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Outcomes of 75 patients over 12 years treated for acoustic neuromas with linear accelerator-based radiosurgery
Journal of Clinical Neuroscience 17 (2010) 556–560
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Outcomes of 75 patients over 12 years treated for acoustic neuromas with linear accelerator-based radiosurgery Peng-Wei Hsu a,d, Cheng-Nen Chang a, Shih-Tseng Lee a, Yin-Cheng Huang a,d, Hsien-Chih Chen a, Chun-Chieh Wang b, Yung-Hsin Hsu a,b, Chen-Kan Tseng b, Yao-Liang Chen c, Kuo-Cheng Wei a,* a
Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University, 5 Fu-Hsing St., Kweishan, Taoyuan 333, Taiwan Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan Department of Radiology, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan d Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan b c
a r t i c l e
i n f o
Article history: Received 3 August 2009 Accepted 21 September 2009
Keywords: Acoustic neuroma CT Gamma knife Image fusion LINAC MRI Radiosurgery
a b s t r a c t The aim of this study was to investigate the efficacy of linear accelerator (LINAC)-based radiosurgery in the treatment of acoustic neuromas. In this retrospective study, we enrolled 75 patients with non-neurofibromatosis type 2 acoustic neuromas who were followed-up for more than 5 years. The 75 patients were divided into 3 groups: patients with a newly diagnosed tumor; those with a residual tumor; and those with a recurrent tumor. The average follow-up period was 97.8 months. The overall tumor progression-free rate was 92%, and corresponding rates among those with newly diagnosed tumors was 100%, residual tumors was 84.4%, and recurrent tumors was 92.8% (p = 0.028). Lesion localization using CT scans correlated with a higher tendency for tumor progression than lesion localization using CT–MRI fusion images (15.6% versus 2.4%, respectively). Residual tumors treated with radiosurgery have a higher progression rate, and careful lesion localization using CT–MRI image fusion is required. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Acoustic neuromas (AN), also known as vestibular schwannomas, arise from the neurilemmal sheath of the superior division of the vestibular nerve at the junction of the central and peripheral myelin. They are histologically benign, slow-growing tumors with an approximate annual incidence of 1 case per 100 000 persons.1,2 The extent of the clinical symptoms, particularly ipsilateral hearing loss, tinnitus and gait abnormalities, are closely correlated with tumor size. Traditionally, AN have been treated with microsurgical resection. The aim of the operation is total tumor resection and preservation of cranial nerve function. However, the resection procedure is associated with considerable morbidity and a high tumor recurrence rate. In previous studies, 45% of patients experienced a postoperative facial deficit. Other surgical complications observed in previous studies include cerebrospinal fluid fistula (9%), meningitis (3%), intracranial hemorrhage (2%), lower cranial neuropathy (2%), hemiparesis (1%), tetraparesis (0.2%), and death (1%).3–5 Stereotactic radiosurgery (SRS) is an alternative treatment method for AN. Lars Leksell first described the application of
* Corresponding author. Tel.: +886 3 328 1200x2412; fax: +886 3 328 5818. E-mail address: [email protected] (K.-C. Wei). 0967-5868/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2009.09.036
gamma-knife SRS for AN in 1971. Linear accelerator-based (LINAC) SRS was developed during the early to mid-1980s.6 Most AN treated with SRS need to be followed up over a long period to monitor tumor progression and SRS-induced complications. However, the long-term outcomes of SRS are discussed in very few reports, and gamma-knife radiosurgery is the treatment modality in most reported cases. The reported overall tumor progression-free rate after SRS is approximately 93%.7–10 Originally, CT scans were used in treatment planning for LINAC SRS. However, using this technique, tumor visualization was not sufficiently clear to plan appropriate treatment, particularly for residual lesions that remained after partial excision. Here, we present a retrospective study of the long-term outcomes of patients with AN treated with LINAC SRS at the Chang Gung Memorial Hospital. 2. Materials and methods Between 1994 and 2006, 75 patients with a unilateral AN were followed up for more than 5 years after they had been treated with LINAC-based SRS at the Chang Gung Memorial Hospital. Patients with neurofibromatosis type 2 AN were excluded from our study because poor treatment outcomes have been reported for these tumors.11,12 Patients with newly diagnosed intracanalicular lesions were also excluded from the present study because of the
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P.-W. Hsu et al. / Journal of Clinical Neuroscience 17 (2010) 556–560
slow-growing nature of these tumors. Our patients comprised 33 males and 42 females (Table 1), and their mean age at the time of treatment was 52.4 years (range: 21–77 years). In this retrospective study, patients were divided into three groups according to tumor status at the time of treatment with LINAC SRS. SRS was performed on 29 patients (38.6%) with newly diagnosed lesions, on 32 patients (42.7%) with residual tumors after a previous subtotal resection, and on 14 patients (18.7%) with recurrent tumors that developed after a previous near-total tumor excision and in whom regrowth was noted in follow-up imaging. None of these patients received external beam conventional radiotherapy. CT scans were used to localize the 32 lesions (42.7%) treated prior to 1999, and the radiation dose applied to these tumors was high (range: 12–20 Gy; median: 15 Gy). After an upgrade of the SRS software in 1999, CT–MRI fusion imaging was used to localize lesions; 43 tumors (57.3%) were localized in this way, and the radiation dose used for these tumors was lower (range: 12–16 Gy; median: 14 Gy; Table 2). CT scans were performed from the vertex of the skull to the frame (2- or 3-mm-thick slices without gaps). The patient’s head was immobilized using a Brown–Roberts–Wells frame. A localizer was used, and 50 mL contrast medium was administered before each scan. After the CT procedure, the data were transferred via our network to the SRS planning system. MRI for radiation treatment planning was performed using a 1.5-T scanner. The head was not fixed with a frame during the MRI scan. Data acquisition was performed using a standard head coil. Axial T1-weighted sequences from the foramen magnum to the vertex, with a slice thickness of 3 mm, were acquired after administration of contrast material (0.2 mL/kg bodyweight of gadolinium–diethylenetriaminepentaacetic acid). MRI scans were again transferred to the planning system via our network or via a data storage medium. The MRI scans were then co-registered with the CT scan images by manual CT–MRI fusion to facilitate the delineation of the treatment target.
Table 1 Clinical characteristics of 75 patients with acoustic neuroma Mean age (years) (range)
52.4 (21–77)
Sex Male Female
33 (44%) 42 (56%)
Lesion location Right Left
36 (48%) 39 (52%)
Tumor status Recurrent Residual Newly diagnosed
14 (18.7%) 32 (42.7%) 29 (38.6%)
Tumor localization images CT scans CT–MRI fusion images
32 (42.7%) 43 (57.3%)
The system for X-knife treatment was purchased from BrainLAB Inc. (Munich, Germany). It included a mounting system, which is required for docking of the Brown–Roberts–Wells head frame, and a circular collimator. We used BrainSCAN (v. 1-4; BrainLAB Inc.) planning software. Between 1994 and 1999, the Siemens KDS-2 linear accelerator (Siemens, Berlin, Germany) was used, to administer 10 MV X-rays. After 1999, the Varian 21Ex (Varian, Palo Alto, CA, USA) was used, to administer 6 MV X-rays. An 80% isodose line was employed to encompass the target volume. Local response was evaluated using clinical examinations and MRI. The first and the second follow-up images were obtained at 3 and 9 months after LINAC SRS, respectively. Thereafter, imaging was performed annually. A patient was defined as tumor progression-free when no change in the tumor volume (as calculated using the maximum diameter) was observed relative to the preceding image. SRS-related complications were defined as any neurological deficits that developed or became worse after LINAC SRS. Pre- and post-SRS audiography were performed to evaluate hearing function. The House–Brackmann scale was used to evaluate facial nerve function. For statistical analysis, Fisher’s exact test, Student’s t-test and the log-rank test were used to evaluate differences between groups in terms of tumor progression rate and SRS-related complication rate. 3. Results The overall average follow-up period after SRS was 97.8 months (range: 60–163 months). The radiation doses to the periphery of the tumor ranged from 12 Gy to 20 Gy (median: 14 Gy) and were prescribed to the 80% isodose line. The median tumor volume was 1.5 cm3 (range: 0.1–23.7 cm3). Tumor progression-free status was achieved for 69 of the 75 patients (92%). Partial tumor shrinkage was observed after LINAC SRS for 30 patients (40%). No change in tumor size was noted for 39 patients (52%). Tumor progression was observed for six patients (8%). Tumor recurrence was noted after an interval of 7–62 months after LINAC SRS. The 10-year local progression-free rate for all patients was 92% (Fig. 1). SRS-related complications were observed for nine of 75 patients (12%). All patients with newly diagnosed tumors at the time of enrolment achieved progression-free status. The size of the tumor decreased in 12 patients and remained constant in 17 patients. Among the 32 patients with a residual tumor, the median duration between subtotal tumor excision and SRS was 4 months (range: 2– 9 months). There was no tumor progression for 27 of the 32 patients (84.4%). The size of the tumor decreased for 13 patients and remained constant for 14 patients. Among the 14 patients with a recurrent tumor, progression-free status was achieved for 13 (92.8%). Tumor volume decreased for five patients and remained constant for eight patients (Table 3). The tumor progression-free rate was significantly lower in the residual tumor group than in the other two groups (p = 0.028; Fig. 2).
Table 2 Radiosurgery parameters for 75 patients with acoustic neuroma Tumor status
Number of patients Median tumor volume (cm3) Median dose (Gy) Median number of isocenters Median number of arcs Values are expressed as median (range).
Tumor localization images
Newly diagnosed
Residual
Recurrent
CT scans
CT–MRI fusion images
29 2.2 (0.14–23.7) 14 (12–20) 3 (1–6) 10 (5–24)
32 1.7 (0.16–13.5) 14 (12–16) 3 (1–7) 10 (5–33)
14 1.13 (0.1–6.9) 15.5 (12–22.5) 2 (1–4) 9 (2–18)
32 1.4 (0.1–23.7) 15 (12–22.5) 3 (1–7) 10 (2–24)
43 1.77 (0.14–13.5) 14 (12–16) 3 (1–7) 10 (5–33)
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P.-W. Hsu et al. / Journal of Clinical Neuroscience 17 (2010) 556–560
Fig. 1. Overall tumor progression-free rates among 75 patients with acoustic neuroma treated with linear accelerator (LINAC)-based stereotactic radiosurgery, as analyzed using the Kaplan–Meier method.
After 1999, we used CT–MRI fusion images to localize the lesions. Tumor progression was noted for five of the 32 patients (15.6%) who were treated before 1999 and for one of the 43 patients (2.4%) who were treated after 1999. The tumor progression rate was significantly higher among patients who were treated before 1999 than among those treated after 1999 (p = 0.04; Fig. 3). After LINAC SRS, nine patients (12%) developed new neurological deficits or experienced a worsening of their existing neurological deficits (Table 4). The incidences of complications were as follows: hearing deterioration: 12.5% (4/32 cases with intact hearing before SRS); gait disturbance due to brainstem involvement: 1.3% (1/75); and worsened or newly developed facial palsy: 8% (6/75). LINAC SRS did not cause trigeminal neuropathy in any patient. There were no significant differences in the complication rates among the newly diagnosed, residual and recurrent tumor groups (13.8%, 6.3%, and 21.4%, respectively; p = 0.30). However, a significant difference in the complication rate was observed between patients treated before and after 1999 (25% versus 2.3%, respectively; p = 0.0038; Table 5). 4. Discussion Although the treatment methods for AN include surgical excision, SRS, conventional radiation therapy, and clinical observation, surgical resection has long been the treatment of choice. The outcomes following surgery have improved owing to the use of preoperative diagnostic tools, intraoperative neuronal function monitoring, and improvements in surgical instruments, microsurgical techniques, and postoperative care. Although total tumor resection is associated with a low tumor recurrence rate, it does not result in zero morbidity or mortality, especially when the maximum diameter of the tumor is more than 4 cm.5,13–15 Larger
Fig. 2. Tumor progression-free rates among the newly diagnosed, residual and recurrent tumor groups of patients. All patients had acoustic neuroma treated with linear accelerator (LINAC)-based stereotactic radiosurgery. Analysis was performed using the Kaplan–Meier method. A significantly lower tumor progression-free rate was observed in the residual group (p = 0.028; log-rank test).
Fig. 3. Tumor progression-free rates among patients according to lesion localization method (CT scans only versus CT–MRI fusion images). All patients had acoustic neuroma treated with linear accelerator (LINAC)-based stereotactic radiosurgery. Analysis was performed using the Kaplan–Meier method. There was a significantly lower tumor progression-free rate for those tumors localized using CT scans only (p = 0.04; log-rank test).
tumors are also associated with a comparatively poor postoperative functional outcome and quality of life.3,4,16 SRS for AN was developed with the aim of achieving better treatment results, in particular, for lowering the complication rate. In recent studies, there have been no significant differences between SRS and microsurgery with regard to outcome variables including growth control rate, hearing preservation rate, and incidence of postoperative cranial nerve function impairment.4,17
Table 3 Tumor condition after SRS among 75 patients with acoustic neuroma Tumor status
Tumor localization images
Newly diagnosed
Residual
Recurrent
CT scans
CT–MRI fusion images
No. lesions
29
32
14
32
43
Lesion size Decreased Constant Increased
12 (41.4%) 17 (58.6%) 0 (0%)
13 (40.6%) 14 (43.8%) 5 (15.6%)
5 (35.7%) 8 (57.1%) 1 (7.2%)
11 (34.4%) 16 (50%) 5 (15.6%)
19 (44.2%) 23 (53.5%) 1 (2.3%)
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P.-W. Hsu et al. / Journal of Clinical Neuroscience 17 (2010) 556–560 Table 4 Treatment for the nine patients who experienced radiosurgery-related complications Patient No.
Tumor status
Treated before or after 1999
Tumor volume (cm3)
Dose (Gy)
Complications
1 2 3 4 5 6 7 8 9
Recurrent Recurrent Recurrent Newly diagnosed Newly diagnosed Newly diagnosed Newly diagnosed Residual Residual
Before Before Before Before Before Before Before Before After
1.4 0.1 0.18 9.4 0.4 5.7 3.5 5.55 12.42
18 17.5 16 20 16 16 18 18 16
Deterioration of hearing Facial palsy Facial palsy Gait disturbance, facial palsy Deterioration of hearing Deterioration of hearing, facial palsy Deterioration of hearing Facial palsy Facial palsy
Table 5 Comparison of the radiosurgery-related complication rates between the tumor status groups Tumor status
Newly diagnosed (n = 29) Residual (n = 32) Recurrent (n = 14) Total
Tumor localization images CT scans (n = 32)
CT–MRI fusion images (n = 43)
Total
4 1 3 8 (25%) p = 0.0038
0 1 0 1 (2.3%)
4 (13.8%) 2 (6.3%) 3 (21.4%)
p = 0.30à
Values are number of patients with complications after treatment of acoustic neuroma with stereotactic radiosurgery for each tumour group. There was no difference in the complication rate for newly diagnosed, residual or recurrent tumours (p = 0.03) but there was a difference for tumours treated pre-1999 with CT imaging only when compared to those treated with CT–MRI fusion after 1999 (p = 0.0038). Fisher’s exact test. à Student’s t-test.
Gamma-knife SRS is a safe, effective, less invasive, economical, and less time-consuming procedure, and has recently gained increasing prominence as a therapeutic technique to be used under certain conditions.6,18–22 In the present study, 75 patients with non-neurofibromatosis type 2 AN were treated with LINAC SRS. Partial tumor shrinkage was observed for 40% of the lesions. The overall tumor progression-free rate was 92%. The progression-free rate was similar to that among patients treated with gamma-knife SRS (88–98%; Supplementary Table 1).7–9 One patient had tumor recurrence as early as 7 months following LINAC SRS due to cyst enlargement. No surgical intervention was required, and the condition stabilized after steroid therapy. The size of the cyst did not increase. We used a log-rank test to assess the differences between tumor status groups in terms of treatment outcomes. The tumor recurrence rate was significantly higher in the group with residual tumors than in the other groups (p = 0.028). Further, four of the five patients with residual tumors that showed signs of recurrence belonged to the patient group treated before 1999. This result may indicate that the CT-based planning system was less effective in terms of lesion localization than the CT–MRI-based system. This might be due to an unclear margin between the tumor and surrounding normal tissue on CT scans due to postoperative tissue reaction. New or worsened neurological deficits following LINAC SRS were noted for 12% of patients (9/75). The deficits included seventh and eighth cranial nerve dysfunction and clinical brainstem dysfunction signs. We found that a higher radiation dose (p = 0.011), which was used before 1999, correlated with a higher complication rate (25% versus 2.3%; p = 0.0038). This result is consistent with a previously reported finding that patients who received a minimal tumor dose of less than 16 Gy were at a significantly lower risk of permanent facial neuropathy after radiosurgery.23,24 In our study, the patient who developed an SRS-induced complication after 1999 received a higher radiation dose of up to 16 Gy (Table 4). We believe that in our patient population the incidence of SRS-related side-effects decreased over time due to the decrease in the radiation dose and the advent of MRI planning software. At present, a peripheral dose of 12 Gy is used for routine treatment of
the lesions. Lower and potentially less effective doses are required for higher target volumes in order to avoid complications.23,25 Thus, fractionated SRS has been used as an alternative therapy for AN.26–29 4.1. Conclusions LINAC SRS is a safe and effective treatment for AN. It provides a satisfactory long-term tumor progression-free rate: 92% over 10 years. A lower marginal radiation dose was able to achieve tumor progression-free status as efficiently as a higher dose. In addition, the lower dose is associated with a lower complication rate. Stereotactic lesion localization using CT–MRI fusion imaging may provide more precise visualization of the tumor margins than CT scans alone, leading to improved treatment outcomes and reduced side-effects. Thus, image fusion is important, particularly for the treatment of residual lesions after subtotal surgical tumor resection. Acknowledgement This work was funded in part by a National Health Research Institute grant (NHRI-EX97-9507NI) to K.-C. Wei. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jocn.2009.09.036. References 1. Yoshimoto Y. Systematic review of the natural history of vestibular schwannoma. J Neurosurg 2005;103:59–63. 2. Lunsford LD, Niranjan A, Flickinger JC, et al. Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg 2005; 102(Suppl.):195–9. 3. Myrseth E, Moller P, Pedersen PH, et al. Vestibular schwannomas: clinical results and quality of life after microsurgery or gamma knife radiosurgery. Neurosurgery 2005;56:927–35.
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4. Regis J, Pellet W, Delsanti C, et al. Functional outcome after gamma knife surgery or microsurgery for vestibular schwannomas. J Neurosurg 2002;97:1091–100. 5. Samii M, Matthies C. Management of 1000 vestibular schwannomas (acoustic neuromas): surgical management and results with an emphasis on complications and how to avoid them. Neurosurgery 1997;40:11–21. 6. Spiegelmann R, Lidar Z, Gofman J, et al. Linear accelerator radiosurgery for vestibular schwannoma. J Neurosurg 2001;94:7–13. 7. Chung WY, Liu KD, Shiau CY, et al. Gamma knife surgery for vestibular schwannoma: 10-year experience of 195 cases. J Neurosurg 2005; 102(Suppl.):87–96. 8. Hasegawa T, Kida Y, Kobayashi T, et al. Long-term outcomes in patients with vestibular schwannomas treated using gamma knife surgery: 10-year follow up. J Neurosurg 2005;102:10–6. 9. Kondziolka D, Lunsford LD, McLaughlin MR, et al. Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med 1998;339:1426–33. 10. Hasegawa T, Fujitani S, Katsumata S, et al. Stereotactic radiosurgery for vestibular schwannomas: analysis of 317 patients followed more than 5 years. Neurosurgery 2005;57:257–65. 11. Subach BR, Kondziolka D, Lunsford LD, et al. Stereotactic radiosurgery in the management of acoustic neuromas associated with neurofibromatosis type 2. J Neurosurg 1999;90:815–22. 12. Kida Y, Kobayashi T, Tanaka T, et al. Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surg Neurol 2000;53:383–9. 13. Samii M, Matthies C. Management of 1000 vestibular schwannomas (acoustic neuromas): the facial nerve – preservation and restitution of function. Neurosurgery 1997;40:684–94. 14. Samii M, Matthies C. Management of 1000 vestibular schwannomas (acoustic neuromas): hearing function in 1000 tumor resections. Neurosurgery 1997; 40:248–60. 15. Gormley WB, Sekhar LN, Wright DC, et al. Acoustic neuromas: results of current surgical management. Neurosurgery 1997;41:50–8. 16. Martin HC, Sethi J, Lang D, et al. Patient-assessed outcomes after excision of acoustic neuroma: postoperative symptoms and quality of life. J Neurosurg 2001;94:211–6. 17. Flickinger JC, Kondziolka D, Lunsford LD. Dose and diameter relationships for facial, trigeminal, and acoustic neuropathies following acoustic neuroma radiosurgery. Radiother Oncol 1996;41:215–9.
18. Pollock BE, Lunsford LD, Kondziolka D, et al. Outcome analysis of acoustic neuroma management: a comparison of microsurgery and stereotactic radiosurgery. Neurosurgery 1995;36:215–24. 19. van Roijen L, Nijs HG, Avezaat CJ, et al. Costs and effects of microsurgery versus radiosurgery in treating acoustic neuroma. Acta Neurochir (Wien) 1997;139: 942–8. 20. Pollock BE, Lunsford LD, Flickinger JC, et al. Vestibular schwannoma management. Part I. Failed microsurgery and the role of delayed stereotactic radiosurgery. J Neurosurg 1998;89:944–8. 21. Friedman WA, Bradshaw P, Myers A, et al. Linear accelerator radiosurgery for vestibular schwannomas. J Neurosurg 2006;105:657–61. 22. Okunaga T, Matsuo T, Hayashi N, et al. Linear accelerator radiosurgery for vestibular schwannoma: measuring tumor volume changes on serial threedimensional spoiled gradient-echo magnetic resonance images. J Neurosurg 2005;103:53–8. 23. Miller RC, Foote RL, Coffey RJ, et al. Decrease in cranial nerve complications after radiosurgery for acoustic neuromas: a prospective study of dose and volume. Int J Radiat Oncol Biol Phys 1999;43:305–11. 24. Foote KD, Friedman WA, Buatti JM, et al. Analysis of risk factors associated with radiosurgery for vestibular schwannoma. J Neurosurg 2001;95:440–9. 25. Nagano H, Tanohata K, Kato E, et al. Dose distribution and shrinkage of acoustic neurinomas 2 years after gamma knife treatment. Stereotact Funct Neurosurg 1996;66(Suppl. 1):146–56. 26. Meijer OW, Wolbers JG, Baayen JC, et al. Fractionated stereotactic radiation therapy and single high-dose radiosurgery for acoustic neuroma: early results of a prospective clinical study. Int J Radiat Oncol Biol Phys 2000;46:45–9. 27. Varlotto JM, Shrieve DC, Alexander 3rd E, et al. Fractionated stereotactic radiotherapy for the treatment of acoustic neuromas: preliminary results. Int J Radiat Oncol Biol Phys 1996;36:141–5. 28. Sakamoto T, Shirato H, Sato N, et al. Audiological assessment before and after fractionated stereotactic irradiation for vestibular schwannoma. Radiother Oncol 1998;49:185–90. 29. Lederman G, Lowry J, Wertheim S, et al. Acoustic neuroma: potential benefits of fractionated stereotactic radiosurgery. Stereotact Funct Neurosurg 1997;69: 175–82.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Outcomes of 75 patients over 12 years treated for acoustic neuromas with linear accelerator-based radiosurgery Peng-Wei Hsu a,d, Cheng-Nen Chang a, Shih-Tseng Lee a, Yin-Cheng Huang a,d, Hsien-Chih Chen a, Chun-Chieh Wang b, Yung-Hsin Hsu a,b, Chen-Kan Tseng b, Yao-Liang Chen c, Kuo-Cheng Wei a,* a
Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University, 5 Fu-Hsing St., Kweishan, Taoyuan 333, Taiwan Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan Department of Radiology, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan d Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan b c
a r t i c l e
i n f o
Article history: Received 3 August 2009 Accepted 21 September 2009
Keywords: Acoustic neuroma CT Gamma knife Image fusion LINAC MRI Radiosurgery
a b s t r a c t The aim of this study was to investigate the efficacy of linear accelerator (LINAC)-based radiosurgery in the treatment of acoustic neuromas. In this retrospective study, we enrolled 75 patients with non-neurofibromatosis type 2 acoustic neuromas who were followed-up for more than 5 years. The 75 patients were divided into 3 groups: patients with a newly diagnosed tumor; those with a residual tumor; and those with a recurrent tumor. The average follow-up period was 97.8 months. The overall tumor progression-free rate was 92%, and corresponding rates among those with newly diagnosed tumors was 100%, residual tumors was 84.4%, and recurrent tumors was 92.8% (p = 0.028). Lesion localization using CT scans correlated with a higher tendency for tumor progression than lesion localization using CT–MRI fusion images (15.6% versus 2.4%, respectively). Residual tumors treated with radiosurgery have a higher progression rate, and careful lesion localization using CT–MRI image fusion is required. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Acoustic neuromas (AN), also known as vestibular schwannomas, arise from the neurilemmal sheath of the superior division of the vestibular nerve at the junction of the central and peripheral myelin. They are histologically benign, slow-growing tumors with an approximate annual incidence of 1 case per 100 000 persons.1,2 The extent of the clinical symptoms, particularly ipsilateral hearing loss, tinnitus and gait abnormalities, are closely correlated with tumor size. Traditionally, AN have been treated with microsurgical resection. The aim of the operation is total tumor resection and preservation of cranial nerve function. However, the resection procedure is associated with considerable morbidity and a high tumor recurrence rate. In previous studies, 45% of patients experienced a postoperative facial deficit. Other surgical complications observed in previous studies include cerebrospinal fluid fistula (9%), meningitis (3%), intracranial hemorrhage (2%), lower cranial neuropathy (2%), hemiparesis (1%), tetraparesis (0.2%), and death (1%).3–5 Stereotactic radiosurgery (SRS) is an alternative treatment method for AN. Lars Leksell first described the application of
* Corresponding author. Tel.: +886 3 328 1200x2412; fax: +886 3 328 5818. E-mail address: [email protected] (K.-C. Wei). 0967-5868/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2009.09.036
gamma-knife SRS for AN in 1971. Linear accelerator-based (LINAC) SRS was developed during the early to mid-1980s.6 Most AN treated with SRS need to be followed up over a long period to monitor tumor progression and SRS-induced complications. However, the long-term outcomes of SRS are discussed in very few reports, and gamma-knife radiosurgery is the treatment modality in most reported cases. The reported overall tumor progression-free rate after SRS is approximately 93%.7–10 Originally, CT scans were used in treatment planning for LINAC SRS. However, using this technique, tumor visualization was not sufficiently clear to plan appropriate treatment, particularly for residual lesions that remained after partial excision. Here, we present a retrospective study of the long-term outcomes of patients with AN treated with LINAC SRS at the Chang Gung Memorial Hospital. 2. Materials and methods Between 1994 and 2006, 75 patients with a unilateral AN were followed up for more than 5 years after they had been treated with LINAC-based SRS at the Chang Gung Memorial Hospital. Patients with neurofibromatosis type 2 AN were excluded from our study because poor treatment outcomes have been reported for these tumors.11,12 Patients with newly diagnosed intracanalicular lesions were also excluded from the present study because of the
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P.-W. Hsu et al. / Journal of Clinical Neuroscience 17 (2010) 556–560
slow-growing nature of these tumors. Our patients comprised 33 males and 42 females (Table 1), and their mean age at the time of treatment was 52.4 years (range: 21–77 years). In this retrospective study, patients were divided into three groups according to tumor status at the time of treatment with LINAC SRS. SRS was performed on 29 patients (38.6%) with newly diagnosed lesions, on 32 patients (42.7%) with residual tumors after a previous subtotal resection, and on 14 patients (18.7%) with recurrent tumors that developed after a previous near-total tumor excision and in whom regrowth was noted in follow-up imaging. None of these patients received external beam conventional radiotherapy. CT scans were used to localize the 32 lesions (42.7%) treated prior to 1999, and the radiation dose applied to these tumors was high (range: 12–20 Gy; median: 15 Gy). After an upgrade of the SRS software in 1999, CT–MRI fusion imaging was used to localize lesions; 43 tumors (57.3%) were localized in this way, and the radiation dose used for these tumors was lower (range: 12–16 Gy; median: 14 Gy; Table 2). CT scans were performed from the vertex of the skull to the frame (2- or 3-mm-thick slices without gaps). The patient’s head was immobilized using a Brown–Roberts–Wells frame. A localizer was used, and 50 mL contrast medium was administered before each scan. After the CT procedure, the data were transferred via our network to the SRS planning system. MRI for radiation treatment planning was performed using a 1.5-T scanner. The head was not fixed with a frame during the MRI scan. Data acquisition was performed using a standard head coil. Axial T1-weighted sequences from the foramen magnum to the vertex, with a slice thickness of 3 mm, were acquired after administration of contrast material (0.2 mL/kg bodyweight of gadolinium–diethylenetriaminepentaacetic acid). MRI scans were again transferred to the planning system via our network or via a data storage medium. The MRI scans were then co-registered with the CT scan images by manual CT–MRI fusion to facilitate the delineation of the treatment target.
Table 1 Clinical characteristics of 75 patients with acoustic neuroma Mean age (years) (range)
52.4 (21–77)
Sex Male Female
33 (44%) 42 (56%)
Lesion location Right Left
36 (48%) 39 (52%)
Tumor status Recurrent Residual Newly diagnosed
14 (18.7%) 32 (42.7%) 29 (38.6%)
Tumor localization images CT scans CT–MRI fusion images
32 (42.7%) 43 (57.3%)
The system for X-knife treatment was purchased from BrainLAB Inc. (Munich, Germany). It included a mounting system, which is required for docking of the Brown–Roberts–Wells head frame, and a circular collimator. We used BrainSCAN (v. 1-4; BrainLAB Inc.) planning software. Between 1994 and 1999, the Siemens KDS-2 linear accelerator (Siemens, Berlin, Germany) was used, to administer 10 MV X-rays. After 1999, the Varian 21Ex (Varian, Palo Alto, CA, USA) was used, to administer 6 MV X-rays. An 80% isodose line was employed to encompass the target volume. Local response was evaluated using clinical examinations and MRI. The first and the second follow-up images were obtained at 3 and 9 months after LINAC SRS, respectively. Thereafter, imaging was performed annually. A patient was defined as tumor progression-free when no change in the tumor volume (as calculated using the maximum diameter) was observed relative to the preceding image. SRS-related complications were defined as any neurological deficits that developed or became worse after LINAC SRS. Pre- and post-SRS audiography were performed to evaluate hearing function. The House–Brackmann scale was used to evaluate facial nerve function. For statistical analysis, Fisher’s exact test, Student’s t-test and the log-rank test were used to evaluate differences between groups in terms of tumor progression rate and SRS-related complication rate. 3. Results The overall average follow-up period after SRS was 97.8 months (range: 60–163 months). The radiation doses to the periphery of the tumor ranged from 12 Gy to 20 Gy (median: 14 Gy) and were prescribed to the 80% isodose line. The median tumor volume was 1.5 cm3 (range: 0.1–23.7 cm3). Tumor progression-free status was achieved for 69 of the 75 patients (92%). Partial tumor shrinkage was observed after LINAC SRS for 30 patients (40%). No change in tumor size was noted for 39 patients (52%). Tumor progression was observed for six patients (8%). Tumor recurrence was noted after an interval of 7–62 months after LINAC SRS. The 10-year local progression-free rate for all patients was 92% (Fig. 1). SRS-related complications were observed for nine of 75 patients (12%). All patients with newly diagnosed tumors at the time of enrolment achieved progression-free status. The size of the tumor decreased in 12 patients and remained constant in 17 patients. Among the 32 patients with a residual tumor, the median duration between subtotal tumor excision and SRS was 4 months (range: 2– 9 months). There was no tumor progression for 27 of the 32 patients (84.4%). The size of the tumor decreased for 13 patients and remained constant for 14 patients. Among the 14 patients with a recurrent tumor, progression-free status was achieved for 13 (92.8%). Tumor volume decreased for five patients and remained constant for eight patients (Table 3). The tumor progression-free rate was significantly lower in the residual tumor group than in the other two groups (p = 0.028; Fig. 2).
Table 2 Radiosurgery parameters for 75 patients with acoustic neuroma Tumor status
Number of patients Median tumor volume (cm3) Median dose (Gy) Median number of isocenters Median number of arcs Values are expressed as median (range).
Tumor localization images
Newly diagnosed
Residual
Recurrent
CT scans
CT–MRI fusion images
29 2.2 (0.14–23.7) 14 (12–20) 3 (1–6) 10 (5–24)
32 1.7 (0.16–13.5) 14 (12–16) 3 (1–7) 10 (5–33)
14 1.13 (0.1–6.9) 15.5 (12–22.5) 2 (1–4) 9 (2–18)
32 1.4 (0.1–23.7) 15 (12–22.5) 3 (1–7) 10 (2–24)
43 1.77 (0.14–13.5) 14 (12–16) 3 (1–7) 10 (5–33)
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Fig. 1. Overall tumor progression-free rates among 75 patients with acoustic neuroma treated with linear accelerator (LINAC)-based stereotactic radiosurgery, as analyzed using the Kaplan–Meier method.
After 1999, we used CT–MRI fusion images to localize the lesions. Tumor progression was noted for five of the 32 patients (15.6%) who were treated before 1999 and for one of the 43 patients (2.4%) who were treated after 1999. The tumor progression rate was significantly higher among patients who were treated before 1999 than among those treated after 1999 (p = 0.04; Fig. 3). After LINAC SRS, nine patients (12%) developed new neurological deficits or experienced a worsening of their existing neurological deficits (Table 4). The incidences of complications were as follows: hearing deterioration: 12.5% (4/32 cases with intact hearing before SRS); gait disturbance due to brainstem involvement: 1.3% (1/75); and worsened or newly developed facial palsy: 8% (6/75). LINAC SRS did not cause trigeminal neuropathy in any patient. There were no significant differences in the complication rates among the newly diagnosed, residual and recurrent tumor groups (13.8%, 6.3%, and 21.4%, respectively; p = 0.30). However, a significant difference in the complication rate was observed between patients treated before and after 1999 (25% versus 2.3%, respectively; p = 0.0038; Table 5). 4. Discussion Although the treatment methods for AN include surgical excision, SRS, conventional radiation therapy, and clinical observation, surgical resection has long been the treatment of choice. The outcomes following surgery have improved owing to the use of preoperative diagnostic tools, intraoperative neuronal function monitoring, and improvements in surgical instruments, microsurgical techniques, and postoperative care. Although total tumor resection is associated with a low tumor recurrence rate, it does not result in zero morbidity or mortality, especially when the maximum diameter of the tumor is more than 4 cm.5,13–15 Larger
Fig. 2. Tumor progression-free rates among the newly diagnosed, residual and recurrent tumor groups of patients. All patients had acoustic neuroma treated with linear accelerator (LINAC)-based stereotactic radiosurgery. Analysis was performed using the Kaplan–Meier method. A significantly lower tumor progression-free rate was observed in the residual group (p = 0.028; log-rank test).
Fig. 3. Tumor progression-free rates among patients according to lesion localization method (CT scans only versus CT–MRI fusion images). All patients had acoustic neuroma treated with linear accelerator (LINAC)-based stereotactic radiosurgery. Analysis was performed using the Kaplan–Meier method. There was a significantly lower tumor progression-free rate for those tumors localized using CT scans only (p = 0.04; log-rank test).
tumors are also associated with a comparatively poor postoperative functional outcome and quality of life.3,4,16 SRS for AN was developed with the aim of achieving better treatment results, in particular, for lowering the complication rate. In recent studies, there have been no significant differences between SRS and microsurgery with regard to outcome variables including growth control rate, hearing preservation rate, and incidence of postoperative cranial nerve function impairment.4,17
Table 3 Tumor condition after SRS among 75 patients with acoustic neuroma Tumor status
Tumor localization images
Newly diagnosed
Residual
Recurrent
CT scans
CT–MRI fusion images
No. lesions
29
32
14
32
43
Lesion size Decreased Constant Increased
12 (41.4%) 17 (58.6%) 0 (0%)
13 (40.6%) 14 (43.8%) 5 (15.6%)
5 (35.7%) 8 (57.1%) 1 (7.2%)
11 (34.4%) 16 (50%) 5 (15.6%)
19 (44.2%) 23 (53.5%) 1 (2.3%)
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P.-W. Hsu et al. / Journal of Clinical Neuroscience 17 (2010) 556–560 Table 4 Treatment for the nine patients who experienced radiosurgery-related complications Patient No.
Tumor status
Treated before or after 1999
Tumor volume (cm3)
Dose (Gy)
Complications
1 2 3 4 5 6 7 8 9
Recurrent Recurrent Recurrent Newly diagnosed Newly diagnosed Newly diagnosed Newly diagnosed Residual Residual
Before Before Before Before Before Before Before Before After
1.4 0.1 0.18 9.4 0.4 5.7 3.5 5.55 12.42
18 17.5 16 20 16 16 18 18 16
Deterioration of hearing Facial palsy Facial palsy Gait disturbance, facial palsy Deterioration of hearing Deterioration of hearing, facial palsy Deterioration of hearing Facial palsy Facial palsy
Table 5 Comparison of the radiosurgery-related complication rates between the tumor status groups Tumor status
Newly diagnosed (n = 29) Residual (n = 32) Recurrent (n = 14) Total
Tumor localization images CT scans (n = 32)
CT–MRI fusion images (n = 43)
Total
4 1 3 8 (25%) p = 0.0038
0 1 0 1 (2.3%)
4 (13.8%) 2 (6.3%) 3 (21.4%)
p = 0.30à
Values are number of patients with complications after treatment of acoustic neuroma with stereotactic radiosurgery for each tumour group. There was no difference in the complication rate for newly diagnosed, residual or recurrent tumours (p = 0.03) but there was a difference for tumours treated pre-1999 with CT imaging only when compared to those treated with CT–MRI fusion after 1999 (p = 0.0038). Fisher’s exact test. à Student’s t-test.
Gamma-knife SRS is a safe, effective, less invasive, economical, and less time-consuming procedure, and has recently gained increasing prominence as a therapeutic technique to be used under certain conditions.6,18–22 In the present study, 75 patients with non-neurofibromatosis type 2 AN were treated with LINAC SRS. Partial tumor shrinkage was observed for 40% of the lesions. The overall tumor progression-free rate was 92%. The progression-free rate was similar to that among patients treated with gamma-knife SRS (88–98%; Supplementary Table 1).7–9 One patient had tumor recurrence as early as 7 months following LINAC SRS due to cyst enlargement. No surgical intervention was required, and the condition stabilized after steroid therapy. The size of the cyst did not increase. We used a log-rank test to assess the differences between tumor status groups in terms of treatment outcomes. The tumor recurrence rate was significantly higher in the group with residual tumors than in the other groups (p = 0.028). Further, four of the five patients with residual tumors that showed signs of recurrence belonged to the patient group treated before 1999. This result may indicate that the CT-based planning system was less effective in terms of lesion localization than the CT–MRI-based system. This might be due to an unclear margin between the tumor and surrounding normal tissue on CT scans due to postoperative tissue reaction. New or worsened neurological deficits following LINAC SRS were noted for 12% of patients (9/75). The deficits included seventh and eighth cranial nerve dysfunction and clinical brainstem dysfunction signs. We found that a higher radiation dose (p = 0.011), which was used before 1999, correlated with a higher complication rate (25% versus 2.3%; p = 0.0038). This result is consistent with a previously reported finding that patients who received a minimal tumor dose of less than 16 Gy were at a significantly lower risk of permanent facial neuropathy after radiosurgery.23,24 In our study, the patient who developed an SRS-induced complication after 1999 received a higher radiation dose of up to 16 Gy (Table 4). We believe that in our patient population the incidence of SRS-related side-effects decreased over time due to the decrease in the radiation dose and the advent of MRI planning software. At present, a peripheral dose of 12 Gy is used for routine treatment of
the lesions. Lower and potentially less effective doses are required for higher target volumes in order to avoid complications.23,25 Thus, fractionated SRS has been used as an alternative therapy for AN.26–29 4.1. Conclusions LINAC SRS is a safe and effective treatment for AN. It provides a satisfactory long-term tumor progression-free rate: 92% over 10 years. A lower marginal radiation dose was able to achieve tumor progression-free status as efficiently as a higher dose. In addition, the lower dose is associated with a lower complication rate. Stereotactic lesion localization using CT–MRI fusion imaging may provide more precise visualization of the tumor margins than CT scans alone, leading to improved treatment outcomes and reduced side-effects. Thus, image fusion is important, particularly for the treatment of residual lesions after subtotal surgical tumor resection. Acknowledgement This work was funded in part by a National Health Research Institute grant (NHRI-EX97-9507NI) to K.-C. Wei. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jocn.2009.09.036. References 1. Yoshimoto Y. Systematic review of the natural history of vestibular schwannoma. J Neurosurg 2005;103:59–63. 2. Lunsford LD, Niranjan A, Flickinger JC, et al. Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg 2005; 102(Suppl.):195–9. 3. Myrseth E, Moller P, Pedersen PH, et al. Vestibular schwannomas: clinical results and quality of life after microsurgery or gamma knife radiosurgery. Neurosurgery 2005;56:927–35.
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