giant intracranial arteriovenous malformations. Neurosurgery 2003;53:1-1.  Back to cited text no. 3
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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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