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Results for local control and functional outcome after linac-based image-guided stereotactic radiosurgery in 190 patients with vestibular schwannoma

Results for local control and functional outcome after linac-based image-guided stereotactic... Journal of Radiation Research, 2014, 55, 288–292 doi: 10.1093/jrr/rrt101 Advance Access Publication 26 August 2013 Results for local control and functional outcome after linac-based image-guided stereotactic radiosurgery in 190 patients with vestibular schwannoma † † 1, 1 1 2 Harun BADAKHSHI , Reinhold GRAF , Dirk BÖHMER , Michael SYNOWITZ , 3 1 Edzard WIENER and Volker BUDACH Departments for Radiation Oncology, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany Department for Neurosurgery, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany Institute for Neuroradiology, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany *Corresponding author. Department for Radiation Oncology, Charité University Medicine, Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49-30-450-527152 (office); Fax: +49-30-450-557988; Email: Harun.Badakhshi@charite.de (Received 10 April 2013; revised 7 July 2013; accepted 18 July 2013) Background We assessed local control (LC) and functional outcome after linac-based stereotactic radiosurgery (SRS) for vestibular schwannoma (VS). Methods Between 1998 and 2008, 190 patients with VS were treated with SRS. All patients had tumors <2 cm diameter. Patients received 13.5 Gy prescribed to the 80th isodose at the tumor margin. The primary endpoint was LC. Secondary endpoints were symptomatic control and morbidity. Results Median follow-up was 40 months. LC was achieved in 88% of patients. There were no acute reactions exceeding Grade I. Trigeminal nerve dysfunction was present in 21.6% (n = 41) prior to SRS. After treatment, 85% (n = 155) had no change, 4.4,% (n = 8) had a relief of symptoms, 10.4% (n = 19) had new symptoms. Facial nerve dysfunction was present in some patients prior to treatment, e.g. paresis (12.6%; n = 24) and dysgeusia (0.5%; n = 1). After treatment 1.1% (n = 2) reported improvement and 6.1% (n = 11) experienced new symptoms. Hearing problems before SRS were present in 69.5% of patients (n = 132). After treatment, 62.6% (n = 144) had no change, 10.4% (n = 19) experienced improvement and 26.9% (n = 49) became hearing impaired. Conclusion This series of SRS for small VS provided similar LC rates to microsurgery; thus, it is effective as a non-invasive, image-guided procedure. The functional outcomes observed indicate the safety and effectiveness of linac-based SRS. Patients may now be informed of the clinical equivalence of SRS to microsurgery. Keywords: vestibular schwannoma; acoustic neurinoma; stereotactic radiosurgery; image-guided interven- tion; local control INTRODUCTION linear accelerators with stereotactic tools [4–7]. This study focuses on the results of long-term outcomes with respect to The clinical management of patients with small-sized vestibu- the feasibility, safety and effectiveness of SRS for VS. lar schwannomas (VS) is still an area of debate. The choice is between watchful waiting, microsurgery and stereotactic MATERIALS AND METHODS radiosurgery (SRS). The option of watchful waiting might be an adequate approach for neurologically marginally-hampered Study design patients [1]. Traditionally, microsurgery has been the mainstay Between 1998 and 2008, 190 patients with small-sized (<2 cm, of treatment of VS in recent decades and offers excellent median 1.2 cm, range, 0.6–2 cm) VS underwent linac-based tumor control [2]. SRS, implemented by Leksell has now SRS of 13.5 Gy (n= 190). After receiving the Institutional become an additional tool [3]. SRS can be delivered modern Review Board’s agreement, we obtained informed consent from all patients. A prospective database was established. Most patients (82%) had regular follow-up visits including MRI Harun Badakhshi and Reinhold Graf contributed equally to the design, data collection, analysis and manuscript preparation. twelve weeks after SRS and at three- to six-month intervals. © The Author 2013. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Therapeutic Radiology and Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Linac-based image-guided radiosurgery for vestibular schwannoma 289 There was a minimum follow-up period of five years for 75% multileaf collimator (mMLC) (BrainLab Co., Germany) of patients. Two-thirds of those had regular MRIs of the brain was used. The target coordinators for SRS were set by a until five years after treatment. An update of missing clinical laser-based stereotactic localizer, which could be adjusted data was compiled by approaching patients and general practi- with six degrees of freedom (6DOF). This hardware and soft- tioners. To assess the treatment efficacy, volumetric measure- ware set-up allowed the delivery of shaped beams. In 2004 ® ® ments of the repetitive MRIs were done in 72.3% (n= 182) of we started using a Novalis (BrainLab ) with built-in MLC, all cases. Primary outcome measured LC rate, defined as the beam-shaping capability and the option of online image case of stable disease or tumor regression assessed by means of guidance of the treatment delivery. This significant develop- cranial MRI at the latest follow-up. Moreover, disease-related ment in technology enabled us to register and verify the symptoms before and after treatment were reported according a target localization and to carry out real-time adaptation of the validated toxicity score as follows: tinnitus, dizziness, dysfunc- therapy set-up. The mechanical accuracy was 0.6 mm. The tion of trigeminal and facial nerves, and gradual loss of hearing. new infrastructure enabled transformation of the set-up of A vast majority of patients had no audiometry by a quantitative immobilization into a less invasive device in combination method; this is a clear limitation of the study. We interviewed with the aforementioned stereoscopic image guidance and patients about their hearing quality in quotidian life, thus inves- 6DOF table corrections. From this point on we used a tigating how serviceable their hearing really was. We trusted Novalis ExacTrac image-guided frameless system, which the steadiness of patient’s subjective statements in regard to the enabled us to image the patient in any couch position using a hearing function. frameless positioning array. For the entire period reported on here, we performed image fusion using MRI and planning CT. The target volumes and organs at risk were delineated on Patient characteristics each slice of MRI and CT using the 3D treatment-planning We analyzed 102 females and 88 males. The median age was system Brainscan (Brain Lab AG, Germany). The gross 59 years. Of the 190 patients, 156 had primary diagnoses tumor volume (GTV) was defined as the area of contrast en- and 34 had recurrences. In three patients VS was associated hancement on T1-weighted MRI images, and the planning with neurofibromatosis (NF-2). The median follow-up was target volume (PTV) included a 1-mm safety margin to 40 months; 46.8% of the patients had a follow-up after >36 allow for possible patient positioning errors. months, 21.2% after >60 months. We observed good clinical The dose was prescribed to a reference point, which was practice, and data analyses were only executed after a posi- the isocenter (or the center of GTV), though 100% was not tive vote by the local ethics committee and the informed the maximum dose but the dose at the aforementioned refer- consent of the patients (Table 1). ence point. Patients received 13.5 Gy prescribed to the 80th isodose at Technical set-up the tumor margin (Fig. 1). From 1998–2003, patients underwent ‘sharp’ fixation using a stereotactic head ring supplemented with an oral bite plate Statistics to ensure placement reproducibility. A conventional 6-MV LC and hearing preservation probabilities after radiotherapy linac (Varian USA) equipped with an add-on micro- were calculated using the Kaplan–Meier method. For inter- group differences, the Student’s t-test and the log-rank test Table 1. Baseline patient and tumor variables for 190 patients treated for vestibular schwannoma with SRS No. of patients Parameter Characteristic (% of total) Gender Male 88 (46.3%) Female 102 (53.7%) Genetic predisposition Sporadic 189 (99.5%) NF-2 1 (0.5%) Hearing difficulties Yes 132 (69.5%) before SRS Trigeminal dysfunction Pain, dysesthesia 41 (21.6%) before SRS Prior surgery Yes 34 (17.9%) Side Left 92 (48.4%) Right 98 (51.6%) Fig. 1. MRI-based target definition, 100% dose at reference point. 290 H. Badakhshi et al. were applied. All statistical analyses were performed using (n= 6) of all cases, respectively. After treatment, no change IBM SPSS Statistics 19 (New York, USA). in symptoms was reported in 73.1% of patients (n= 133), improvement was reported in 14.4% (n= 26), and impair- ment was reported in 12.6% (n= 23) (Table 2). RESULTS Dizziness Local tumor control Dizziness was reported in 42.1% (n= 119) prior to radiation. LC was defined as lack of progression or tumor regression Mild, moderate and severe symptoms were reported in on MRIs at follow-up visits. Of the 190 patients, 15 (7.8%) 20.5% (n= 39), 34.7% (n= 66) and 7.4% (n= 14) of all were lost to follow-up, leaving 92.1% (n= 175) of patients cases, respectively. After treatment, no change in symptoms with complete clinical data for the analysis. was reported in 75.1% of patients (n = 104), improvement For 88.0% (n= 154) a crude LC rate was achieved. was reported in 28.6% (n= 52), and impairment was Progression was observed in 11.1% (n= 21) of all cases. At reported in 14.3% (n= 26) (Table 3). 3 years, an LC rate of 92%, and at 5 years an LC rate of 68%, was achieved. Volumetric analysis was done using MRI Trigeminal nerve dysfunction examinations during follow-up. Only 1.3% (n= 3) of all Trigeminal nerve dysfunction was reported prior to therapy lesions showed a volumetric progression to such an extent in 21.6% (n= 41) of cases. After treatment, 85% (n= 155) that surgical treatment was required. Thus, 98.7% of the had no change, 4.4% (n= 8) of formerly affected patients patients needed no additional surgical intervention (Fig. 2). had a relief of symptoms, 10.4% (n= 19) had new onset of symptoms such as pain and dysesthesia (Table 4). Morbidity Acute side effects during or shortly after treatment (period of Facial nerve dysfunction 90 days) were rare. No Grade II or greater toxicity occurred. Facial nerve dysfunction was documented prior to treatment, Glucocorticoids had to be prescribed because of headache e.g. paresis 12.6% (n= 24) and dysgeusia (0.5%; n= 1). and nausea during and after treatment in 36 (18.6%) patients, After treatment, improvement was reported in 1.1% (n= 2), the majority (n= 28) of this subgroup had been in need for a 6.1% (n= 11) experienced new symptoms (Table 5) and short time of some weeks. 92.8% had no symptoms. Functional outcome Tinnitus Table 2. Functional outcome with respect to tinnitus before Tinnitus was documented in 59% of all patients (n= 112) and after treatment prior to treatment. Mild, moderate and severe symptoms Number of patients were reported in 25.3% (n= 48), 30.5% (n= 58) and 3.2% Prior to SRS 59% (n = 112) Impairment of symptoms after SRS 12.6% (n = 23) Relief of symptoms after SRS 14.4% (n = 26) Table 3. Functional outcome with respect to dizziness before and after treatment Number of patients Prior to SRS 42.1% (n= 119) Impairment of symptoms after SRS 14.3% (n= 26) Relief of symptoms after SRS 28.6% (n= 52) Table 4. Functional outcome with respect to trigeminal neuropathy before and after treatment Number of patients Prior to SRS 21.6% (n= 41) Impairment of symptoms after SRS 10.4% (n= 19) Relief of symptoms after SRS 4.4,% (n= 8) Fig. 2. Local control (LC) in months. Linac-based image-guided radiosurgery for vestibular schwannoma 291 functional problems, was done subjectively by the patient or Table 5. Functional outcome with respect to facial the physician and not objectively. The information gathered neuropathy before and after treatment on functionalities, e.g. hearing preservation, as a relevant par- Number of patients ameter for patient quality of life, was not based on objective Prior to SRS 12.6% (n= 24) auditory analyses. These factors are major drawbacks. Additionally, it is very important to note that the vast majority Impairment of symptoms after SRS 6.1% (n= 11) (ca. 40%) of patients experienced transient tumor expansion Relief of symptoms after SRS 1.1% (n= 2) during the first 4 years after SRS. Therefore, the LC rate shown in this study might be confounded by transient volu- metric change after SRS. The transient volumetric change can Table 6. Functional outcome with respect to hearing cause worsening of symptoms that usually resolves once difficulties before and after treatment tumors enter the shrinking phase. The vast majority of publications are based on Gamma Number of patients knife applications [9]. In order to critically evaluate our results Prior to SRS 69.5% (n= 132) with linac-based SRS techniques, we extracted those papers New onset of symptoms after SRS 26.9% (n= 49) reporting only linac-based SRS. Suh and colleagues reported Relief of symptoms after SRS 10.4% (n= 19) on 29 patients, 12 of whom underwent surgery before SRS. The median tumor volume reported was 2.1 cm , and LC was achieved in 28 of 29 patients. This finding translated into an Table 7. Outcome of image-guided linac-based SRS with actuarial 5-year LC rate of 94% [10]. Foote and colleagues respect to local control and functions reported on the results of SRS in 149 VS cases, of whom 28% Study n Dose in Gy Control rate (%) had had prior surgery and the mean tumor volume was 4.8 cm . A mean dose of 14 Gy (range, 10–22.5 Gy) was given to Suh 29 16 94 @ 5 year the 80% isodose. After a median follow-up of 34 months, LC Foote 149 14 87 @ 5 year was achieved in 93% of patients; the actuarial LC rate at five Spiegelmann 48 14 98 @ 3 year years was 87% (95% CI, 76–98) [11]. This data corresponds Okunaga 46 14 100 @ 5 year well with the present study, although our dose prescription was 13.5 Gy at the 80% isodose. Spiegelmann et al. published data Roos 65 13 95 @ 4 year on 48 cases, with a median tumor diameter of 20 mm. Lesions Combs 26 13 91 @ 5 year up to 16 mm in size received a maximum of 14 Gy encom- Rutten 26 12 95 @ 5 year passing the PTV; larger tumors were treated with a minimum Friedman 390 13 90 @ 5 year dose of 11 Gy. After a median follow-up of 32 months, LC was achieved in 98% of patients, which is comparable to the Hsu 75 15 92 @ 5 year results of surgical series [12]. Okunaga et al. published results Badakhshi 190 13.5 88 @ 3 year for 46 patients; 26.1% of the patients had had prior surgery 3 3 and a median tumor volume of 2.29 cm (0.4–7cm )was Hearing problems reported. The prescribed dose was 14 Gy. Median follow-up Hearing problems before SRS were present in 69.5% was 56.5 months. An LC of 73.8% was observed in all patients (n= 132). After treatment, 62.6% (n= 144) had no change, followed up for >1 year, and an LC of 100% was observed in 10.4% (n= 19) experienced improvement, and 26.9% (n= the 18 patients followed for > 5 years [13]. Roos et al. reported 49) developed impaired hearing (Table 6). on 65 patients with VS with a median diameter of 22 mm, treated with SRS of 13 Gy. The median follow-up period was DISCUSSION 48 months, and LC was observed in 95% of patients [14]. Combs published data on 26 patients treated with a dose of 13 Treatment options for VS include surgery and SRS. Watchful Gy. The actuarial LC rates at 5 and 10 years for all patients waiting is an accepted strategy. Surgery by expert surgeons were 91% in both cases [15]. Rutten et al.havereportedon has an LC rate greater than 95% [2]. SRS is achieving similar SRS for 26 patients with VS with a median size of 18 mm, a LC rates according to a recently published meta-analysis of dose of 12 Gy, and a median follow-up of 49 months. The 37 case series, comprising 3,677 patients. The overall LC rate 5-year LC rate reported was 95% [16]. The largest series to observed was 92.2% (95%, CI: 90.4–93.7%) [8]. date included 390 cases and reported an LC rate of 98% at The main limitation of this study was the retrospective ana- 2 years and 90% at 5 years [17]. lysis, although it was based on a prospective database. The above studies show clear evidence for the use of SRS Another major confounding factor in this analysis was the fact with a dose of 12–14 Gy resulting in 5- and 10-year LC rates that data acquisition, in terms of disease and treatment-related of ~ 90% [18]. 292 H. Badakhshi et al. Early and early-delayed toxicity can be defined as seque- 4. Murphy ES, Suh JH. Radiotherapy for vestibular schwanno- mas: a critical review. Int J Radiat Oncol Biol Phys lae and complications within weeks to months after SRS. 2011;79:985–9. These include headache, local erythema of the skin, alopecia 5. Compter I, Zaugg K, Houben RM et al. High symptom of in-field treatment areas, and fatigue. We experienced no improvement and local tumor control using stereotactic cases of severe acute toxicity among our patients. radiotherapy when given early after diagnosis of meningioma. Functional outcome with respect to nerve function is a diffi- A multicentre study. Strahlenther Onkol 2012;188:887–93. cult issue to judge clearly because of the range of reported data 6. Runge MJ, Maarouf M, Hunsche S et al. LINAC-radiosurgery that could be affected by different cofactors. Combs reported for nonsecreting pituitary adenomas. Long-term results. 2.5% new cases of tinnitus after SRS. Most cranial neuropa- Strahlenther Onkol 2012;188:319–25. thies following radiosurgery are mild, transient and commonly 7. Fuetsch M, El Majdoub F, Hoevels M et al. Stereotactic present as late-delayed complications. The mean latency of LINAC radiosurgery for the treatment of brainstem caverno- trigeminal and facial neuropathies after SRS for VS has mas. Strahlenther Onkol 2012;188:311–6. 8. Pannullo SC, Fraser JF, Moliterno J et al. Stereotactic radiosur- been noted to be ~ 7 months. Ito et al. report a similar latency gery: a meta-analysis of current therapeutic applications in of 4–5 months for the onset of cranial neuropathies [19]. neuro-oncologic disease. J Neurooncol 2011;103:1–17. Trigeminal and facial neuropathy has been reported in 8% 9. Lunsford LD, Niranjan A, Flickinger JC et al. Radiosurgery of and 5%, respectively, in Comb’s paper [15], and in 8–18% in vestibular schwannomas: summary of experience in 829 cases. Spiegelmann’s publication [12]. Our data seem to be in the J Neurosurg 2005;102 (Suppl):195–9. range of potential toxicity with respect to hearing (and there- 10. Suh JH, Barnett GH, Sohn JW et al. Results of linear accelerator- fore quality of life). However, for other symptoms, data from based stereotactic radiosurgery for recurrent and newly diagnosed a recent meta-analysis indicates a clear benefit of SRS [20] acoustic neuromas. Int J Cancer 2000;90:145–51. in comparison with surgery, which is in line with our results. 11. Foote KD, Friedman WA, Buatti JM et al. Analysis of risk factors associated with radiosurgery for vestibular schwan- noma. J Neurosurg 2001;95:440–9. CONCLUSION 12. Spiegelmann R, Lidar Z, Gofman J et al. Linear accelerator radiosurgery for vestibular schwannoma. J Neurosurg This study of a very large patient cohort treated with image- 2001;94:7–13. guided linac-based SRS yielded a high rate of LC, favorably 13. Okunaga T, Matsuo T, Hayashi N et al. Linear accelerator comparable with microsurgery. Individual counseling of radiosurgery for vestibular schwannoma: measuring tumor patients by an interdisciplinary team is desirable in order to volume changes on serial three-dimensional spoiled gradient- echo magnetic resonance images. J Neurosurg 2005;103:53–8. provide adequate information for decision-making about 14. Roos DE, Brophy BP, Bhat MK et al. Update of radio- treatment. Taking into account the above-mentioned con- surgery at the Royal Adelaide Hospital. Australas Radiol founding factors, the results of the present study provide 2006;50:158–67. valuable data on LC and functionality of cranial nerves for 15. Combs SE, Thilmann C, Debus J et al. Long-term outcome of VS treated with linac-based SRS. stereotactic radiosurgery (SRS) in patients with acoustic neur- omas. Int J Radiat Oncol Biol Phys 2006;64:1341–7. 16. Rutten I, Baumert BG, Seidel L et al. Long-term follow-up FUNDING reveals low toxicity of radiosurgery for vestibular schwan- noma. Radiother Oncol 2007;82:83–9. The authors all confirm that there has been no funding to 17. Friedman WA, Bradshaw P, Myers A et al. Linear accelerator support the research for this paper. radiosurgery for vestibular schwannomas. J Neurosurg 2006;105:657–61. 18. Hsu PW, Chang CN, Lee ST et al. Outcomes of 75 patients REFERENCES over 12 years treated for acoustic neuromas with linear 1. Sughrue ME, Yang I, Aranda D et al. The natural history of un- accelerator-based radiosurgery. J Clin Neurosci 2010;17:556–60. treated sporadic vestibular schwannomas: a comprehensive 19. Ito K, Shin M, Matsuzaki M et al. Risk factors for neurological review of hearing outcomes. J Neurosurg 2010;112:163–7. complications after acoustic neurinoma radiosurgery: refine- 2. Yamakami I, Uchino Y, Kobayashi E et al. Conservative man- ment from further experiences. Int J Radiat Oncol Biol Phys 2000;48:75–80. agement, gamma-knife radiosurgery, and microsurgery for 20. Wolbers JG, Dallenga AH, Mendez Romero A et al. What acoustic neurinomas: a systematic review of outcome and risk intervention is best practice for vestibular schwannomas? A of three therapeutic options. Neurol Res 2003;25:682–90. systematic review of controlled studies. BMJ Open 2013;3: 3. Leksell L. A note on the treatment of acoustic tumors. Acta e001345. Chir Scand 1971;137:763–5. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Radiation Research Oxford University Press

Results for local control and functional outcome after linac-based image-guided stereotactic radiosurgery in 190 patients with vestibular schwannoma

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Oxford University Press
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The Author 2013. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Therapeutic Radiology and Oncology.
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Oncology
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0449-3060
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10.1093/jrr/rrt101
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23979079
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Abstract

Journal of Radiation Research, 2014, 55, 288–292 doi: 10.1093/jrr/rrt101 Advance Access Publication 26 August 2013 Results for local control and functional outcome after linac-based image-guided stereotactic radiosurgery in 190 patients with vestibular schwannoma † † 1, 1 1 2 Harun BADAKHSHI , Reinhold GRAF , Dirk BÖHMER , Michael SYNOWITZ , 3 1 Edzard WIENER and Volker BUDACH Departments for Radiation Oncology, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany Department for Neurosurgery, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany Institute for Neuroradiology, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany *Corresponding author. Department for Radiation Oncology, Charité University Medicine, Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49-30-450-527152 (office); Fax: +49-30-450-557988; Email: Harun.Badakhshi@charite.de (Received 10 April 2013; revised 7 July 2013; accepted 18 July 2013) Background We assessed local control (LC) and functional outcome after linac-based stereotactic radiosurgery (SRS) for vestibular schwannoma (VS). Methods Between 1998 and 2008, 190 patients with VS were treated with SRS. All patients had tumors <2 cm diameter. Patients received 13.5 Gy prescribed to the 80th isodose at the tumor margin. The primary endpoint was LC. Secondary endpoints were symptomatic control and morbidity. Results Median follow-up was 40 months. LC was achieved in 88% of patients. There were no acute reactions exceeding Grade I. Trigeminal nerve dysfunction was present in 21.6% (n = 41) prior to SRS. After treatment, 85% (n = 155) had no change, 4.4,% (n = 8) had a relief of symptoms, 10.4% (n = 19) had new symptoms. Facial nerve dysfunction was present in some patients prior to treatment, e.g. paresis (12.6%; n = 24) and dysgeusia (0.5%; n = 1). After treatment 1.1% (n = 2) reported improvement and 6.1% (n = 11) experienced new symptoms. Hearing problems before SRS were present in 69.5% of patients (n = 132). After treatment, 62.6% (n = 144) had no change, 10.4% (n = 19) experienced improvement and 26.9% (n = 49) became hearing impaired. Conclusion This series of SRS for small VS provided similar LC rates to microsurgery; thus, it is effective as a non-invasive, image-guided procedure. The functional outcomes observed indicate the safety and effectiveness of linac-based SRS. Patients may now be informed of the clinical equivalence of SRS to microsurgery. Keywords: vestibular schwannoma; acoustic neurinoma; stereotactic radiosurgery; image-guided interven- tion; local control INTRODUCTION linear accelerators with stereotactic tools [4–7]. This study focuses on the results of long-term outcomes with respect to The clinical management of patients with small-sized vestibu- the feasibility, safety and effectiveness of SRS for VS. lar schwannomas (VS) is still an area of debate. The choice is between watchful waiting, microsurgery and stereotactic MATERIALS AND METHODS radiosurgery (SRS). The option of watchful waiting might be an adequate approach for neurologically marginally-hampered Study design patients [1]. Traditionally, microsurgery has been the mainstay Between 1998 and 2008, 190 patients with small-sized (<2 cm, of treatment of VS in recent decades and offers excellent median 1.2 cm, range, 0.6–2 cm) VS underwent linac-based tumor control [2]. SRS, implemented by Leksell has now SRS of 13.5 Gy (n= 190). After receiving the Institutional become an additional tool [3]. SRS can be delivered modern Review Board’s agreement, we obtained informed consent from all patients. A prospective database was established. Most patients (82%) had regular follow-up visits including MRI Harun Badakhshi and Reinhold Graf contributed equally to the design, data collection, analysis and manuscript preparation. twelve weeks after SRS and at three- to six-month intervals. © The Author 2013. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Therapeutic Radiology and Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Linac-based image-guided radiosurgery for vestibular schwannoma 289 There was a minimum follow-up period of five years for 75% multileaf collimator (mMLC) (BrainLab Co., Germany) of patients. Two-thirds of those had regular MRIs of the brain was used. The target coordinators for SRS were set by a until five years after treatment. An update of missing clinical laser-based stereotactic localizer, which could be adjusted data was compiled by approaching patients and general practi- with six degrees of freedom (6DOF). This hardware and soft- tioners. To assess the treatment efficacy, volumetric measure- ware set-up allowed the delivery of shaped beams. In 2004 ® ® ments of the repetitive MRIs were done in 72.3% (n= 182) of we started using a Novalis (BrainLab ) with built-in MLC, all cases. Primary outcome measured LC rate, defined as the beam-shaping capability and the option of online image case of stable disease or tumor regression assessed by means of guidance of the treatment delivery. This significant develop- cranial MRI at the latest follow-up. Moreover, disease-related ment in technology enabled us to register and verify the symptoms before and after treatment were reported according a target localization and to carry out real-time adaptation of the validated toxicity score as follows: tinnitus, dizziness, dysfunc- therapy set-up. The mechanical accuracy was 0.6 mm. The tion of trigeminal and facial nerves, and gradual loss of hearing. new infrastructure enabled transformation of the set-up of A vast majority of patients had no audiometry by a quantitative immobilization into a less invasive device in combination method; this is a clear limitation of the study. We interviewed with the aforementioned stereoscopic image guidance and patients about their hearing quality in quotidian life, thus inves- 6DOF table corrections. From this point on we used a tigating how serviceable their hearing really was. We trusted Novalis ExacTrac image-guided frameless system, which the steadiness of patient’s subjective statements in regard to the enabled us to image the patient in any couch position using a hearing function. frameless positioning array. For the entire period reported on here, we performed image fusion using MRI and planning CT. The target volumes and organs at risk were delineated on Patient characteristics each slice of MRI and CT using the 3D treatment-planning We analyzed 102 females and 88 males. The median age was system Brainscan (Brain Lab AG, Germany). The gross 59 years. Of the 190 patients, 156 had primary diagnoses tumor volume (GTV) was defined as the area of contrast en- and 34 had recurrences. In three patients VS was associated hancement on T1-weighted MRI images, and the planning with neurofibromatosis (NF-2). The median follow-up was target volume (PTV) included a 1-mm safety margin to 40 months; 46.8% of the patients had a follow-up after >36 allow for possible patient positioning errors. months, 21.2% after >60 months. We observed good clinical The dose was prescribed to a reference point, which was practice, and data analyses were only executed after a posi- the isocenter (or the center of GTV), though 100% was not tive vote by the local ethics committee and the informed the maximum dose but the dose at the aforementioned refer- consent of the patients (Table 1). ence point. Patients received 13.5 Gy prescribed to the 80th isodose at Technical set-up the tumor margin (Fig. 1). From 1998–2003, patients underwent ‘sharp’ fixation using a stereotactic head ring supplemented with an oral bite plate Statistics to ensure placement reproducibility. A conventional 6-MV LC and hearing preservation probabilities after radiotherapy linac (Varian USA) equipped with an add-on micro- were calculated using the Kaplan–Meier method. For inter- group differences, the Student’s t-test and the log-rank test Table 1. Baseline patient and tumor variables for 190 patients treated for vestibular schwannoma with SRS No. of patients Parameter Characteristic (% of total) Gender Male 88 (46.3%) Female 102 (53.7%) Genetic predisposition Sporadic 189 (99.5%) NF-2 1 (0.5%) Hearing difficulties Yes 132 (69.5%) before SRS Trigeminal dysfunction Pain, dysesthesia 41 (21.6%) before SRS Prior surgery Yes 34 (17.9%) Side Left 92 (48.4%) Right 98 (51.6%) Fig. 1. MRI-based target definition, 100% dose at reference point. 290 H. Badakhshi et al. were applied. All statistical analyses were performed using (n= 6) of all cases, respectively. After treatment, no change IBM SPSS Statistics 19 (New York, USA). in symptoms was reported in 73.1% of patients (n= 133), improvement was reported in 14.4% (n= 26), and impair- ment was reported in 12.6% (n= 23) (Table 2). RESULTS Dizziness Local tumor control Dizziness was reported in 42.1% (n= 119) prior to radiation. LC was defined as lack of progression or tumor regression Mild, moderate and severe symptoms were reported in on MRIs at follow-up visits. Of the 190 patients, 15 (7.8%) 20.5% (n= 39), 34.7% (n= 66) and 7.4% (n= 14) of all were lost to follow-up, leaving 92.1% (n= 175) of patients cases, respectively. After treatment, no change in symptoms with complete clinical data for the analysis. was reported in 75.1% of patients (n = 104), improvement For 88.0% (n= 154) a crude LC rate was achieved. was reported in 28.6% (n= 52), and impairment was Progression was observed in 11.1% (n= 21) of all cases. At reported in 14.3% (n= 26) (Table 3). 3 years, an LC rate of 92%, and at 5 years an LC rate of 68%, was achieved. Volumetric analysis was done using MRI Trigeminal nerve dysfunction examinations during follow-up. Only 1.3% (n= 3) of all Trigeminal nerve dysfunction was reported prior to therapy lesions showed a volumetric progression to such an extent in 21.6% (n= 41) of cases. After treatment, 85% (n= 155) that surgical treatment was required. Thus, 98.7% of the had no change, 4.4% (n= 8) of formerly affected patients patients needed no additional surgical intervention (Fig. 2). had a relief of symptoms, 10.4% (n= 19) had new onset of symptoms such as pain and dysesthesia (Table 4). Morbidity Acute side effects during or shortly after treatment (period of Facial nerve dysfunction 90 days) were rare. No Grade II or greater toxicity occurred. Facial nerve dysfunction was documented prior to treatment, Glucocorticoids had to be prescribed because of headache e.g. paresis 12.6% (n= 24) and dysgeusia (0.5%; n= 1). and nausea during and after treatment in 36 (18.6%) patients, After treatment, improvement was reported in 1.1% (n= 2), the majority (n= 28) of this subgroup had been in need for a 6.1% (n= 11) experienced new symptoms (Table 5) and short time of some weeks. 92.8% had no symptoms. Functional outcome Tinnitus Table 2. Functional outcome with respect to tinnitus before Tinnitus was documented in 59% of all patients (n= 112) and after treatment prior to treatment. Mild, moderate and severe symptoms Number of patients were reported in 25.3% (n= 48), 30.5% (n= 58) and 3.2% Prior to SRS 59% (n = 112) Impairment of symptoms after SRS 12.6% (n = 23) Relief of symptoms after SRS 14.4% (n = 26) Table 3. Functional outcome with respect to dizziness before and after treatment Number of patients Prior to SRS 42.1% (n= 119) Impairment of symptoms after SRS 14.3% (n= 26) Relief of symptoms after SRS 28.6% (n= 52) Table 4. Functional outcome with respect to trigeminal neuropathy before and after treatment Number of patients Prior to SRS 21.6% (n= 41) Impairment of symptoms after SRS 10.4% (n= 19) Relief of symptoms after SRS 4.4,% (n= 8) Fig. 2. Local control (LC) in months. Linac-based image-guided radiosurgery for vestibular schwannoma 291 functional problems, was done subjectively by the patient or Table 5. Functional outcome with respect to facial the physician and not objectively. The information gathered neuropathy before and after treatment on functionalities, e.g. hearing preservation, as a relevant par- Number of patients ameter for patient quality of life, was not based on objective Prior to SRS 12.6% (n= 24) auditory analyses. These factors are major drawbacks. Additionally, it is very important to note that the vast majority Impairment of symptoms after SRS 6.1% (n= 11) (ca. 40%) of patients experienced transient tumor expansion Relief of symptoms after SRS 1.1% (n= 2) during the first 4 years after SRS. Therefore, the LC rate shown in this study might be confounded by transient volu- metric change after SRS. The transient volumetric change can Table 6. Functional outcome with respect to hearing cause worsening of symptoms that usually resolves once difficulties before and after treatment tumors enter the shrinking phase. The vast majority of publications are based on Gamma Number of patients knife applications [9]. In order to critically evaluate our results Prior to SRS 69.5% (n= 132) with linac-based SRS techniques, we extracted those papers New onset of symptoms after SRS 26.9% (n= 49) reporting only linac-based SRS. Suh and colleagues reported Relief of symptoms after SRS 10.4% (n= 19) on 29 patients, 12 of whom underwent surgery before SRS. The median tumor volume reported was 2.1 cm , and LC was achieved in 28 of 29 patients. This finding translated into an Table 7. Outcome of image-guided linac-based SRS with actuarial 5-year LC rate of 94% [10]. Foote and colleagues respect to local control and functions reported on the results of SRS in 149 VS cases, of whom 28% Study n Dose in Gy Control rate (%) had had prior surgery and the mean tumor volume was 4.8 cm . A mean dose of 14 Gy (range, 10–22.5 Gy) was given to Suh 29 16 94 @ 5 year the 80% isodose. After a median follow-up of 34 months, LC Foote 149 14 87 @ 5 year was achieved in 93% of patients; the actuarial LC rate at five Spiegelmann 48 14 98 @ 3 year years was 87% (95% CI, 76–98) [11]. This data corresponds Okunaga 46 14 100 @ 5 year well with the present study, although our dose prescription was 13.5 Gy at the 80% isodose. Spiegelmann et al. published data Roos 65 13 95 @ 4 year on 48 cases, with a median tumor diameter of 20 mm. Lesions Combs 26 13 91 @ 5 year up to 16 mm in size received a maximum of 14 Gy encom- Rutten 26 12 95 @ 5 year passing the PTV; larger tumors were treated with a minimum Friedman 390 13 90 @ 5 year dose of 11 Gy. After a median follow-up of 32 months, LC was achieved in 98% of patients, which is comparable to the Hsu 75 15 92 @ 5 year results of surgical series [12]. Okunaga et al. published results Badakhshi 190 13.5 88 @ 3 year for 46 patients; 26.1% of the patients had had prior surgery 3 3 and a median tumor volume of 2.29 cm (0.4–7cm )was Hearing problems reported. The prescribed dose was 14 Gy. Median follow-up Hearing problems before SRS were present in 69.5% was 56.5 months. An LC of 73.8% was observed in all patients (n= 132). After treatment, 62.6% (n= 144) had no change, followed up for >1 year, and an LC of 100% was observed in 10.4% (n= 19) experienced improvement, and 26.9% (n= the 18 patients followed for > 5 years [13]. Roos et al. reported 49) developed impaired hearing (Table 6). on 65 patients with VS with a median diameter of 22 mm, treated with SRS of 13 Gy. The median follow-up period was DISCUSSION 48 months, and LC was observed in 95% of patients [14]. Combs published data on 26 patients treated with a dose of 13 Treatment options for VS include surgery and SRS. Watchful Gy. The actuarial LC rates at 5 and 10 years for all patients waiting is an accepted strategy. Surgery by expert surgeons were 91% in both cases [15]. Rutten et al.havereportedon has an LC rate greater than 95% [2]. SRS is achieving similar SRS for 26 patients with VS with a median size of 18 mm, a LC rates according to a recently published meta-analysis of dose of 12 Gy, and a median follow-up of 49 months. The 37 case series, comprising 3,677 patients. The overall LC rate 5-year LC rate reported was 95% [16]. The largest series to observed was 92.2% (95%, CI: 90.4–93.7%) [8]. date included 390 cases and reported an LC rate of 98% at The main limitation of this study was the retrospective ana- 2 years and 90% at 5 years [17]. lysis, although it was based on a prospective database. The above studies show clear evidence for the use of SRS Another major confounding factor in this analysis was the fact with a dose of 12–14 Gy resulting in 5- and 10-year LC rates that data acquisition, in terms of disease and treatment-related of ~ 90% [18]. 292 H. Badakhshi et al. Early and early-delayed toxicity can be defined as seque- 4. Murphy ES, Suh JH. Radiotherapy for vestibular schwanno- mas: a critical review. Int J Radiat Oncol Biol Phys lae and complications within weeks to months after SRS. 2011;79:985–9. These include headache, local erythema of the skin, alopecia 5. Compter I, Zaugg K, Houben RM et al. High symptom of in-field treatment areas, and fatigue. We experienced no improvement and local tumor control using stereotactic cases of severe acute toxicity among our patients. radiotherapy when given early after diagnosis of meningioma. Functional outcome with respect to nerve function is a diffi- A multicentre study. Strahlenther Onkol 2012;188:887–93. cult issue to judge clearly because of the range of reported data 6. Runge MJ, Maarouf M, Hunsche S et al. LINAC-radiosurgery that could be affected by different cofactors. Combs reported for nonsecreting pituitary adenomas. Long-term results. 2.5% new cases of tinnitus after SRS. Most cranial neuropa- Strahlenther Onkol 2012;188:319–25. thies following radiosurgery are mild, transient and commonly 7. Fuetsch M, El Majdoub F, Hoevels M et al. Stereotactic present as late-delayed complications. The mean latency of LINAC radiosurgery for the treatment of brainstem caverno- trigeminal and facial neuropathies after SRS for VS has mas. Strahlenther Onkol 2012;188:311–6. 8. Pannullo SC, Fraser JF, Moliterno J et al. Stereotactic radiosur- been noted to be ~ 7 months. Ito et al. report a similar latency gery: a meta-analysis of current therapeutic applications in of 4–5 months for the onset of cranial neuropathies [19]. neuro-oncologic disease. J Neurooncol 2011;103:1–17. Trigeminal and facial neuropathy has been reported in 8% 9. Lunsford LD, Niranjan A, Flickinger JC et al. Radiosurgery of and 5%, respectively, in Comb’s paper [15], and in 8–18% in vestibular schwannomas: summary of experience in 829 cases. Spiegelmann’s publication [12]. Our data seem to be in the J Neurosurg 2005;102 (Suppl):195–9. range of potential toxicity with respect to hearing (and there- 10. Suh JH, Barnett GH, Sohn JW et al. Results of linear accelerator- fore quality of life). However, for other symptoms, data from based stereotactic radiosurgery for recurrent and newly diagnosed a recent meta-analysis indicates a clear benefit of SRS [20] acoustic neuromas. Int J Cancer 2000;90:145–51. in comparison with surgery, which is in line with our results. 11. Foote KD, Friedman WA, Buatti JM et al. Analysis of risk factors associated with radiosurgery for vestibular schwan- noma. J Neurosurg 2001;95:440–9. CONCLUSION 12. Spiegelmann R, Lidar Z, Gofman J et al. Linear accelerator radiosurgery for vestibular schwannoma. J Neurosurg This study of a very large patient cohort treated with image- 2001;94:7–13. guided linac-based SRS yielded a high rate of LC, favorably 13. Okunaga T, Matsuo T, Hayashi N et al. Linear accelerator comparable with microsurgery. Individual counseling of radiosurgery for vestibular schwannoma: measuring tumor patients by an interdisciplinary team is desirable in order to volume changes on serial three-dimensional spoiled gradient- echo magnetic resonance images. J Neurosurg 2005;103:53–8. provide adequate information for decision-making about 14. Roos DE, Brophy BP, Bhat MK et al. Update of radio- treatment. Taking into account the above-mentioned con- surgery at the Royal Adelaide Hospital. Australas Radiol founding factors, the results of the present study provide 2006;50:158–67. valuable data on LC and functionality of cranial nerves for 15. Combs SE, Thilmann C, Debus J et al. Long-term outcome of VS treated with linac-based SRS. stereotactic radiosurgery (SRS) in patients with acoustic neur- omas. Int J Radiat Oncol Biol Phys 2006;64:1341–7. 16. Rutten I, Baumert BG, Seidel L et al. Long-term follow-up FUNDING reveals low toxicity of radiosurgery for vestibular schwan- noma. Radiother Oncol 2007;82:83–9. The authors all confirm that there has been no funding to 17. Friedman WA, Bradshaw P, Myers A et al. Linear accelerator support the research for this paper. radiosurgery for vestibular schwannomas. J Neurosurg 2006;105:657–61. 18. Hsu PW, Chang CN, Lee ST et al. Outcomes of 75 patients REFERENCES over 12 years treated for acoustic neuromas with linear 1. Sughrue ME, Yang I, Aranda D et al. The natural history of un- accelerator-based radiosurgery. J Clin Neurosci 2010;17:556–60. treated sporadic vestibular schwannomas: a comprehensive 19. Ito K, Shin M, Matsuzaki M et al. Risk factors for neurological review of hearing outcomes. J Neurosurg 2010;112:163–7. complications after acoustic neurinoma radiosurgery: refine- 2. Yamakami I, Uchino Y, Kobayashi E et al. Conservative man- ment from further experiences. Int J Radiat Oncol Biol Phys 2000;48:75–80. agement, gamma-knife radiosurgery, and microsurgery for 20. Wolbers JG, Dallenga AH, Mendez Romero A et al. What acoustic neurinomas: a systematic review of outcome and risk intervention is best practice for vestibular schwannomas? A of three therapeutic options. Neurol Res 2003;25:682–90. systematic review of controlled studies. BMJ Open 2013;3: 3. Leksell L. A note on the treatment of acoustic tumors. Acta e001345. Chir Scand 1971;137:763–5.

Journal

Journal of Radiation ResearchOxford University Press

Published: Mar 26, 2014

Keywords: vestibular schwannoma acoustic neurinoma stereotactic radiosurgery image-guided intervention local control

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