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NI FEATURE: THE EDITORIAL DEBATE I PROS AND CONS 



Year : 2017  Volume
: 65
 Issue : 4  Page : 697698 
Dose fractionated gamma knife radiosurgery for large arteriovenous malformations
Ajay Niranjan^{1}, John C Flickinger^{2}
^{1} Department of Neurological Surgery, Center of ImageGuided Neurosurgery, University of Pittsburgh, PA, USA ^{2} Department of Radiation Oncology, Center of ImageGuided Neurosurgery, University of Pittsburgh, PA, USA
Date of Web Publication  5Jul2017 
Correspondence Address: Ajay Niranjan Department of Neurological Surgery, Center of ImageGuided Neurosurgery, University of Pittsburgh, PA USA
Source of Support: None, Conflict of Interest: None  Check 
DOI: 10.4103/neuroindia.NI_518_17
How to cite this article: Niranjan A, Flickinger JC. Dose fractionated gamma knife radiosurgery for large arteriovenous malformations. Neurol India 2017;65:6978 
The optimal management of large (volume >10 cm ^{3}) brain arteriovenous malformations (AVMs) is controversial. As standalone treatment modality for large AVMs, microsurgery is associated with relatively high rates of morbidity and mortality, whereas embolization results in low rates of complete nidal obliteration. Stereotactic radiosurgery (SRS) is effective for many small tomediumsized AVMs but yields lower obliteration rates for large AVMs with increased rates of neurological morbidity. The volume of the surrounding normal brain covered in 12 Gy isodose is considered a significant predictor of adverse radiation effects following AVM radiosurgery.^{[1]} As the 12 Gy volume increases, so are the chances of adverse radiation effects. In the cases of large AVMs where a single session radiosurgery (10 cc or more) is administered, invariably lower margin doses were prescribed in order to keep the 12 Gy volume within acceptable limits. Lowering prescribed margin doses is associated with reduced obliteration rates. In order to avoid complications (related to dose falloff in the surrounding normal brain) and still maintain a reasonably high obliteration rate, the concepts of volumestaged stereotactic radiosurgery (VSSRS) and dosestaged (DS) SRS (fractionated SRS) using more than one session were introduced. The goal for these strategies is to improve the risktobenefit profile for the radiosurgical treatment of large AVMs. Volumestaged SRS divides large AVMs into distinct volumes, each of which is independently targeted by SRS, with 3 to 9month intervals between the sessions, until the entire AVM is treated. In contrast, DSSRS involves repeated delivery of radiation to the entire AVM until a cumulative total dose has been delivered over a period of a few days or weeks. Either technique can be used as a standalone approach to achieve obliteration.
The authors reported their experience with dose fractionated gamma knife radiosurgery (DFGKSRS) for large volume AVMs. The authors treated 14 patients with three (8.911.5Gy per fraction) or two (11.315Gy per fraction) fraction scheme. These doses appear higher than that used in other studies using LINAC based fraction schedules. Out of seven patients who reached at least a 3year followup, 3 had complete obliteration (43%). Six out of 14 patients (43%) developed headache requiring steroids and 2 required bevacizumab. One patient developed hemiparesis and the second showed behavioral changes. The rate of complications was not insignificant.^{[2]}
While several studies on the outcome of staged SRS have been published, the data on DSSRS using the gamma knife is sparse. Our study of VSSRS showed an improved response with margin doses ≥17 Gy using VSSRS.^{[3]} VSSRS, in comparison to single stagedSRS for large AVMs, significantly reduces the rates of permanently symptomatic adverse radiation effects. Although most reports have used a 3–8 month time interval between the VSSRS stages, the optimal interval that is required between the stages remains unknown. A recent systematic review suggests that VSSRS may afford higher rates of both complete and partial obliteration than DSSRS.^{[4]}
It is important to consider both the total delivered dose as well as the dose per fraction of DSSRS. Previous reports have documented that a higher total dose is associated with an increased risk of complications without improving the potential for obliteration. Therefore, some studies have suggested that the total dose for DSSRS be limited to <35 Gy. Published reports suggest that the optimal dose per stage is 6–7 Gy.^{[5]} Thus, an efficient DSSRS schedule appears to be 4 fractions at 7 Gy per fraction or 5 fractions at 6–6.5 Gy per fraction.^{[4]} Estimating equivalent doses with the linearquadratic model for changing from single fraction to fractionated radiosurgery is problematic for a number of reasons. The linearquadratic formula leads to extrapolation errors with large fractions, which are evident when the alphabeta ratios are calculated from singlefraction radiosurgery.^{[6]} In addition, targeting errors frequently occur in AVM radiosurgery where part of the AVM nidus is not enclosed in the radiosurgery treatment volume.^{[6]} This occurs more frequently when patients have undergone embolization. Targeting error makes it problematic to calculate the alphabeta ratios for AVM obliteration with different dosefractionation schemes.
The current study certainly proves that dose fractionation can be performed using the gamma knife.^{[2]} Frameless gamma knife radiosurgery may be a better option for such fractionation. Although at the present time, angiograms cannot be incorporated into frameless maskbased radiosurgery, using gamma knife Ikon, it is certainly possible to treat the first fraction using the frame and deliver the 2^{nd} and 3^{rd} fractions using the mask. The management of large AVMs is challenging, and the role of VSSRS and DSSRS continues to evolve as the outcome data accrues. A large multicenter prospective study or randomized controlled trial is needed to prove the value of dose fractionation for large AVMs.
» References   
1.  Flickinger JC, Kondziolka D, Lunsford LD, Kassam A, Phuong LK, Liscak R, et al. Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radiosurgery Study Group. Int J Radiat Oncol Biol Phys 2000;46:11438. [ PUBMED] 
2.  Mukherjee KK, Kumar N, Tripathi M, Oinam AS, Ahuja CK, Dhandapani S, Kapoor R, Ghoshal S, Kaur R, Bhat S. Dose fractionated gamma knife radiosurgery for large arteriovenous malformations on daily or alternate day schedule outside the linear quadratic model: Proof of concept and early results. A substitute to volume fractionation. Neurol India 2017;65:82635. [Full text] 
3.  Kano H, Kondziolka D, Flickinger JC, Park KJ, Parry PV, Yang HC, et al. Multistaged volumetric management of large arteriovenous malformations. Prog Neurol Surg 2013;27:7380. [ PUBMED] 
4.  Ilyas A, Chen CJ, Ding D, Taylor DG, Moosa S, Lee CC, et al. Volumestaged versus dosestaged stereotactic radiosurgery outcomes for large brain arteriovenous malformations: A systematic review. J Neurosurg 2017:111. doi: 10.3171/2016.9.JNS161571. 
5.  Chen JC, Mariscal L, Girvigian MR, Vanefsky MA, Glousman BN, Miller MJ, et al. Hypofractionated stereotactic radiosurgery for treatment of cerebral arteriovenous malformations: Outcome analysis with use of the modified arteriovenous malformation scoring system. J Clin Neurosci 2016;29:15561. [ PUBMED] 
6.  Flickinger JC, Kondziolka D, Maitz AH, Lunsford LD. An analysis of the doseresponse for arteriovenous malformation radiosurgery and other factors affecting obliteration. Radiother Oncol 2002;63:34754. [ PUBMED] 





