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accompaNyiNg article See pp 938–944. DOI: 10.3171/2014.10.JNS14499.iNclude wheN citiNg Published online June 19, 2015; DOI: 10.3171/2014.10.JNS142305.disclosure The authors report no conflict of interest.

editorialRadiosurgery and cavernous malformations Jason sheehan, md, phd,1,2 dale ding, md,1 and robert m. starke, md1

Departments of 1Neurological Surgery and 2Radiation Oncology, University of Virginia, Charlottesville, Virginia

The successful obliteration of selected cerebral ar-teriovenous malformations (AVMs) using the Gamma Knife prompted the treatment of cavern-

ous malformations (CMs) and aneurysms. For CMs, their small volume, lack of intervening normal brain tissue, and relatively low rate of clinically significant hemorrhage made them an appealing target for stereotactic radiosur-gery (SRS). Radiosurgery for aneurysms was quickly abandoned as a failure, but radiosurgery for CMs persists despite controversy regarding its therapeutic value.13

Unlike for AVMs, radiosurgery for CMs often appears to have little to no effect evident on follow-up neuroimag-ing studies. In a previous report, a CM treated with Gam-ma Knife radiosurgery appeared unchanged on follow-up MRI 5 years afterwards.13 Extirpation of the lesion was undertaken, and histological examination revealed the le-sion was partially obliterated with patency to a single per-sistent capillary channel (Fig. 1). Therefore, the correla-tion between radiographic and pathological changes may be unreliable following CM radiosurgery.

From a series of more than 100 CMs treated at the Uni-versity of Pittsburgh, Shin and colleagues report on the histopathological responses of 4 patients with CM who underwent resection 4 months to 7 years following radio-surgery.10 The CMs were treated with prescription doses of 14–15 Gy of radiation. In all 4 cases, radiosurgery failed and the patients suffered recurrent hemorrhages. Histo-pathological analysis revealed partially obliterated vessels and incomplete sclerosis as early as 4 months following radiosurgery. Partial obliteration could be a response to repeated microbleeds, recent hemorrhage, or past radio-surgery. Foci of neovascularization were also observed, as evidenced by staining for vascular endothelial growth factor (VEGF).

In the case from our institution as well as the 4 from the University of Pittsburgh, we run the risk of drawing too much significance from a small and undoubtedly biased

cohort. Nevertheless, the findings from Shin et al.’s study are some of the best available for elucidating the under-lying radiobiological changes from radiosurgery on CMs. Coupling these histopathological findings with the neuro-imaging and clinical outcomes published in the literature, it would seem safe to conclude that radiosurgery induces some of the same vessel sclerosis in CMs as it does in AVMs. However, the changes in AVM compared to CM vasculature following radiosurgery are substantially more robust and complete in the majority of patients.1,9,12 The incomplete response seen in CMs after radiosurgery may explain the potentially lower but still tangible risk of re-current hemorrhage (8.8% annual risk for the first 2 years, then 1.1% annual risk after 2 years based on the group’s prior publication) in patients even years after radiosur-gery.6 In contrast, in more than 1400 AVM patients treated using SRS, we have not observed a single hemorrhage in an AVM confirmed to be obliterated on angiography.11 The incomplete histopathological changes in CMs are consistent with the reduced but persistent risk of hemor-rhage following radiosurgery.

These findings raise 2 potential options for improving CM radiosurgery outcomes. First, the 4 patients in the current series were treated with a radiosurgical dose of 14–15 Gy to the margin of the CM. Prior preclinical and clinical studies have demonstrated more beneficial vascu-lar changes with higher doses.1,5,7 However, such higher doses in patients with CM have also been associated with more complications. For example, in an early cohort of 22 CM patients treated with a mean margin dose of 18 Gy, 6 patients suffered neurological decline due to radiation-induced changes, and 5 (22.7%) had permanent deficits.4 Radiation-induced complications were defined as radio-necrosis or transient radiation-induced changes demon-strated on CT or MRI and associated with a neurological decline. The radiation-induced complication rate in CMs was more than 2 times higher than expected for a simi-

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larly treated group of patients with AVM. An increased incidence of radiation-induced changes following CM ra-diosurgery has been described by others, and the risk ap-pears related at least in part to the margin dose.3,8 Thus, a higher dose alone for CMs may provide improved vascular occlusion, but conveys a greater risk of adverse radiation effects. Given the VEGF expression seen in these CMs, a second potential approach for enhancing CM radiosurgery outcomes is targeted VEGF inhibition (for example, be-vacizumab). Vascular endothelial growth factor inhibition may serve to potentiate the effects of radiosurgery and lower the risks of radiation injury to adjacent brain tissues, thereby allowing a higher margin dose to be delivered to CMs.2,14 It may also downregulate neovascularization in the CM following irradiation.

In conclusion, the authors have shed substantial light on the histopathological changes that follow radiosurgery for CMs. These findings point toward areas for refinement of the radiosurgical approach. Until then, we recommend reserving radiosurgery for carefully selected CM patients suffering from repeated seizures, hemorrhages, or pro-gressive neurological deficits and for whom the risks of resection are deemed unacceptably high.http://thejns.org/doi/abs/10.3171/2014.10.JNS142305

references 1. Chang SD, Shuster DL, Steinberg GK, Levy RP, Frankel K:

Stereotactic radiosurgery of arteriovenous malformations: pathologic changes in resected tissue. Clin Neuropathol 16:111–116, 1997

2. Deibert CP, Ahluwalia MS, Sheehan JP, Link MJ, Hasegawa T, Yomo S, et al: Bevacizumab for refractory adverse radia-tion effects after stereotactic radiosurgery. J Neurooncol 115:217–223, 2013

3. Hasegawa T, McInerney J, Kondziolka D, Lee JY, Flickinger JC, Lunsford LD: Long-term results after stereotactic radio-surgery for patients with cavernous malformations. Neuro-surgery 50:1190–1198, 2002

4. Karlsson B, Kihlström L, Lindquist C, Ericson K, Steiner L: Radiosurgery for cavernous malformations. J Neurosurg 88:293–297, 1998

5. Kiliç K, Konya D, Kurtkaya O, Sav A, Pamir MN, Kiliç T: Inhibition of angiogenesis induced by cerebral arteriovenous malformations using gamma knife irradiation. J Neurosurg 106:463–469, 2007

6. Kondziolka D, Lunsford LD, Flickinger JC, Kestle JR: Re-duction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg 83:825–831, 1995

7. Major O, Szeifert GT, Kemeny AA: Physiological and patho-logical observations on rat middle cerebral arteries and hu-man AVM tissue cultures following single high-dose gamma irradiation. Prog Neurol Surg 20:375–387, 2007

8. Pollock BE, Garces YI, Stafford SL, Foote RL, Schomberg PJ, Link MJ: Stereotactic radiosurgery for cavernous malfor-mations. J Neurosurg 93:987–991, 2000

9. Schneider BF, Eberhard DA, Steiner LE: Histopathology of arteriovenous malformations after gamma knife radiosur-gery. J Neurosurg 87:352–357, 1997

10. Shin SS, Murdoch G, Hamilton RL, Faraji AH, Kano H, Zwagerman NT, et al: Pathological response of cavern-ous malformations following radiosurgery. J Neurosurg [epub ahead of print June 19, 2015. DOI: 10.3171/2014.10.JNS14499]

11. Starke RM, Yen CP, Ding D, Sheehan JP: A practical grad-ing scale for predicting outcome after radiosurgery for arte-riovenous malformations: analysis of 1012 treated patients. J Neurosurg 119:981–987, 2013

12. Steinberg GK, Chang SD, Levy RP, Marks MP, Frankel K, Marcellus M: Surgical resection of large incompletely treated intracranial arteriovenous malformations following stereotactic radiosurgery. J Neurosurg 84:920–928, 1996

13. Steiner L, Sheehan J, Lindquist C, Stroila M, Steiner M: Gamma surgery in cerebral vascular lesions, malformations, tumors, and functional disorders, in Schmidek HH, Roberts DW (eds): Operative Neurosurgical Techniques: Indica-tions, Methods, and Results, ed 5. Philadelphia: Saunders, 2006, Vol 1, pp 530–576

14. Tozer GM, Bicknell R: Therapeutic targeting of the tumor vasculature. Semin Radiat Oncol 14:222–232, 2004

responsesamuel s. shin, md, phd, l. dade lunsford, md, and robert m. Friedlander, mdDepartment of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 

As we have reported in a prior publication, our experi-ence indicates that SRS for CMs in patients with repeated bleeding reduces subsequent bleed rates, a finding that becomes quite clear after the initial 2 years. However, there is still room for improvement in further reducing re-hemorrhage rates. The pathological response of CMs to SRS is similar to what is seen in AVMs but perhaps not as robust as described in the current histological analysis as well as several prior studies.1,9,10 This result may be re-lated to the dose reduction to improve the safety profile. In patients with CM, perilesional iron deposition associ-ated with prior bleeding events acts as a relatively potent radiation sensitizer. The radiosurgical target must be con-fined by highly selective delivery of the focused radiation within the hemosiderin ring defined on T2-weighted MRI. To provide more complete obliteration of CM, a strategy

Fig. 1. An immunohistochemical section depicting a CM, which was treated with radiosurgery. The lesion was excised 5 years after stereo-tactic radiosurgery. With the exception of a single persistent capillary channel (arrow), the CM appears obliterated. This image was published in Operative Neurosurgical Techniques: Indications, Methods, and Results, fifth ed., Steiner L, Sheehan J, Lindquist C, Stroila M, Steiner M, Gamma surgery in cerebral vascular lesions, malformations, tumors, and functional disorders, pp 530–576, Copyright Elsevier, 2006.

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of sensitizing CM to radiation or increasing the radiation dose without adversely affecting adjacent critical brain structures would be useful.

Sheehan et al. emphasize an excellent point regard-ing the potential development of agents that can enhance CM radiosurgery outcomes. The current study shows that VEGF and angiogenesis may have a major role in the continued pathogenic vasoproliferation of CM even years following SRS. We have previously described the use of bevacizumab (VEGF inhibitor) in the setting of radiosur-gery.3 This drug has also been shown to be effective in reducing adverse radiation effects in tumors5,11 as well as vascular malformations.3,12 These prior studies focused on the use of bevacizumab to reduce the role of VEGF as a cytokine mediator of radiation injury. Vascular endotheli-al growth factor is probably one of the primary mediators of peritumoral edema and is found in high concentrations in reactive astrocytes in necrotic tissues.8 However, its use in reducing delayed angiogenesis of CM treated with SRS has not been explored. The use of bevacizumab for CMs can serve 2 functions: 1) reducing adverse radiation ef-fects by allowing higher radiation doses, and 2) preventing additional angiogenesis of CMs.

The strategy of combining radiation techniques with antiangiogenic agents has been applied to a variety of pa-thologies. This strategy has shown promising results in animal models as well as clinical trials of head and neck cancers,6 lung cancer,7 and hereditary hemorrhagic telan-giectasia.4 Similarly, clinical and preclinical trials using radiation therapy combined with various vascular disrupt-ing agents have been reviewed.2 These agents combined with radiosurgery may provide significant improvement in outcomes for CMs treated with SRS.

Currently, SRS is used for patients with multiple bleeds (high rebleeding rates) and whose CMs are located in brain regions where the access route may pose an exces-sive risk of new permanent neurological injury. Further developments of pharmacological agents that improve the effectiveness of SRS may facilitate a reduction in compli-cations and increase success rates.

references 1. Chang SD, Shuster DL, Steinberg GK, Levy RP, Frankel K:

Stereotactic radiosurgery of arteriovenous malformations: pathologic changes in resected tissue. Clin Neuropathol 16:111–116, 1997

2. Clemenson C, Chargari C, Deutsch E: Combination of vascu-lar disrupting agents and ionizing radiation. Crit Rev Oncol Hematol 86:143–160, 2013

3. Deibert CP, Ahluwalia MS, Sheehan JP, Link MJ, Hasegawa T, Yomo S, et al: Bevacizumab for refractory adverse radia-tion effects after stereotactic radiosurgery. J Neurooncol 115:217–223, 2013

4. Epperla N, Hocking W: Blessing for the bleeder: bevacizu-mab in hereditary hemorrhagic telangiectasia. Clin Med Res [epub ahead of print], 2014

5. Gonzalez J, Kumar AJ, Conrad CA, Levin VA: Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys 67:323–326, 2007

6. Hsu HW, Wall NR, Hsueh CT, Kim S, Ferris RL, Chen CS, et al: Combination antiangiogenic therapy and radiation in head and neck cancers. Oral Oncol 50:19–26, 2014

7. Li XP, Zhang HL, Wang HJ, Li YX, Li M, Lu L, et al: Ad-endostatin treatment combined with low-dose irradiation in a murine lung cancer model. Oncol Rep 32:650–658, 2014

8. Nonoguchi N, Miyatake S, Fukumoto M, Furuse M, Hi-ramatsu R, Kawabata S, et al: The distribution of vascular endothelial growth factor-producing cells in clinical radia-tion necrosis of the brain: pathological consideration of their potential roles. J Neurooncol 105:423–431, 2011

9. Schneider BF, Eberhard DA, Steiner LE: Histopathology of arteriovenous malformations after gamma knife radiosur-gery. J Neurosurg 87:352–357, 1997

10. Steinberg GK, Chang SD, Levy RP, Marks MP, Frankel K, Marcellus M: Surgical resection of large incompletely treated intracranial arteriovenous malformations following stereotactic radiosurgery. J Neurosurg 84:920–928, 1996

11. Torcuator R, Zuniga R, Mohan YS, Rock J, Doyle T, Ander-son J, et al: Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis. J Neuroon-col 94:63–68, 2009

12. Williams BJ, Park DM, Sheehan JP: Bevacizumab used for the treatment of severe, refractory perilesional edema due to an arteriovenous malformation treated with stereotactic radiosurgery. J Neurosurg 116:972–977, 2012

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