effect of prior embolization on cerebral.14

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Effect of Prior Embolization on CerebralArteriovenous Malformation RadiosurgeryOutcomes: A Case-Control Study

BACKGROUND: Embolization before stereotactic radiosurgery (SRS) for cerebral arte-riovenous malformations (AVM) has been shown to negatively affect obliteration rates,but its impact on the risks of radiosurgery-induced complications and latency periodhemorrhage is poorly defined.OBJECTIVE: To determine, in a case-control study, the effect of prior embolization onAVM SRS outcomes.METHODS: We evaluated a database of AVM patients who underwent SRS. Propensityscore analysis was used to match the case (embolized nidi) and control (nonembolizednidi) cohorts. AVM angioarchitectural complexity was defined as the sum of the number

of major feeding arteries and draining veins to the nidus. Multivariate Cox proportionalhazards regression analyses were performed on the overall study population todetermine independent predictors of obliteration and radiation-induced changes.RESULTS: The matching process yielded 242 patients in each cohort. The actuarialobliteration rates were significantly lower in the embolized (31%, 49% at 5, 10 years,respectively) compared with the nonembolized (48%, 64% at 5, 10 years, respectively)cohort (P= .003). In the multivariate analysis for obliteration, lower angioarchitecturalcomplexity (P, .001) and radiologically evident radiation-induced changes (P= .016)were independent predictors, but embolization was not significant (P= .744). In themultivariate analysis for radiologic radiation-induced changes, lack of prior embolization(P= .009) and fewer draining veins (P= .011) were independent predictors.CONCLUSION: The effect of prior embolization on AVM obliteration after SRS may be

significantly confounded by nidus angioarchitectural complexity. Additionally, emboli-zation could reduce the risk of radiation-induced changes. Thus, combined emboliza-tion and SRS may be warranted for appropriately selected nidi.

KEY WORDS: Embolization, Endovascular procedures, Gamma knife, Intracranial arteriovenous malformations,Radiosurgery, Stroke, Vascular malformations

Neurosurgery 77:406417, 2015 DOI: 10.1227/NEU.0000000000000772 www.neurosurgery-online.com

Cerebral arteriovenous malformations(AVMs) are uncommon intracranial vas-cular lesions that possess an inherent pro-

pensity to hemorrhage, although the risk of

rupture varies by the occurrence of prior AVMhemorrhage and by nidus size, location, andangioarchitecture.1-5 Because of the neurologicaldevastation rendered by intracranial hemorrhage

from a ruptured AVM, the primary goal of AVMintervention is complete obliteration of the nidusin order to eliminate subsequent hemorrhagerisk.6-12 Stereotactic radiosurgery (SRS) offers

a minimally invasive alternative to surgical resec-tion and curative embolization for the obliterationof AVMs, especially those situated in deep oreloquent regions.13-18 However, the risk-to-benefit profile of SRS is unfavorable for largeAVMs, with relatively low rates of obliteration andhigh rates of SRS-induced complications.19-24

Partial nidus embolization has become a com-monly used adjunct in the multimodality man-agement of AVMs to reduce the volume of large

Eric K. Oermann, MD*

Dale Ding, MD

Chun-Po Yen, MD

Robert M. Starke, MD, MSc

Joshua B. Bederson, MD*

Douglas Kondziolka, MD,

MSc

Jason P. Sheehan, MD, PhD

*Mount Sinai Health System, Department

of Neurosurgery, New York City, New

York; University of Virginia, Department

of Neurosurgery, Charlottesville, Virginia;

New York University Langone Medical

Center, Department of Neurosurgery,

New York City, New York

Correspondence:

Jason P. Sheehan, MD, PhD,

University of Virginia,

Department of Neurosurgery,

P.O. Box 800212,

Charlottesville, VA 22908.

E-mail: [email protected]

Received,December 7, 2014.

Accepted,March 16, 2015.

Published Online, April 11, 2015.

Copyright 2015 by the

Congress of Neurological Surgeons.

ABBREVIATIONS: AVM, arteriovenous malforma-tion; RBAS, radiosurgery-based AVM score; SRS,stereotactic radiosurgery; VRAS, Virginia Radiosur-gery AVM Scale

RESEARCHHUMANCLINICAL STUDIES

RESEARCHHUMANCLINICAL STUDIES

406 | VOLUME 77 | NUMBER 3 | SEPTEMBER 2015 www.neurosurgery-online.com

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited


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AVMs to facilitate definitive treatment with radiosurgery.25

Previous studies have shown that prior AVM embolizationreduces radiosurgical obliteration rates.26-31 However, the effectof embolization on the incidence of SRS-induced complicationsand the risk of latency period hemorrhage is inconsistentlyreported and, thus, poorly understood. Additionally, the mech-

anisms by which embolization reduces obliteration rates follow-ing AVM SRS have not been thoroughly investigated.32 The aimof this case-control study, which compares AVM patients withand without prior embolization who were treated with SRS, is todetermine the effect of prior nidal embolization on radiosurgicaloutcomes, with respect to obliteration, SRS-induced complica-tions, and latency period hemorrhage.

METHODS

Participant Selection and Study Design

We performed a retrospective evaluation of a prospectively collected,institutional review board approved database of approximately 1400

AVM patients who were treated with Gamma Knife SRS at a singleinstitution from 1989 to 2013. The inclusion criteria were (1) patients

with sufficient data regarding prior interventions (ie, surgical resectionand/or embolization), clinical presentation, AVM characteristics, andpost-SRS outcomes, and (2) minimum radiologic follow-up duration of 2years or complete AVM obliteration on follow-up angiography ormagnetic resonance imaging (MRI). Patients who underwent dose- orvolume-staged SRS were excluded. The case cohort consisted of patients

who underwent initial embolization, followed by SRS. The control cohortconsisted of patients who underwent SRS alone.

Baseline Variables

The patient variables were: sex,age, clinicalpresentation, and radiologic

and clinical follow-up durations. The AVM variables were: modifiedradiosurgery-based AVM score (RBAS), Virginia Radiosurgery AVMScale (VRAS), location (eloquent or noneloquent), associated aneurysms,

AVM size (maximum diameter and volume), and Spetzler-Martingrade.33-35 The AVM size and AVM grading system classification(Spetzler-Martin grade, RBAS, VRAS) for each patient were based on thepostembolization nidus volume and angioarchitecture. The maximumdimension and volume of each nidus were determined based on review ofthe patients MRI and angiography by a neurosurgeon and neuroradi-ologist at our institution. Because the primary goal of AVM embolization

was volume reduction of large AVMs (typically a maximum diameter.3 cm or volume .12 cm3), the postembolization volume of each nidus

was typically less than its initial volume. Eloquent location was definedbased on the Spetzler-Martin grading system.33 Associated aneurysms

included intranidal or perinidal aneurysms. All patients were treatedusing the Leksell Gamma Knife (Elekta AB, Stockholm, Sweden).Details of the SRS procedures performed at the University of Virginia

havebeen previouslyreported.36 Patients treated before 1991 had planningperformed with biplane angiography, whereas patients treated after 1991had volumetric computed tomography (CT) or MRI for supplementalimaging as well. Planning was performed with the Kula software from May1989 until June 1994, and with the Gamma Plan software thereafter. Onlythe nonembolized, patent (ie, filled with contrast during angiography)portion of each nidus was targeted with SRS. The SRS variables were:margin dose, isodose line, and number of isocenters.

Patient Follow-up and Outcomes Assessment

Radiologic follow-up wasobtained by MRI every 6 months for the first2 years, and then annually thereafter. Obliteration was defined as theabsence of flow voids on MRI or the absence of anomalous arteriovenousshunting on angiography. Angiography was performed, when possible,after obliteration was noted on MRI to confirm nidus occlusion. Further

neuroimaging, either CT or MRI, was performed as necessary in patientswith new or worsening neurological symptoms.

Radiation-induced changes were defined as new perinidal T2 signalchange on MRI. Radiation-induced changes were monitored for associatedclinical symptoms and SRS-associated toxicity throughout the duration offollow-up. Latency period hemorrhage was defined by neuroimaging as any

AVM hemorrhage following SRS treatment, regardless of clinical status.The annual post-SRS hemorrhage risk was calculated by dividing thetotal number of latency period hemorrhage events by the total number ofrisk years (interval between SRS treatment and nidus obliteration orlast radiographic follow-up for incompletely obliterated nidi). Clinicalfollow-up was obtained by a combination of clinic and hospital visits anddata collected by outside referring institutions and patientslocal physiciansfrom the University of Virginia.

Case Matching and Statistical Analysis

Propensity scores were calculated for case and control patients by usinga logistic regression model consisting of the following input variables: sex,age, follow-up time, RBAS, margin dose, prior AVM hemorrhage,Spetzler-Martin grade, nidus volume, and maximum nidus diameter.

We matched the case cohort to the control cohort using a 1:1, fuzzy(tolerance of 0.6 standard deviation), greedy matching algorithm run over100 iterations, with selection of the maximally matched set forfinal use.37

The final matched cohort was validated for appropriate matching byusing means testing orx2 testing as appropriate on a per variable basis toconfirm equivalence of individual variables between each cohort. Toaccount for potential variability due to propensity score matching over

a small sample size, the analysis was confirmed empirically by repetitionwith a second matched cohort.The number of feeding arteries and number of draining veins were

analyzed both as ordinal variables, and as binarized categorical variableslooking at individual or multiple vessels. We quantified AVM angioarch-itectural complexity for inclusion in our vascular analysis. Angioarchitec-tural complexity was defined as the sum of the number of major drainingveins and major feeding arteries, under the assumption that higher flowmay be associated with a greater amount of feeding and draining vessels.The calculation of angioarchitectural complexity was based solely onangiography, which was assessed by the treating neurosurgeon anda neuroradiologist at the time of the Gamma Knife procedure as well asby one of the coauthors, who is also a neurosurgeon, at the time of datacollection. No formal vessel caliber was used to qualify an artery or vein as

major.In general, each feeding artery proximal and each draining veindistal to the nidus which were readily discernible on angiography wereconsidered a major vessel, although the final decision to classify an arteryor vein asmajorwas left to a consensus of the evaluating physicians (ie,2 neurosurgeons and a neuroradiologist).

Between-group differences were assessed using the log-rank test orx2 testwithin each of the study cohorts for categorical data. Ordinal variables wereassessed by using gamma (a type of rank correlation). Time to events wasassessed by using the Wilcoxon signed rank test or Friedman test asappropriate. Cumulative event rates were calculated according to theproduct limit method of Kaplan and Meier with differences in survival

RADIOSURGERY OUTCOMES FOR EMBOLIZED AVMS

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curves assessed by using the log-rank method. Cox proportional hazardsregression analysis was performed on the overall study population toconstruct a multivariable model of obliteration rates by using variables foundto be significant (a= .05) on univariate analysis not including the matchingvariables, which were matched on embolization status. Angioarchitecturalcomplexity was analyzed as part of a separate set of multivariable models, notinclusive of the number of feeding arteries and number of draining veins,owing to their linear dependence. A computerized binning algorithm wasused to identify the cutoff for angioarchitectural complexity, below which

AVM obliteration was significantly more likely. To do so, we used theMinimum Description Length Principle Cut strategy, a supervised binningalgorithm that works by minimizing the interbin informational entropy.38

All reported ranges are interquartile ranges defined as the range between the25th percentile and the 75th percentile. All reportedPvalues are 2-sided,

with an a of .05. All data management and analyses were conducted usingSPSS 21.0 (IBM, Inc, Armonk, New York) as well as the open sourceSCikit-learn library in Python.39

RESULTS

Case and Control CohortsOf the 1010 AVM patients in the eligible data set, 242

underwent treatment with a combination of embolization andSRS (24.0%), whereas 768 underwent treatment with SRS alone(76.0%) and were eligible to serve as matched controls. Thematching process yielded 242 patients in each of the case andcontrol cohorts (Figure 1). Patients were predominately embol-ized with N-butyl cyanoacrylate (79%) and coils (13%). Othertechniques, including Onyx (ethylene vinyl alcohol copolymer,ev3 Endovascular, Irvine, California), constituted the remaining9% of the cases. The number of feeding arteries was discernible in226 nidi in the case cohort (93.4%) and in 110 nidi in the controlcohort (45.5%). The case and control cohorts were equivalent

across all matched variables (Table 1). However, there werestatistically significant differences between the 2 cohorts with

regard to unmatched AVM and SRS variables (Table 2). Nidi inthe case cohort were more frequently fed by multiple arteries(63% vs 39%, P = .001) and treated using more isocenters(median 3 vs 2, P= .008).

AVM Obliteration

Of the 484 patients included for analysis in both cohorts, AVMobliteration was determined by MRI alone in 71 patients (14.7%)and confirmed by angiography in 207 patients (42.8%), yieldinga cumulative obliteration rate of 57.4% (278/484 patients). Themedian time to obliteration for all patients was 94 months (7.8years). The actuarial obliteration rates for all AVM patients were22.8% at3 years, 39.8% at 5 years, and 56.4% at 10years. For theAVMs treated with embolization and SRS (case cohort), theactuarial obliteration rates were 19.4% at 3 years, 30.9% at 5 years,and 49.0% at 10 years. The cumulativeobliteration rate of the case

TABLE 1.Comparison of Baseline Patient Characteristics, AVM

Features, and Radiosurgery Parameters Between the Case and

Control Cohortsa

Patient Characteristic

SRS1 Embo

(n = 242)

SRS Only

(n = 242)

P

Value

Sex, n (%) .856Male 122 (50) 125 (52)Female 120 (50) 117 (48)

Age, y (IQR) 32 (23-42) 30 (21-42) .418Radiologic follow-up time,

mo (IQR)56 (36-106) 53 (31-98) .142

RBAS, median score (IQR) 1.19 (0.97-1.45) 1.17 (0.88-1.52) .485VRAS, n (%) .850

0 8 (3) 6 (2)1 32 (13) 32 (13)2 79 (33) 87 (36)3 84 (35) 85 (35)4 39 (16) 32 (13)

Location, n (%) .213

Noneloquent 90 (37) 76 (31)Eloquent 152 (63) 166 (69)

Associated aneurysms 29 (12) 25 (10) .224Margin dose, Gy (IQR) 20 (18-22) 20 (18-23) .671Prior hemorrhage, n (%) 121 (50) 123 (51) .928Maximum diameter, cm

(IQR)2.7 (2.0-3.4) 2.5 (2.0-3.0) .095

Volume, cm3 (IQR) 4.6 (2.5-6) 4 (2.3-5.5) .091Spetzler-Martin

classification, n (%).179

I 34 (14) 31 (13)II 67 (28) 81 (33)III 109 (45) 87 (36)IV 32 (13) 42 (17)V 0 (0) 1 (,1)

aAVM, arteriovenous malformation; Embo, embolization; IQR, interquartile range;

SRS, stereotactic radiosurgery; RBAS, radiosurgery-based AVM score; VRAS, Virginia

Radiosurgery AVM Scale.

FIGURE 1. Flow chart of patient selection process for the case and control

cohorts. AVM, arteriovenous malformation; RBAS, radiosurgery-based AVM

score; SRS, stereotactic radiosurgery.

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cohort was 47.5%, with a median time to obliteration of 122months (10.2 years). For the AVMs treated with SRS alone(control cohort), the actuarial obliteration rates were 25.4% at 3years, 48.2% at 5 years, and 62.8% at 10 years. The cumulativeobliteration rate of the control cohort was 67.4%, with a mediantime to obliteration of 63 months (5.3 years). Embolization and

SRS resulted in decreased rate of AVM obliteration over time(P= .003; Figure 2).

Univariate Cox proportional hazards regression analysis of theoverall study population for the matched variables found prior AVMhemorrhage (P = .007), lower nidus maximum diameter(P , .001), lower nidus volume (P , .001), higher margindose (P, .001), shorter follow-up duration (P, .001), lowerRBAS (P,.001), lower VRAS (P,.001), and lower Spetzler-

Martin grade (P ,

.001) to be significantly associated withobliteration (Table 3). Univariate Cox regression analysis of theoverall study population for the unmatched variables found the lackof prior embolization (P, .001), fewer isocenters (P, .001),fewer feeding arteries (P, .001), fewer draining veins (P, .001),and radiologic evidence of radiation-induced changes (P, .001) tobe significantly associated with obliteration (Table 4).

In the multivariate Cox proportional hazards regression analysisof the overall study population, which included only unmatchedvariables found to be statistically significant in the univariateanalysis, fewer feeding arteries (P = .006), fewer draining veins(P, .001), lower angioarchitectural complexity (P, .001), andradiologic evidence of radiation-induced changes (P= .016) were

identified as independent predictors of obliteration (Table 4).Notably, prior embolization was not predictive of obliteration inthe multivariate model (P= .744). The actuarial obliteration rateswere significantly higher for nidi with a single feeding artery (P=.006; Figure 3A) and those with a single draining vein ( P, .001;Figure 3B). The actuarial obliteration rates for AVMs with anangioarchitectural complexity less than 3 were 36.4% at 3 years,52.3% at 5 years, and 68.0% at 10 years, and for AVMs with anangioarchitectural complexity of 3 or higher were 13.8% at 3years, 24.1% at 5 years, and 39.5% at 10 years. Nidi with an

TABLE 2.Angiographic Differences Between Groupsa

Characteristic

SRS1 Embo

(n = 242)

SRS Only

(n = 242)

P

Value

Number of major feedingarteries, n (%)b

,.001

1 84 (37) 67 (61)2 108 (48) 35 (32)3 34 (15) 8 (7)

Number of draining veins, n (%) .6561 117 (48) 126 (52)2 68 (28) 72 (30)31 57 (24) 44 (18)

% .1 major feeding arteries, % 63 39 .001

% .1 draining veins, % 52 48 .467Median number of isocenters,

n (IQR)3 (2-3) 2 (2-3) .008

aEmbo, embolization; IQR, interquartile range; SRS, stereotactic radiosurgery.bFor arterial analysis, n = 110 for the SRS only patients and n = 226 for SRS 1 Embo

patients. Statistically significant Pvalues (,.05) are in bold.

FIGURE 2. Kaplan-Meier plots of obliteration rate over time for AVM patients

who underwent treatment with embolization and SRS vs SRS alone. For patients

who underwent treatment with embolization and SRS, the 3-, 5-, and 10-year

obliteration rates were 19.4%, 30.9%, and 49.0%, respectively. For patients

who underwent treatment with SRS alone, the 3-, 5-, and 10-year obliterationrates were 26.1%, 48.4%, and 63.5%, respectively. AVMs treated with

embolization and SRS had significantly lower obliteration rates (P= .003, log-

rank test). AVM, arteriovenous malformation; SRS, stereotactic radiosurgery.

TABLE 3.Analysis of Matched Factors Influencing Obliteration for

All Patientsa,b

Patient

Characteristic

UnivariateP

Value

Univariate Hazard Ratio

(95% CI)

Age .626 1.00 (0.99-1.02)Sex .559 0.90 (0.63-1.29)Prior AVM

hemorrhage

.007 1.65 (1.15-2.37)

Maximum diameter ,.001 0.93 (0.91-0.95)Volume ,.001 0.87 (0.83-0.91)Marginal dose ,.001 1.24 (1.16-1.32)Follow-up duration ,.001 0.99 (0.98-0.99)RBAS ,.001 0.51 (0.34-0.74)VRAS ,.001 0.69 (0.57-0.83)Spetzler-Martin

Grade,.001 0.66 (0.54-0.81)

aAVM, arteriovenous malformation; CI, confidence interval; RBAS, radiosurgery-

based AVM score; VRAS, Virginia Radiosurgery AVM scale.bStatistically significant Pvalues (,.05) are in bold.





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angioarchitectural complexity less than 3 had significantly higherobliteration rates (P,.001; Figure 3C).

Radiosurgery-Induced Complications and Latency

Period Hemorrhage

In the AVM patients treated with embolization and SRS,cumulative (transient and permanent) radiation-induced changeswere radiologically evident in 88 patients (36.4%), symptomaticin 15 patients (6.2%), and permanent in 6 patients (2.5%;Table 5). In the AVM patients treated with SRS alone,cumulative radiation-induced changes were radiologically evidentin 109 patients (45.0%), symptomatic in 35 patients (14.5%),and permanent in 6 patients (2.5%). There was a trend towarda lower incidence of radiologically evident radiation-induced

changes in the case cohort (P= .052). Patients in the case cohortwere significantly less likely to develop symptomatic radiation-induced changes (P= .003), although the incidence of permanent(P = 1.000) radiation-induced changes was the same in bothcohorts. In the case cohort, the actuarial rates of cumulativeradiologically evident radiation-induced changes were 20% at 1year, 35% at 2 years, and 42% at 5 years. In the control cohort,the actuarial rates of cumulative radiologically evident radiation-induced changes were 36% at 1 year, 47% at 2 years, and 52% at5 years. The development of radiologic radiation-inducedchanges over time was significantly lower in the case cohort(P= .003; Figure 4A).

Univariate Cox proportional hazards regression analysis of the

overall study population for the matched variables found the lackof prior AVM hemorrhage (P= .001) and larger maximum nidusdiameter (P= .021) to be significantly associated with radiologi-cally evident radiation-induced changes (Table 6). UnivariateCox regression analysis of the overall study population for theunmatched variables found the lack of prior embolization (P=.013) and fewer draining veins (P = .011) to be significantlyassociated with radiologic radiation-induced changes (Table 7).In the multivariate Cox regression analysis of the overall studypopulation, which included only unmatched variables found to

be statistically significant in the univariate analysis, the lack ofprior embolization (P= .009) and fewer draining veins (P= .011)were identified as independent predictors of radiologic radiation-induced changes (Table 7). Notably, the number of majorfeeding arteries (P= .380) and angioarchitectural complexity (P=.118) were not significantly associated with radiologic radiation-induced changes. The actuarial rates of cumulative radiologicallyevident radiation-induced changes for AVMs with an angioarch-itectural complexity less than 3 were 45% at 1 year, 47% at 2years, and 47% at 5 years, and for AVMs with an angioarchitec-tural complexity of 3 or higher were 39% at 1 year, 42% at 2years, and 42% at 5 years (P= .363; Figure 4B).

In the embolized cohort, a total of 30 hemorrhages occurred in27 patients over a combined latency period of 1498 risk-years,

yielding an annual post-SRS hemorrhage risk of 2.0%. In thecontrol cohort, a total of 29 hemorrhages occurred in 25 patientsover a combined latency period of 1459 risk-years, yielding anannual post-SRS hemorrhage risk of 2.0%. Post-SRS cystformation occurred in 5 patients in the case cohort (2.1%) andin 6 patients in the control cohort (2.5%). The incidences of bothpost-SRS hemorrhage (P = .769) and post-SRS cyst formation(P= .760) were similar between the 2 cohorts (Table 5).

DISCUSSION

AVMs continue to pose as one of the most significant challengesa cerebrovascular surgeon must face because of their complex

physiology, variable angioarchitecture across patients, and pro-pensity to cause neurological injury over the course of their naturalhistory. Combined therapy with embolization and SRS isa minimally invasive approach for large or morphologicallycomplex AVMs that are associated with high surgical risk andare not amenable to successful treatment with either embolizationor SRS alone. However, the unfavorable effect of embolization onobliteration rates following SRS reported in prior studies,including those from the treating institution, has dampened theenthusiasm forcombiningthe 2 modalities.26-28,30 By quantifying

TABLE 4. Analysis of Nonmatched Factors Influencing Obliteration for All Patientsa,b

Patient Characteristic UnivariatePValue

Univariate Hazard

Ratio (95% CI) Multivariate PValue

Multivariate Hazard

Ratio (95% CI)

Prior embolization ,.001 0.44 (0.30-0.63) .744 1.06 (0.75-1.5)Isodose .057 1.02 (0.99-1.05) Number of isocenters ,.001 0.78 (0.69-0.87) .549 0.96 (0.85-1.09)Number of feeding arteries ,.001 0.55 (0.38-0.76) .006 0.70 (0.55-0.90)Number of draining veins ,.001 0.55 (0.45-0.68) ,.001 0.68 (0.55-0.84)Angioarchitectural complexityc ,.001 0.68 (0.58-0.79) ,.001 0.69 (0.59-0.80)Radiologically evident RIC ,.001 2.13 (1.45-3.14) .016 1.50 (1.08-2.09)

aCI, confidence interval; RIC, radiation-induced changes.bStatistically significantPvalues (,.05) are in bold. All hazard ratios are from a model not inclusive of angioarchitectural complexity, but inclusive of its constituent variables

(number of feeding arteries, number of draining veins).cIn a separate model without the number of feeding arteries and number of draining veins due to its colinearity dependency on those variables.

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the angioarchitectural complexity of an AVM nidus (ie, the sumof the number of major feeding arteries and draining veins), wepresent new evidence that supports the use of combinedembolization and SRS for appropriately selected AVMs.

Risks and Benefits of AVM Embolization

The role of AVM embolization varies widely across institutions.For compact nidi with favorable angioarchitecture, embolizationalone can be curative. Saatci et al40 reported a 51% completeocclusion rate in 350 AVMs embolized with the permanentembolic agent Onyx. The permanent morbidity and mortalityrates were 7.1% and 1.4%, respectively, and the recanalization rateof completely occluded nidi at a mean follow-up duration of 47months was 1.1%. However, typical curative embolization rates aresubstantially lower, at 10% to 20%.41-46 Given the relativelymodest complete obliteration rate with embolization comparedwith surgical resection or SRS, and that the combined morbidityand mortality rates for embolization have been reported in excess

of 10%, the AVM embolization is used as an adjunctive therapyat the majority of centers.46-48 As endovascular technology andliquid embolic agents continue to improve, the role ofembolization in the treatment of AVMs will require reevalua-tion in future studies.49 In the current series, we tended to usepre-SRS embolization as a means of reducing the nidus volumeto a more manageable level for single-session SRS (typicallya residual nidus volume of 12 cm3 or less) and to obliterate high-risk features (eg, perinidal aneurysms) before SRS.

Mechanisms of Radiosurgical Failure in

Embolized AVMs

A number of different causes for the detrimental effect ofembolization on AVM obliteration rates following treatment withSRS have been proposed, but no single theory has prevailed.32

Despite the capability to selectively catheterize individual AVMfeeding vessels, the ability of a neurointerventionalist to controlthe distribution of an embolic agent is limited. Additionally, theradiodensity of certain embolic agents, such as Onyx, may hinderangiographic definition of a nidus. Thus, AVM embolization canincrease the difficulty of SRS treatment planning by creating anirregular target with obscured angioarchitecture.50

Embolization has been shown to promote neoangiogenesis byincreasing the expression of hypoxia-inducible factor-1a andvascular endothelial growth factor, although whether this occurs

to an appreciable degree to achieve clinical relevance isunknown.51,52 The alteration of radiosurgical beams, eitherabsorption or scattering, by embolic agents has not beensubstantiated by in vitro studies, which have shown negligibledose reduction following beam penetration of embolic agents.53

It is likely that inherent distinctions between the vascular biologyof embolized vs nonembolized AVMs contribute to the differ-ences in SRS outcomes. However, in totality, the mechanismsunderlying the lower obliteration rates of embolized AVMsremain largely hypothetical.

FIGURE 3. Kaplan-Meier plots of obliteration rate over time,stratified by nidus angioarchitectural features. A, the actuarial

obliteration rates at 3, 5, and 10 years for AVMs with a single

feeding artery were 46.1%, 52.2%, and 60.8%, respectively, and

for AVMs with multiple feeding arteries were 33.8%, 38.1%,

and 51.5%, respectively. Nidi with a single feeding artery had

significantly higher obliteration rates (P= .006, log-rank test).B,

the actuarial obliteration rates at 3, 5, and 10 years for AVMs

with a single draining vein were 30.7%, 49.4%, and 67.1%,respectively, and for AVMs with multiple draining veins were

14.3%, 29.6%, and 44.5%, respectively. Nidi with a single

draining vein had significantly higher obliteration rates (P ,.001, log-rank test). C, theactuarial obliteration rates at 3, 5, and

10 years for AVMs withan angioarchitectural complexity less than

3 were 36.4%, 52.3%, and 68.0%, respectively, and for AVMs

with an angioarchitectural complexity of 3 or higher were 13.8%,

24.1%, and 39.5%, respectively. Nidi with an angioarchitectural

complexity less than 3 had significantly higher obliteration rates(P ,.001, log-rank test). AVM, arteriovenous malformation.





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Role of Combined Embolization and Radiosurgery in

the Management of AVMs

The present study confirms the previously described phenome-non that pre-SRS embolization decreases obliteration rates (P =.003).27,28 This study also highlights the difficulties in ascertainingthe impact of embolization upon AVMs treated with radiosurgerybecause of the significant differences in the angioarchitecture of theAVMs that undergo combined embolization and SRS vs SRS

alone. Nidi that underwent combined therapy were morecommonly fed by multiple arteries (P, .001) and were treatedwith more isocenters (P= .038), suggesting that AVMs in the casecohort had higher vascular and anatomic complexity than in thecontrol cohort. This is consistent with the primary goals ofembolization at the treating institution, which are to (1) reduce thevolume of large AVMs (.12 cm3), (2) occlude high-flow feedingarteries harboring intranidal perinidal aneurysms, and (3) occludeintranidal arteriovenous shunts, which may be relatively resistant toradiosurgically induced obliteration. However, it appears that thepostembolization nidi retain a high degree of angioarchitecturalcomplexity relative to nonembolized nidi.

Similar prior studies that analyzed the effect of AVM emboli-

zation on obliteration following SRS did not account for the nidusangioarchitecture.26-28 We show, for the first time, that theinclusion of nidus angioarchitecture (ie, angioarchitecturalcomplexity) in a multivariate model results in a nonsignificantinteraction between embolization and AVM obliteration (P =.744). Instead, fewer feeding (P= .006) and draining (P, .001)vessels, lower angioarchitectural complexity (P , .001), andradiologic radiation-induced changes (P= .016) were indepen-dent predictors of obliteration. Although further studiesare necessary to determine the extent to which nidus

angioarchitecture affects obliteration, our study at least suggeststhat nidus angioarchitecture may significantly confound theeffect of embolization on SRS-induced AVM obliteration.

In addition to challenging prior associations between emboli-zation and decreased radiosurgical obliteration, our findingsindicate that embolization may abrogate the risk of radiation-

induced changes. The development of radiologically evidentradiation-induced changes over time was significantly lower inthe case cohort (P= .003), and there was a trend toward a lowercumulative incidence of radiologic radiation-induced changes(P= .052). Furthermore, symptomatic radiation-induced changeswere also significantly less common in patients with embolizedAVMs (P = .003). In the multivariate model, lack of priorembolization (P= .009) and fewer draining veins (P= .011) wereindependent predictors of radiation-induced changes. Yen et al54

previously found that large, unruptured AVMs with a singledraining vein are particularly prone to the development ofradiation-induced changes. It is possible that the presence of anembolic cast provides a physical separation between normalcortex and the radiosurgical dose, thus acting as a shield fromradiation-induced changes. Embolization also decreases arterialflow into the nidus, thereby relieving venous congestion, whichhas also been suggested as an etiology of radiation-inducedchanges.

Although the radiobiology of radiation-induced changes isincompletely understood, they are believed to result from gliosis,arteriosclerosis, and other reactive vascular and parenchymalchanges in response to radiation.55-57 This is a radiobiologicalmodel similar to that of AVM obliteration, wherein endothelialdisruption and radiation-induced arteriopathy is thought to be theprimary mechanism of SRS-induced obliteration.56-60 Clinical

evidence of this potentially shared radiobiology can be found in thepresent results, which show that radiation-induced changes arepredictive of AVM obliteration. However, this appears to be anembolization-dependent effect. Given that embolization resultedin both a decrease in the overall incidence of radiation-inducedchanges and the symptomatic severity of radiation-inducedchanges and the correlation between radiation-induced changesand obliteration, a common mechanism may underlie the 2 SRS-induced phenomena.

Although the precise mechanisms underlying radiation-inducedchanges after AVM SRS are unknown, venous congestion has beenproposed as a potential etiology, secondary to SRS-inducedendothelial damage and resultant occlusion of an AVMs draining

veins.61

A similar mechanism, specifically intimal proliferationafter SRS-induced endothelial injury, results in progressiveocclusion of an AVMs feeding arteries and eventual obliterationof the nidus.57,62 Thus, embolization-mediated devascularizationof an AVM may abrogate the effect of SRS on the venouscomponent of the nidus to a greater extent than the arterialcomponent, hence resulting in a significant reduction of radiation-induced changes but similar rates of obliteration, after adjusting forconfounding factors, such as angioarchitectural complexity. Oneshould also consider the temporal differences in the development

TABLE 5.Summary of Postprocedural Complicationsa,b

Patient Characteristic

SRS1 Embo

(n = 242)

SRS Only

(n = 242)

P

Value

Post-SRS hemorrhages, n (%) .769Total 30 (12) 29 (12)

1 Hemorrhage 24 (10) 21 (9)2 Hemorrhages 3 (1) 4 (2)

Radiologically evident RIC 88 (36) 109 (45) .052Symptomatic RIC .003

Total 15 (6) 35 (14)Headaches 3 (1) 8 (3)Neurological deficit 10 (4) 23 (10)Seizures 2 (1) 4 (2)

Permanent RIC, n (%) 6 (2) 6 (2) 1.000Postradiosurgery cyst

formation, n (%)5 (2) 6 (2) .760

aEmbo, embolization; SRS, stereotactic radiosurgery; RIC, radiation-induced

changes.

bStatistically significant Pvalues (,.05) are in bold.

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of radiation-induced changes (typical interval, 6-18 months afterSRS) compared with the attainment of nidal obliteration (typicalinterval, 2-3 years after SRS). It is conceivable that embolizationpreferentially attenuates SRS-induced effects that occur earlier inthe postradiosurgery interval (ie, radiation-induced changes), thus

supporting the findings of our statistical analyses.Despite the goal of targeting rupture-prone components of thenidus with embolization, there has yet to be any evidence tosupport a reduction in the natural history hemorrhage riskfollowing embolization. In fact, data extrapolated from 2 recentprospective, multicenter studies suggests that partial embolizationmay, in fact, increase the hemorrhage risk of AVMs.63,64 In ourseries, the incidence of post-SRS hemorrhage was similar betweenembolized and nonembolized nidi (P= .769). Additionally, theannual post-SRS hemorrhage risk was the same in both cohorts(2.0%) and not appreciably different from the natural history ofuntreated AVMs.65-68

Based on the present study, it may be time to revisit the issue of

preradiosurgery embolization of AVMs. Multimodal therapy withembolization and SRS subjects the patient to the cumulative risks

of both procedures, which can grow significantly over time ifmultiple embolization sessions are required. However, emboliza-tion also appears to confer protection against radiation-inducedchanges, which may offset some of the additional risk associatedwith embolization. It also remains an open question as to what

extent the difference in outcomes is due to the effects ofembolization vs pretreatment differences in AVM vasculature,flow rate, and volume. A detailed study including preembolizationAVM volume and angioarchitecture will be better able to isolatethe effect of embolization on radiosurgical obliteration. Ulti-mately, a multimodality cerebrovascular approach must balancethe added risk of one or more embolization procedures with itspotential effects on SRS outcomes. However, the judicious use ofembolization remains a crucial component in the therapeuticarmamentarium for the management of AVMs.

Limitations

This study has a number of limitations. The single-center,retrospective design of this study subjects it to the selection andmanagement biases of the institution and its physicians. Thenature of beinga tertiary referral center for SRS resulted in a lack ofdetailed clinical outcomes, including limited documentation ofthe complications related to the embolization procedures. Fur-thermore, we were unable to account for changes in endovasculardevices and embolic agents throughout the study period. Giventhe rapid evolution of these embolization technologies in recentyears, this may restrict the generalizability of our findings. Thus,our ability to extrapolate the results of this study to the overallmanagement of AVM patients is incomplete.

Perhaps the most significant limitation of our study, which has

also plagued prior analyses of the same topic, is the inherent biastoward poorer SRS outcomes for embolized AVMs, owing to theirlarger original size, and, in most instances, higher Spetzler-Martingrade, RBAS, and VRAS. Because the longitudinal nature of thisstudy and the nature of being a tertiary SRS referral center, we wereunable to determine the angioarchitectural characteristics of theinitial AVMs in the case cohort before embolization. Additionally,a proportion of the embolizations were performed at otherinstitutions, which further complicates our ability to determinethe original AVM characteristics.

FIGURE 4. Kaplan-Meier plots of cumulative radiologically evident radiation-induced changes (RIC) rate over

time.A, AVM patients who underwent treatment with combined embolization and SRS had significantly lowerincidences of radiologic radiation-induced changes (P= .003, log-rank test). For patients who underwent treatment

with embolization and SRS, the actuarial rates of radiologic radiation-induced changes at 1, 2, and 5 years were

20%, 35%, and 42%, respectively. For patients who underwent treatment with SRS alone, the actuarial rates of

radiologic radiation-induced changes at 1, 2, and 5 years were 36%, 47%, and 52%, respectively. B , AVMpatients with a nidus angioarchitectural complexity less than 3 had similar incidences of radiologic radiation-

induced changes to those with a nidus angioarchitectural complexity of 3 or higher (P= .363, log-rank test). ForAVMs with an angioarchitectural complexity less than 3, the actuarial rates of radiologic radiation-induced changes

at 1, 2, and 5 years were 45%, 47%, and 47%, respectively. For AVMs with an angioarchitectural complexity of 3

or higher, the actuarial rates of radiologic radiation-induced changes at 1, 2, and 5 years were 39%, 42%, and

42%, respectively. AVM, arteriovenous malformation; SRS, stereotactic radiosurgery.

TABLE 6.Analysis of Matched Factors Influencing Radiologic RIC

for All Patientsa,b

Patient Characteristic UnivariatePValue

Univariate Hazard

Ratio (95% CI)

Age .207 1.01 (0.99-1.02)Sex .704 0.92 (0.63-1.34)Prior AVM hemorrhage .001 0.53 (0.36-0.77)Maximum diameter .021 1.03 (1.00-1.05)Volume .139 0.99 (0.94-1.04)Margin dose .253 0.98 (0.92-1.03)Follow-up duration .218 0.99 (0.99-1.00)RBAS .703 0.93 (0.63-1.36)VRAS .609 0.96 (0.83-1.11)Spetzler-Martin grade .531 0.94 (0.76-1.15)

aAVM, arteriovenous malformation; CI, confidence interval; RIC, radiation-induced

changes; RBAS, radiosurgery-based AVM score; VRAS, Virginia Radiosurgery AVM

Scale.bStatistically significant Pvalues (,.05) are in bold.

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Acknowledgments

The authors would like to acknowledge the late Professor Steiner and Pro-

fessors Kassell, Jensen, and Evans for their roles in the care and treatment of some

of the patients in this study.

COMMENTS

The authors report the results of a matched case control study examiningoutcomes (obliteration rate and radiation-induced complications) for

AVMstreatedwithSRS withand without prior embolization.The perennialdifficulty in performing this comparison is the fundamentally differentnature of AVMs that are selected for prior embolization as opposed to thosetreated with SRS alone. The authors make an elegant effort to overcome, orat least mitigate, this issue by matching cases based on propensity scoringincorporating a number of key differentiatingfeatures includingdose, nidusvolume, RBAS, etc. Based on the direct comparison of cases and controls,prior embolization was found to be associated with both lower obliteration

rates and lower incidence of radiation-induced complications. Howeversubsequent multivariate analysis introducing a surrogate marker of an-gioarchitecture, a variablethe authors termangioarchitectural complexity,appears to negate the importance of prior embolization, emerging, insteadas a key predictor of obliteration itself.

This series brings to light the complexity of assessing the outcomes ofSRS, and the authors should be congratulated for their in depth anddetailed approach. However, the limitations of the analysis must not beforgotten. The surrogate marker for AVM complexity is not validated.The retrospective nature of the data and the differential ascertainment offeatures such as angioarchitecural complexity are also major drawbacks.Thus, conclusions as to theimpact of priorembolizationon SRSoutcomeneed to remain circumspect. Prospective data collection, as may becomemore widely feasible with adjudicated multicenter registries in the future,

will undoubtedlybe importantin helping to settle the debate regardingtheeffects of prior embolization on SRS efficacy.

Sepideh Amin-HanjaniChicago, Illinois

With this publication, the authors make important contributionstoward our comprehension of the effect of prior embolization on

obliteration rates after stereotactic radiosurgery. Using a newly proposedmeasure of angioarchitectural complexity, defined as the sumof thenumberof major draining veins and major feeding arteries, the authors demonstratethat the effect of prior embolization on obliteration after radiosurgery maybe significantly confounded by nidus angioarchitectural complexity.

Relative to prior publications on this subject, the advantages of thisarticle are:1. a sound statistical method of case-control design with propensity

score matching2. a robust volume of more than 200 patients in each cohort3. multivariate analysis of numerous factors that could confound the

association between prior embolization and radiosurgery outcomes

However, in addition to the limitations offered by the authors, theiranalysis suffers from a few pitfalls:1. Some of their assumptions have not been validated. As defined, the

measurement of angioarchitectural complexity might be too simplistic,or it might have paradoxical implications. For instance, smaller nidihave been reportedto have higherruptureratesdue to higherintranidalpressures, yet they would likely have fewer feeding arteries and drainingveins.

2. Studies like this inherently lack enough granularity to look at specifictreatment parameters.For instance, it is not certain how the AVM volume and maximal

dimensionwere calculated in each case relative to the prior embolizedportion. If the embolization resulted in reduced total volume and onlythe filling portion of the nidus were targeted, outcomes would be dif-

ferent than if the embolic material simply occupied portions of thecentral volume within the target.3. The approach leads to some paradoxical results. Prior embolization is

associated with both decreased radiation-induced complications (RIC)and decreased obliteration rates, yet RIC is an independent predictor ofobliteration success (presumably this effect is not confounded by dose).Despite these limitations, the article is well written and offers additional

insight to a subject of great importance and uncertainty.

Arun Paul AmarLos Angeles, California



effect of prior embolization on cerebral.14

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