- Department of Neurosurgery, National Taiwan University Hospital, Taipei, Taiwan
- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
Correspondence Address:
Furen Xiao
Department of Neurosurgery, National Taiwan University Hospital, Taipei, Taiwan
DOI:10.4103/2152-7806.95421
Copyright: © 2012 Wang H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Wang H, Chang RJ, Xiao F. Hypofractionated stereotactic radiotherapy for large arteriovenous malformations. Surg Neurol Int 26-Apr-2012;3:
How to cite this URL: Wang H, Chang RJ, Xiao F. Hypofractionated stereotactic radiotherapy for large arteriovenous malformations. Surg Neurol Int 26-Apr-2012;3:. Available from: http://sni.wpengine.com/surgicalint_articles/hypofractionated-stereotactic-radiotherapy-for-large-arteriovenous-malformations/
Abstract
Cerebral arteriovenous malformations (AVMs) are abnormal connections between the arteries and veins, with possible serious consequences of intracranial hemorrhage. The curative treatment for AVMs includes microsurgery and radiosurgery, sometimes with embolization as an adjunct. However, controversies exist with the treatment options available for large to giant AVMs. Hypofractionated stereotactic radiotherapy (HSRT) is one treatment option for such difficult lesions. We aim to review recent literature, looking at the treatment outcome of HSRT in terms of AVM obliteration rate and complications. The rate of AVM obliteration utilizing HSRT as a primary treatment was comparable with that of stereotactic radiosurgery (SRS). For those not totally obliterated, HSRT makes them smaller and turns some lesions manageable by single-dose SRS or microsurgery. Higher doses per fraction seemed to exhibit better response. However, patients receiving higher total dose may be at risk for higher rates of complications. Fractionated regimens of 7 Gy × 4 and 6–6.5 Gy × 5 may be accepted compromises between obliteration and complication. Embolization may not be beneficial prior to HSRT in terms of obliteration rate or the volume reduction. Future work should aim on a prospectively designed study for larger patient groups and long-term follow-up results.
Keywords: Arteriovenous malformation, hypofractionated stereotactic radiotherapy, radiosurgery
INTRODUCTION
Cerebral arteriovenous malformations (AVMs) are congenital lesions in which abnormal collections of blood vessels composed of dilated arteries and draining veins with dysplastic vessels are present without interposed capillary beds and intervening neural parenchyma. The annual incidence is estimated at 1 person per 100,000[
The successful treatment of large AVMs remains a challenging task. No single treatment for large or giant AVMs can provide satisfactory results. Many of them were previously considered inoperable, especially those classified as Spetzler–Martin Grade IV or V.[
Single-fraction stereotactic radiosurgery (SRS) has been proven effective in treating small AVMs, with complete obliteration rates of 72–96%.[
Since the earliest attempt, fractionated stereotactic radiotherapy has been used in the treatment of large AVMs for over 20 years.[
In contrast, fractionated stereotactic radiosurgery, also known as hypofractionated stereotactic radiotherapy (HSRT), usually involves delivering higher fraction dose to the target for up to 5 or 6 fractions. It can now be readily delivered by commercially available devices such as CyberKnife (Accuray Inc., Sunnyvale, CA, USA) and Novalis/Tx (BrainLAB AG, Feldkirchen, Germany; and Varian Medical Systems, Palo Alto, CA, USA). The objective of this article is to review recent literature for the treatment outcome of HSRT in terms of AVM obliteration rate and complication.
INDICATION AND PATIENT SELECTION
Unlike intracranial aneurysms, there is still no consensus in the definition of large or giant AVMs. The most widely accepted surgical grading system of AVM is the Spetzler–Martin classification,[
The major indication for HSRT, just like other alternative radiosurgical techniques, is large inoperable AVMs. As there is no consensus in definition, large AVMs refer to those too large to be effectively and safely treated with single-fraction SRS in this article. The term inoperable is also disputable. However, most authors preferred not to operate on AVMs of Spetzler–Martin Grade IIIB, IV, and V.[
Not all patients with large inoperable AVMs require aggressive treatment, including HSRT. On the contrary, treatment is not recommended for such patients with minimal or only mild symptoms. Accepted indications for treatment include repeated hemorrhage, progressive neurological deficits, intractable seizures, and other severe symptoms.[
TREATMENT DELIVERY
Radiobiologically, the linear-quadratic formulation is a model describing the cell survival curve. The α/β ratio is the dose where cell killing due to the linear and quadratic components are equal. Typically, the target cells for the obliteration of AVMs have a small α/β ratio in the dose–response curve, like late-responding normal tissues, so that fractionation is unfavorable for the obliteration of an AVM nidus. The real α/β ratios of AVMs, normal vessels, and normal neural structures are in fact not well known. Qi et al. reviewed HSRT literature and reported the α/β ratio of 2.2 ± 1.6 Gy.[
Generally, the fraction doses in the literature were within 4–7 Gy per fraction. Four to six fractions were delivered daily or every other day, making the whole course up to 2 weeks. The total doses usually ranged from 28 to 42 Gy. Some authors determined the dose according to the AVM volume and location, while others adjusted the dosage as the experience accumulated.[
Because the technical advancement in radiation delivery is very fast, we believe that, at the time being, most HSRT for AVMs are delivered by CyberKnife or Novalis/Tx systems. However, older techniques were utilized in most available literature. Newer techniques, such as RapidArc (Varian Medical Systems), are also being applied, but only short-term outcome is available.[
OBLITERATION RATE
Single-fraction SRS has proved to be an effective method, especially in smaller AVMs. Several studies demonstrated both non-obliteration and complication rates rise when AVMs exceed 10 mL in size, with only a 32% obliteration rate after receiving single-dose SRS in one study of Gamma knife radiosurgery.[
Comparison of the effects between SRS and HSRT showed no inferiority of AVM obliteration rate in the HSRT group. Aoyama and Chang used HSRT for patients with larger AVMs or AVMs at the eloquent area; even though the crude obliteration rate seemed lower in the HSRT group, statistical analysis did not reveal significant difference [
Regardless of the total irradiation dose given, there seems to be a minimal dose per fraction required to obtain the desired high obliteration rates. A 7.2-fold greater obliteration rate of 7-Gy over 5-Gy cohorts was reported by Veznedaroglu et al.,[
A pooled analysis of previous reports has shown the HSRT of 7-Gy fraction to be superior with a AVM obliteration rate of 65% compared to 38.5% of single treatment, 25% of volume fractionation, and 58% of salvage treatment.[
For smaller AVMs, several studies have suggested that embolization is a negative predictor of obliteration.[
COMPLICATIONS
Eliminating the risk of hemorrhage in patients with AVMs through obliteration is the primary goal of therapy. Latency period between irradiation and eventual obliteration is cited as the chief disadvantage when compared to microsurgery. There was a decrease in the incidence of hemorrhage as compared to the natural course according to one report.[
Radiation-related adverse effects also constituted another category of commonly seen complications after HSRT. Transient symptoms are usually associated with increased signal change on T2-weight magnetic resonance image, while radiation necrosis or cyst formation may also develop.[
STAGED TREATMENT
While other reports compared the effects of HSRT with SRS for large AVMs, Xiao et al. viewed HSRT as a first stage of the multimodality treatment for large inoperable AVMs.[
CONCLUSION
The rate of AVM obliteration utilizing HSRT as a primary treatment was comparable with that of SRS. For those not totally obliterated, HSRT makes them smaller and turns some lesions manageable by single-dose SRS or microsurgery. Higher doses per fraction seemed to exhibit better response. However, patients receiving higher total dose may be risked for higher rate of complication. Fractionated regimens of 7 Gy × 4 and 6–6.5 Gy × 5 may be accepted compromises between obliteration and complication. Prior embolization may not be beneficial prior to HSRT in terms of obliteration rate or the volume reduction. Future work should focus on a prospectively designed study, for larger patient groups and long-term follow-up results.[
Publication of this manuscript has been made possible by an educational grant from
References
1. Al-Shahi R, Bhattacharya JJ, Currie DG, Papanastassiou V, Ritchie V, Roberts RC. Prospective, population-based detection of intracranial vascular malformations in adults: The Scottish Intracranial Vascular Malformation Study (SIVMS). Stroke. 2003. 34: 1163-9
2. Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain. 2001. 124: 1900-26
3. Amponsah K, Ellis TL, Chan MD, Bourland JD, Glazier SS, McMullen KP. Staged gamma knife radiosurgery for large cerebral arteriovenous malformations. Stereotact Funct Neurosurg. 2011. 89: 365-71
4. Aoyama H, Shirato H, Nishioka T, Kagei K, Onimaru R, Suzuki K. Treatment outcome of single or hypofractionated single-isocentric stereotactic irradiation (STI) using a linear accelerator for intracranial arteriovenous malformation. Radiother Oncol. 2001. 59: 323-8
5. Brown RD, Wiebers DO, Forbes G, O’Fallon WM, Piepgras DG, Marsh WR. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg. 1988. 68: 352-7
6. Brown RD, Wiebers DO, Torner JC, O’Fallon WM. Frequency of intracranial hemorrhage as a presenting symptom and subtype analysis: A population-based study of intracranial vascular malformations in Olmsted Country, Minnesota. J Neurosurg. 1996. 85: 29-32
7. Chang SD, Marcellus ML, Marks MP, Levy RP, Do HM, Steinberg GK. Multimodality treatment of giant intracranial arteriovenous malformations. Neurosurgery. 2003. 53: 1-11
8. Chang TC, Shirato H, Aoyama H, Ushikoshi S, Kato N, Kuroda S. Stereotactic irradiation for intracranial arteriovenous malformation using stereotactic radiosurgery or hypofractionated stereotactic radiotherapy. Int J Radiat Oncol Biol Phys. 2004. 60: 861-70
9. Chung WY, Shiau CY, Wu HM, Liu KD, Guo WY, Wang LW. Staged radiosurgery for extra-large cerebral arteriovenous malformations: method, implementation, and results. J Neurosurg. 2008. 109: S65-72
10. Crawford PM, West CR, Chadwick DW, Shaw MD. Arteriovenous malformations of the brain: Natural history in unoperated patients. J Neurol Neurosurg Psychiatry. 1986. 49: 1-10
11. Flickinger JC, Kondziolka D, Maitz AH, Lunsford LD. An analysis of the dose-response for arteriovenous malformation radiosurgery and other factors affecting obliteration. Radiother Oncol. 2002. 63: 347-54
12. Flickinger JC, Kondziolka D, Pollock BE, Maitz AH, Lunsford LD. Complications from arteriovenous malformation radiosurgery: Multivariate analysis and risk modeling. Int J Radiat Oncol Biol Phys. 1997. 38: 485-90
13. Flickinger JC, Pollock BE, Kondziolka D, Lunsford LD. A dose-response analysis of arteriovenous malformation obliteration after radiosurgery. Int J Radiat Oncol Biol Phys. 1996. 36: 873-9
14. Friedman WA, Bova FJ, Mendenhall WM. Linear accelerator radiosurgery for arteriovenous malformations: The relationship of size to outcome. J Neurosurg. 1995. 82: 180-9
15. Han PP, Ponce FA, Spetzler RF. Intention-to-treat analysis of Spetzler-Martin grades IV and V arteriovenous malformations: Natural history and treatment paradigm. J Neurosurg. 2003. 98: 3-7
16. Jayaraman MV, Marcellus ML, Do HM, Chang SD, Rosenberg JK, Steinberg GK. Hemorrhage rate in patients with Spetzler-Martin grades IV and V arteriovenous malformations: Is treatment justified?. Stroke. 2007. 38: 325-9
17. Jessurun GA, Kamphuis DJ, van der Zande FH, Nossent JC. Cerebral arteriovenous malformations in The Netherlands Antilles. High prevalence of hereditary hemorrhagic telangiectasia-related single and multiple cerebral arteriovenous malformations. Clin Neurol Neurosurg. 1993. 95: 193-8
18. Jones J, Jang S, Getch CC, Kepka AG, Marymont MH. Advances in the radiosurgical treatment of large inoperable arteriovenous malformations. Neurosurg Focus. 2007. 23: E7-
19. Karlsson B, Kihlstrom L, Lindquist C, Steiner L. Gamma knife surgery for previously irradiated arteriovenous malformations. Neurosurgery. 1998. 42: 1-5
20. Karlsson B, Lindquist C, Steiner L. Effect of Gamma Knife surgery on the risk of rupture prior to AVM obliteration. Minim Invasive Neurosurg. 1996. 39: 21-7
21. Karlsson B, Lindqvist M, Blomgren H, Wan-Yeo G, Soderman M, Lax I. Long-term results after fractionated radiation therapy for large brain arteriovenous malformations. Neurosurgery. 2005. 57: 42-9
22. Lindqvist M, Steiner L, Blomgren H, Arndt J, Berggren BM. Stereotactic radiation therapy of intracranial arteriovenous malformations. Acta Radiol Suppl. 1986. 369: 610-3
23. Lindvall P, Bergstrom P, Lofroth PO, Hariz MI, Henriksson R, Jonasson P. Hypofractionated conformal stereotactic radiotherapy for arteriovenous malformations. Neurosurgery. 2003. 53: 1036-42
24. Lunsford LD, Kondziolka D, Flickinger JC, Bissonette DJ, Jungreis CA, Maitz AH. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg. 1991. 75: 512-24
25. Miyamoto S, Hashimoto N, Nagata I, Nozaki K, Morimoto M, Taki W. Posttreatment sequelae of palliatively treated cerebral arteriovenous malformations. Neurosurgery. 2000. 46: 589-94
26. Miyawaki L, Dowd C, Wara W, Goldsmith B, Albright N, Gutin P. Five year results of LINAC radiosurgery for arteriovenous malformations: Outcome for large AVMS. Int J Radiat Oncol Biol Phys. 1999. 44: 1089-106
27. Pan DH, Guo WY, Chung WY, Shiau CY, Chang YC, Wang LW. Gamma knife radiosurgery as a single treatment modality for large cerebral arteriovenous malformations. J Neurosurg. 2000. 93: S113-9
28. Pollock BE, Flickinger JC. A proposed radiosurgery-based grading system for arteriovenous malformations. J Neurosurg. 2002. 96: 79-85
29. Qi XS, Schultz CJ, Li XA. Possible fractionated regimens for image-guided intensity-modulated radiation therapy of large arteriovenous malformations. Phys Med Biol. 2007. 52: 5667-82
30. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986. 65: 476-83
31. Starke RM, Komotar RJ, Hwang BY, Fischer LE, Garrett MC, Otten ML. Treatment guidelines for cerebral arteriovenous malformation microsurgery. Br J Neurosurg. 2009. 23: 376-86
32. Subramanian S, Srinivas C, Ramalingam K, Babaiah M, Swamy ST, Arun G. Volumetric modulated arc-based hypofractionated stereotactic radiotherapy for the treatment of selected intracranial arteriovenous malformations: Dosimetric report and early clinical experience. Int J Radiat Oncol Biol Phys. 2012. 82: 1278-84
33. Touboul E, Al Halabi A, Buffat L, Merienne L, Huart J, Schlienger M. Single-fraction stereotactic radiotherapy: A dose-response analysis of arteriovenous malformation obliteration. Int J Radiat Oncol Biol Phys. 1998. 41: 855-61
34. Valentino V. Stereotactic radiation therapy in arteriovenous malformations and brain tumors using the Fixster system. Acta Radiol Suppl. 1986. 369: 608-9
35. Veznedaroglu E, Andrews DW, Benitez RP, Downes MB, Werner-Wasik M, Rosenstock J. Fractionated stereotactic radiotherapy for the treatment of large arteriovenous malformations with or without previous partial embolization. Neurosurgery. 2004. 55: 519-30
36. Wowra B, Muacevic A, Tonn JC, Schoenberg SO, Reiser M, Herrmann KA. Obliteration dynamics in cerebral arteriovenous malformations after cyberknife radiosurgery: Quantification with sequential nidus volumetry and 3-tesla 3-dimensional time-of-flight magnetic resonance angiography. Neurosurgery. 2009. 64: A102-9
37. Xiao F, Gorgulho AA, Lin CS, Chen CH, Agazaryan N, Vinuela F. Treatment of giant cerebral arteriovenous malformation: Hypofractionated stereotactic radiation as the first stage. Neurosurgery. 2010. 67: 1253-9
38. Yamamoto M, Jimbo M, Hara M, Saito I, Mori K. Gamma knife radiosurgery for arteriovenous malformations: Long-term follow-up results focusing on complications occurring more than 5 years after irradiation. Neurosurgery. 1996. 38: 906-14
39. Yang SY, Kim DG, Chung HT, Paek SH, Park JH, Han DH. Radiosurgery for large cerebral arteriovenous malformations. Acta Neurochir (Wien). 2009. 151: 113-24
40. Yuki I, Kim RH, Duckwiler G, Jahan R, Tateshima S, Gonzalez N. Treatment of brain arteriovenous malformations with high-flow arteriovenous fistulas: Risk and complications associated with endovascular embolization in multimodality treatment. Clinical article. J Neurosurg. 2010. 113: 715-22
41. Zabel-du Bois A, Milker-Zabel S, Huber P, Schlegel W, Debus J. Linac-based radiosurgery or hypofractionated stereotactic radiotherapy in the treatment of large cerebral arteriovenous malformations. Int J Radiat Oncol Biol Phys. 2006. 64: 1049-54
42. Zhao J, Yu T, Wang S, Zhao Y, Yang WY. Surgical treatment of giant intracranial arteriovenous malformations. Neurosurgery. 2010. 67: 1359-70