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Hearing preservation after stereotactic radiosurgery for vestibular schwannoma: A systematic review
Journal of Clinical Neuroscience 16 (2009) 742–747
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Review
Hearing preservation after stereotactic radiosurgery for vestibular schwannoma: A systematic review Isaac Yang a, Derrick Aranda a, Seunggu J. Han a, Sravana Chennupati a, Michael E. Sughrue a, Steven W. Cheung b, Lawrence H. Pitts a,b, Andrew T. Parsa a,b,* a b
Department of Neurological Surgery, University of California at San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA Department of Otolaryngology, Head and Neck Surgery, University of California at San Francisco, San Francisco, California, USA
a r t i c l e
i n f o
Article history: Received 9 August 2008 Accepted 18 September 2008
Keywords: Radiosurgery Vestibular schwannoma Hearing preservation Stereotactic radiosurgery Gamma knife Linac Proton beam
a b s t r a c t Radiosurgery has evolved into an effective alternative to microsurgical resection in the treatment of patients with vestibular schwannoma. We performed a systematic analysis of the literature in English on the radiosurgical treatment of vestibular schwannoma patients. A total of 254 published studies reported assessable and quantifiable outcome data of patients undergoing radiosurgery for vestibular schwannomas. American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) class A or B and Gardner-Robertson (GR) classification I or II were defined as having preserved hearing. A total of 5825 patients (74 articles) met our inclusion criteria. Practitioners who delivered an average dose of 612.5 Gy as the marginal dose reported having a higher hearing preservation rate (612.5 Gy = 59% vs. >12.5 Gy = 53%, p = 0.0285). Age of the patient was not a significant prognostic factor for hearing preservation rates (<65 years = 58% vs. >65 years = 62%; p = 0.4317). The average overall follow-up was 41.2 months. Our data suggest that an overall hearing preservation rate of about 57% can be expected after radiosurgical treatment, and patients treated with 612.5 Gy were more likely to have preserved hearing. Ó 2009 Published by Elsevier Ltd.
1. Introduction Since the first reported case of a vestibular schwannoma (VS) patient treated with radiosurgery, stereotactic radiosurgery has established itself as a viable alternative to microsurgical resection for these tumors.1–30 In most cases radiosurgery does not require inpatient hospitalization and requires virtually no convalescence following treatment; however, short-term and long-term risks do exist with radiosurgery treatment.31,32 In particular, stereotactic radiosurgery for the treatment of VS introduces radiation toxicity risks to adjacent neurologic structures and result in a functional threat to the facial nerve, hearing and balance.14,16,17,23,27,30,33–41 Hydrocephalus and other cranial neuropathies such as facial spasm have also been noted after radiosurgery for VS.4,5,23,37,42–47 Surgical shunting and cerebrospinal fluid diversion may be required to address the late hydrocephalus complication.4,5,23,47,48 Despite the availability of published data that highlights the clinical, radiographic, and biological parameters when managing VS patients with radiosurgery, predicting hearing preservation after radiosurgery remains a challenge for practitioners.14,36,40,49–52 This difficulty may result from most studies having been small to modest in size, frequently from a single institution, and lacking statistical power and freedom from potential practitioner bias to draw
* Corresponding author. Tel.: +1 415 353 2629. E-mail address: [email protected] (A.T. Parsa). 0967-5868/$ - see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.jocn.2008.09.023
firm conclusions. In our review we found impressive variations in reported hearing preservation outcomes for VS patients treated with radiosurgery. Because of the numerous variables associated with assessing hearing preservation after radiosurgery in the literature, the hearing preservation rate after radiosurgery is not well defined.37,53,54 The reported rates of hearing preservation vary between 11% and 77%, with most recent reports between 50% and 70% range.4,11,18,28–30,35,39,44,46,53–64 Clearly, the reported outcomes do not provide the clinician with a consensus estimate of expected hearing preservation outcomes when counseling patients. The factors implicated in affecting post-radiation hearing preservation after radiosurgery are the dose of radiation delivered, tumor volume and patient age. We performed an extensive review of the English literature to analyze the results of patients with VS treated with radiosurgery. Using an aggregated database of patients from our systematic analysis, we investigated specific variables that may influence hearing preservation rates after radiosurgery for VS. 2. Methodology 2.1. Article selection Articles were identified via Boolean PubMed searches using the key words ‘‘radiosurgery”, ‘‘acoustic neuroma,” ‘‘hearing,” ‘‘vestibular schwannoma,” and ‘‘hearing preservation,” alone and
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in combination. This query identified 254 papers from which all quantifiable and assessable data regarding patients treated with radiosurgery were analyzed for satisfying our inclusion criteria. The inclusion criteria for articles were that: (i) hearing preservation rates were reported specifically for VS; (ii) hearing status was reported using the American Association of Otolaryngology – Head and Neck Surgery (AAO–HNS) or the Gardner–Robertson (GR) classification; (iii) tumor growth rate was monitored by serial MRIs; and (iv) initial tumor size was documented. Papers up to and before the current year were included in this analysis. In all papers ‘‘tumor size” was defined as the largest measurable diameter of the tumor. Stereotactic radiosurgery was defined as the precise application of radiation to a defined target in a limited number of sessions less than or equal to five, which was clarified by the American Association of Neurological Surgeons, Congress of Neurological Surgeons, and the American Society for Therapeutic Radiology and Oncology.65
the data based on their tumor volume with a cut-off of 1.5 cm3. The final cluster analysis divided the data based on patient age, with a cut-off of 65 years. 2.3. Statistical analysis We compared between-group rates of hearing preservation using the Fisher exact test and unpaired t-tests when appropriate. We compared initial tumor size between hearing preserved and non-preserved patients using the Wilcoxon rank-sum test. Correlation analyses between length of follow-up, rates of hearing preservation, and rate of growth were performed using the Pearson’s correlation test. For all tests, the p value was considered significant at p < 0.05. Unless otherwise stated, all continuous values presented were mean ± standard deviation (SD). 3. Results
2.2. Data extraction
3.1. Systematic analysis
Data from individual and aggregated cases were extracted from each paper. Only patients who had AAO–HNS class A or B or patients who had GR I or II at their last follow-up visit were defined as having their hearing preserved in our analysis. For those articles that quoted an overall hearing preservation rate for their series only, without giving further specific patient data, the rates were used as described. Patients who had lost hearing prior to radiosurgery (AAO–HNS class C, D or GR class III, IV, or V) were excluded. All VS patients treated with recent microsurgery were also excluded. We contacted the authors to accumulate non-aggregated data when necessary. When multiple articles by the same center from different time frames reported patients, each center’s patients and experience were counted once. In order to limit redundancy, duplicate patients and cases when ascertained were not added to our analysis. Data were analyzed as a whole and stratified into three cohorts. The first comprehensive analysis divided the data according to the average marginal dose of radiation delivered (i.e. whether the dose was 612.5 Gy or >12.5 Gy). The second cohort analysis segregated
A total of 74 articles, involving 5,825 patients, met the criteria of the established protocol and were evaluated (Supplementary Table 1),2,4,5,10,17,19,26,29,35,41,43–46,53,56–58,60,62–64,66–93 and the overall rate of hearing preservation in these studies was 57% (Table 1).1,11–13,28,39,47,55,62,63,94–112 The age range of patients treated with radiosurgery varied from 20 years to 73.5 years, with an average of 53.6 years (±10.7 years) and an average follow-up time of 41.2 months (±27.1 months). Similarly, the median length of follow-up in our analysis was 34.3 months. The average radiation dose used to treat patients was 16.0 Gy. 3.2. The effect of dosage on hearing preservation A total of 401 patients were cited receiving an average marginal dose of 612.5 Gy whereas 1241 patients received an average marginal dose of >12.5 Gy. The group receiving the lower doses of radiosurgery had superior hearing preservation rates (59% vs. 53%, p = 0.0285 [Fig. 1]), which suggests that hearing preservation is significantly affected by radiation dose. Patients receiving the
Table 1 Data summary of articles evaluated for the systematic review of hearing preservation after stereotactic radiosurgery for vestibular schwannoma. Total no. of articles
Total no. patients
Total no. patients with intact hearing
Average patient age (years)
Average marginal dose (Gy)
Average tumor volume (cm3)
Mean tumor control rate (%)
Average follow-up (months)
Overall hearing preservation rate (%)
74
5825
2083
53.6
16.0
4.05
94
41.2
57
Fig. 1. Hearing preservation analyzed by average marginal radiation dose of radiosurgery (612.5 Gy vs. >12.5 Gy) (p value indicated) showing improved hearing preservation in the low radiation dose group.
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Fig. 2. Hearing preservation analyzed by tumor volume (61.5 cm3 vs. >1.5 cm3) (p value indicated) showing similar hearing outcomes in small and large tumors.
Fig. 3. Hearing preservation analyzed as a function of age with an age cut-off of older or younger than 65 years (p value indicated) showing similar hearing preservation in both older and younger patients.
lower radiation dose still had excellent tumor control rates (average 94% ± 3%). An analysis of the follow-up times in regards to hearing preservation using a Pearson correlation calculation found that hearing preservation rates did not vary with follow-up time (r = 0.09, p = 0.451).
the older population (tumor volume 3.65 cm3 ± 2.7 cm3 vs. 6.57 cm3 ± 7.5 cm3, p < 0.0001) despite the similar hearing preservation rates.
3.3. The effect of tumor volume on hearing preservation
Hearing preservation continues to be an important concern of patients undergoing radiosurgery for VS. Few investigators have combined the published research to achieve the statistical power needed to accurately characterize hearing preservation outcome in radiosurgery treatment for VS. We performed an aggregated systematic analysis of hearing preservation in a large population of patients who have undergone radiation treatment for VS. Our analysis revealed that patients treated with an average marginal dose of 12.5 Gy or less were more likely to preserve their hearing after radiosurgery compared to those patients who received higher doses of radiation. This was true irrespective of tumor size in our analysis, so patients who had larger tumors treated with lower doses of radiation had improved hearing preservation. Higher doses of radiation are associated with higher rates of cranial nerve toxicity.61,89,112,113 Low dose radiosurgery has a favorable efficacy to toxicity ratio as compared to higher doses,4,5,23,40,44,72,78,79 and doses of 12.5 Gy or less carry a lower risk for cranial neuropathy.40 Earlier radiosurgery treatments used higher rates of radiation, but more modern treatments have used lower dose radiosurgery with similar rates of tumor control. Our systematic analysis confirms the safety of utilizing a lower radiation dose of 12.5 Gy with good tumor control (average 94% ± 3%) at an average follow-up of 41.2 months (median 34.3 months). In our comprehensive analysis, radiosurgery treatment of patients with an average tumor volume of 1.5 cm3 or less had similar
A total of 140 patients in our analysis had an average tumor volume of 1.5 cm3 or less, and 738 patients had an average tumor volume of >1.5 cm3. Patients with smaller tumors had similar hearing preservation rates (64% vs. 69%, p = 0.3228 [Fig. 2]). This statistically non-significant difference suggests that tumor volume may not be a critical clinical prognostic factor for hearing preservation in all patients undergoing radiosurgery for VS. Patients with the smaller tumors received a higher average radiation dosage of 17.8 Gy (±6.6 Gy) and had worse hearing preservation, whereas patients with larger tumors received a lower average radiation of 15.0 Gy (±4.9 Gy) and had improved hearing preservation (p < 0.0001). 3.4. The effect of age on hearing preservation A total of 1681 patients were reported with an average age of younger than 65 years, and 85 patients were reported with an average age of 65 years or older at the time of radiosurgery. Younger patients (<65 years) had similar hearing preservation as patients who were older than 65 years of age (58% vs. 62%, p = 0.4317 [Fig. 3]). This difference was not statistically significant, which suggested that age may not be an important prognostic factor for hearing preservation. Tumor size was on average significantly larger in
4. Discussion
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hearing preservation rates compared to studies with tumors of larger volumes (64% vs. 69%, p = 0.3228 [Fig. 2]). These data suggest that tumor size is not an important risk factor for hearing preservation with radiosurgery treatment. Patients with smaller tumors received a higher average radiation dosage of 17.8 Gy (±6.6 Gy) than those with larger tumors who received a lower average radiation of 15.0 Gy (±4.9 Gy), and had inferior hearing preservation with the higher radiation (p < 0.0001). This suggests that tumor size may not be an important prognostic factor for hearing preservation after radiosurgical treatment for VS, but that radiation dose may be a more critical prognostic factor for hearing preservation. Although the mechanism for this is unclear, larger tumors may have less cochlear involvement with radiosurgical treatment and may allow radiosurgical planning with less and lower radiation exposure to the cochlear nerve, leading to improved hearing outcomes in patients with larger VS. Furthermore, larger tumors may allow for less radiation dose to the cochlear nerve by having a greater displacement of the nerve. This may explain why larger tumors had improved hearing preservation with lower radiation doses. Lastly, lower radiation doses to larger tumors decreases the radiation susceptibility of adjacent nerves, which improves the likelihood of hearing preservation after radiosurgery. Older patients typically have higher rates of co-morbid conditions which may preclude them from open surgery. Despite these co-morbidities, patients older than 65 years had similar hearing preservation rates as younger patients. Age was not an important prognostic factor for hearing preservation in our analysis. Furthermore, older patients were more likely to have a significantly larger average tumor size treated with radiosurgery (tumor volume 3.65 cm3 ± 2.7 cm3 vs. 6.57 cm3 ± 7.5 cm3, p < 0.0001). This statistically significant difference suggests that older patients with large VS can be treated with radiosurgery with similar rates of hearing preservation despite older age and larger VS. Advanced age and larger tumor size does not appear to be a critical prognostic factor in hearing preservation outcomes in patients treated with radiosurgery for VS. The variability of data presentation reported in the papers precluded us from further analysis in stratifying the data to determine if statistically significant cut-off points existed. These reported studies typically represent the experience at academic centers that may have a more uniform standard of care for radiosurgical treatment. Community medical centers may have radiosurgical treatment standards that vary even further than the data reported by most academic centers. Hence, determining the significant prognostic factors is critical for determining an improved and uniform standard of care that will improve patient outcomes. Although actuarial time-dependant data would be ideal, this was not possible with a retrospective systematic analysis as performed, and is an inherent limitation in our study. Hearing preservation in this retrospective study could be assessed only through last follow-up, which had an average of 41.2 months and a median of 34.3 months. Furthermore, use of a Pearson correlation analysis found that hearing preservation rates did not vary with follow-up time (r = 0.09, p = 0.451). Future prospective studies should provide further insight into the relationship between these prognostic variables and hearing preservation, perhaps with fewer patients or lower statistical power than the present study. This aggregated systematic analysis is the first reported investigation of the available English literature to evaluate the overall impact of radiosurgery for VS on hearing preservation. We report our results from a large aggregated systematic analysis of hearing outcomes in patients with VS treated with radiosurgery. Utilizing this large data set from the available published literature minimizes the effect of bias from individual institutions
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in determining accurate and overall hearing preservation prognostic characteristics for these patients. Our analysis suggests that radiation dose is the most important prognostic factor for hearing preservation irrespective of tumor size or age in VS patients treated with radiosurgery. Our data reveal that patients treated with 612.5 Gy have improved hearing outcomes and that patients with larger tumor sizes also have improved hearing preservation when treated with lower radiation doses. Although older patients are more likely to have larger tumors treated with radiosurgery, older patients had similar hearing preservation outcomes as younger patients. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jocn.2008.09.023. References 1. Delbrouck C, Hassid S, Massager N, et al. Preservation of hearing in vestibular schwannomas treated by radiosurgery using Leksell Gamma Knife: preliminary report of a prospective Belgian clinical study. Acta Otorhinolaryngol Belg 2003;57:197–204. 2. Karpinos M, Teh BS, Zeck O, et al. Treatment of acoustic neuroma: stereotactic radiosurgery vs. microsurgery. Int J Radiat Oncol Biol Phys 2002;54:1410–21. 3. Kaylie DM, McMenomey SO. Microsurgery vs gamma knife radiosurgery for the treatment of vestibular schwannomas. Arch Otolaryngol Head Neck Surg 2003;129:903–6. 4. Kondziolka D, Lunsford LD, McLaughlin MR, et al. Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med 1998;339:1426–33. 5. Kondziolka D, Subach BR, Lunsford LD, et al. Outcomes after gamma knife radiosurgery in solitary acoustic tumors and neurofibromatosis Type 2. Neurosurg Focus 1998;5:e2. 6. Noren G. Long-term complications following gamma knife radiosurgery of vestibular schwannomas. Stereotact Funct Neurosurg 1998;70:65–73. 7. Pellet W, Regis J, Roche PH, et al. Relative indications for radiosurgery and microsurgery for acoustic schwannoma. Adv Tech Stand Neurosurg 2003;28:227–82; discussion 282–4. 8. Pogodzinski MS, Harner SG, Link MJ. Patient choice in treatment of vestibular schwannoma. Otolaryngol Head Neck Surg 2004;130:611–6. 9. Regis J, Delsanti C, Roche P, et al. Preservation of hearing function in the radiosurgical treatment of unilateral vestibular schwannomas. Preliminary results. Neurochirurgie 2002;48:471–8. 10. 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. 11. Unger F, Walch C, Papaefthymiou G, et al. Radiosurgery of residual and recurrent vestibular schwannomas. Acta Neurochir (Wien) 2002;144:671–6; discussion 676–7. 12. Unger F, Walch C, Schrottner O, et al. Cranial nerve preservation after radiosurgery of vestibular schwannomas. Acta Neurochir Suppl 2002;84: 77–83. 13. Unger F, Walch C, Haselsberger K, et al. Radiosurgery of vestibular schwannomas: a minimally invasive alternative to microsurgery. Acta Neurochir (Wien) 1999;141:1281–5; discussion 1285–6. 14. Friedman WA, Foote KD. Linear accelerator-based radiosurgery for vestibular schwannoma. Neurosurg Focus 2003;14:e2. 15. Shoshan Y, Wygoda M, Umansky F. Stereotactic radiosurgery and fractionated stereotactic radiotherapy: background, definitions, applications. Isr Med Assoc J 2005;7:597–9. 16. Battista RA, Wiet RJ. Stereotactic radiosurgery for acoustic neuromas: a survey of the American Neurotology Society. Am J Otol 2000;21:371–81. 17. 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; discussion 224–9. 18. Sekhar LN, Gormley WB, Wright DC. The best treatment for vestibular schwannoma (acoustic neuroma): microsurgery or radiosurgery? Am J Otol 1996;17:676–82; discussion 683–9. 19. Kamerer DB, Lunsford LD, Moller M. Gamma knife: an alternative treatment for acoustic neurinomas. Ann Otol Rhinol Laryngol 1988;97:631–5. 20. Lunsford LD, Kamerer DB, Flickinger JC. Stereotactic radiosurgery for acoustic neuromas. Arch Otolaryngol Head Neck Surg 1990;116:907–9. 21. Wiet RJ, Micco AG, Bauer GP. Complications of the gamma knife. Arch Otolaryngol Head Neck Surg 1996;122:414–6. 22. Ramsay HA, Luxford WM. Treatment of acoustic tumours in elderly patients: is surgery warranted? J Laryngol Otol 1993;107:295–7. 23. Mendenhall WM, Friedman WA, Buatti JM, et al. Preliminary results of linear accelerator radiosurgery for acoustic schwannomas. J Neurosurg 1996;85: 1013–9.
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Proton beam stereotactic radiosurgery of vestibular schwannomas. Int J Radiat Oncol Biol Phys 2002;54:35–44. 78. 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; discussion 257–65. 79. 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. 80. Hempel JM, Hempel E, Wowra B, et al. Functional outcome after gamma knife treatment in vestibular schwannoma. Eur Arch Otorhinolaryngol 2006;263:714–8. 81. Huang CF, Tu HT, Lo HK, et al. Radiosurgery for vestibular schwannomas. J Chin Med Assoc 2005;68:315–20. 82. Inoue HK. Low-dose radiosurgery for large vestibular schwannomas: longterm results of functional preservation. J Neurosurg 2005;102:111–3. 83. Kida Y, Kobayashi T, Tanaka T, et al. Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surg Neurol 2000;53:383–9; discussion 389–90. 84. Koh ES, Millar BA, Menard C, et al. Fractionated stereotactic radiotherapy for acoustic neuroma: single-institution experience at The Princess Margaret Hospital. Cancer 2007;109:1203–10.
I. Yang et al. / Journal of Clinical Neuroscience 16 (2009) 742–747 85. Lind CR, Costello SA, Mathur S, et al. Stereotactic radiosurgery in New Zealand. N Z Med J 2001;114:182–4. 86. Lunsford LD, Niranjan A, Flickinger JC, et al. Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg 2005;102:195–9. 87. Massager N, Nissim O, Delbrouck C, et al. Role of intracanalicular volumetric and dosimetric parameters on hearing preservation after vestibular schwannoma radiosurgery. Int J Radiat Oncol Biol Phys 2006;64:1331–40. 88. Ogunrinde OK, Lunsford LD, Flickinger JC, et al. Cranial nerve preservation after stereotactic radiosurgery for small acoustic tumors. Arch Neurol 1995;52:73–9. 89. Petit JH, Hudes RS, Chen TT, et al. Reduced-dose radiosurgery for vestibular schwannomas. Neurosurgery 2001;49:1299–306; discussion 1306–7. 90. Poen JC, Golby AJ, Forster KM, et al. Fractionated stereotactic radiosurgery and preservation of hearing in patients with vestibular schwannoma: a preliminary report. Neurosurgery 1999;45:1299–305; discussion 1305–7. 91. Pollack AG, Marymont MH, Kalapurakal JA, et al. Acute neurological complications following gamma knife surgery for vestibular schwannoma. Case report. J Neurosurg 2005;103:546–51. 92. Pollock BE, Driscoll CL, Foote RL, et al. Patient outcomes after vestibular schwannoma management: a prospective comparison of microsurgical resection and stereotactic radiosurgery. Neurosurgery 2006;59:77–85; discussion 77–85. 93. Prasad D, Steiner M, Steiner L. Gamma surgery for vestibular schwannoma. J Neurosurg 2000;92:745–59. 94. Rutten I, Baumert BG, Seidel L, et al. Long-term follow-up reveals low toxicity of radiosurgery for vestibular schwannoma. Radiother Oncol 2007;82: 83–89. 95. Sawamura Y, Shirato H, Sakamoto T, et al. Management of vestibular schwannoma by fractionated stereotactic radiotherapy and associated cerebrospinal fluid malabsorption. J Neurosurg 2003;99:685–92. 96. Selch MT, Pedroso A, Lee SP, et al. Stereotactic radiotherapy for the treatment of acoustic neuromas. J Neurosurg 2004;101:362–72. 97. Shirato H, Sakamoto T, Sawamura Y, et al. Comparison between observation policy and fractionated stereotactic radiotherapy (SRT) as an initial management for vestibular schwannoma. Int J Radiat Oncol Biol Phys 1999;44:545–50. 98. Shirato H, Sakamoto T, Takeichi N, et al. Fractionated stereotactic radiotherapy for vestibular schwannoma (VS): comparison between cystic-type and solidtype VS. Int J Radiat Oncol Biol Phys 2000;48:1395–401.
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99. 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. 100. Tago M, Terahara A, Nakagawa K, et al. Immediate neurological deterioration after gamma knife radiosurgery for acoustic neuroma. Case report. J Neurosurg 2000;93:78–81. 101. van Eck AT, Horstmann GA. Increased preservation of functional hearing after gamma knife surgery for vestibular schwannoma. J Neurosurg 2005;102:204–6. 102. 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. 103. Wang CP, Hsu WC, Young YH. Vestibular evoked myogenic potentials in neurofibromatosis 2. Ann Otol Rhinol Laryngol 2005;114:69–73. 104. Weber DC, Chan AW, Bussiere MR, et al. Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity. Neurosurgery 2003;53:577–86; discussion 586–8. 105. Williams JA. Fractionated stereotactic radiotherapy for acoustic neuromas. Int J Radiat Oncol Biol Phys 2002;54:500–4. 106. Williams JA. Fractionated stereotactic radiotherapy for acoustic neuromas: preservation of function versus size. J Clin Neurosci 2003;10:48–52. 107. Litvack ZN, Noren G, Chougule PB, et al. Preservation of functional hearing after gamma knife surgery for vestibular schwannoma. Neurosurg Focus 2003;14:e3. 108. Chopra R, Kondziolka D, Niranjan A, et al. Long-term follow-up of acoustic schwannoma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys 2007;68:845–51. 109. Song DY, Williams JA. Fractionated stereotactic radiosurgery for treatment of acoustic neuromas. Stereotact Funct Neurosurg 1999;73:45–9. 110. Ishihara H, Saito K, Nishizaki T, et al. CyberKnife radiosurgery for vestibular schwannoma. Minim Invasive Neurosurg 2004;47:290–3. 111. Andrews DW, Silverman CL, Glass J, et al. Preservation of cranial nerve function after treatment of acoustic neurinomas with fractionated stereotactic radiotherapy. Preliminary observations in 26 patients. Stereotact Funct Neurosurg 1995;64:165–82. 112. Hirato M, Inoue H, Zama A, et al. Gamma Knife radiosurgery for acoustic schwannoma: effects of low radiation dose and functional prognosis. Stereotact Funct Neurosurg 1996;66:134–41. 113. Niranjan A, Lunsford LD, Flickinger JC, et al. Can hearing improve after acoustic tumor radiosurgery? Neurosurg Clin N Am 1999;10:305–15.
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Review
Hearing preservation after stereotactic radiosurgery for vestibular schwannoma: A systematic review Isaac Yang a, Derrick Aranda a, Seunggu J. Han a, Sravana Chennupati a, Michael E. Sughrue a, Steven W. Cheung b, Lawrence H. Pitts a,b, Andrew T. Parsa a,b,* a b
Department of Neurological Surgery, University of California at San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA Department of Otolaryngology, Head and Neck Surgery, University of California at San Francisco, San Francisco, California, USA
a r t i c l e
i n f o
Article history: Received 9 August 2008 Accepted 18 September 2008
Keywords: Radiosurgery Vestibular schwannoma Hearing preservation Stereotactic radiosurgery Gamma knife Linac Proton beam
a b s t r a c t Radiosurgery has evolved into an effective alternative to microsurgical resection in the treatment of patients with vestibular schwannoma. We performed a systematic analysis of the literature in English on the radiosurgical treatment of vestibular schwannoma patients. A total of 254 published studies reported assessable and quantifiable outcome data of patients undergoing radiosurgery for vestibular schwannomas. American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) class A or B and Gardner-Robertson (GR) classification I or II were defined as having preserved hearing. A total of 5825 patients (74 articles) met our inclusion criteria. Practitioners who delivered an average dose of 612.5 Gy as the marginal dose reported having a higher hearing preservation rate (612.5 Gy = 59% vs. >12.5 Gy = 53%, p = 0.0285). Age of the patient was not a significant prognostic factor for hearing preservation rates (<65 years = 58% vs. >65 years = 62%; p = 0.4317). The average overall follow-up was 41.2 months. Our data suggest that an overall hearing preservation rate of about 57% can be expected after radiosurgical treatment, and patients treated with 612.5 Gy were more likely to have preserved hearing. Ó 2009 Published by Elsevier Ltd.
1. Introduction Since the first reported case of a vestibular schwannoma (VS) patient treated with radiosurgery, stereotactic radiosurgery has established itself as a viable alternative to microsurgical resection for these tumors.1–30 In most cases radiosurgery does not require inpatient hospitalization and requires virtually no convalescence following treatment; however, short-term and long-term risks do exist with radiosurgery treatment.31,32 In particular, stereotactic radiosurgery for the treatment of VS introduces radiation toxicity risks to adjacent neurologic structures and result in a functional threat to the facial nerve, hearing and balance.14,16,17,23,27,30,33–41 Hydrocephalus and other cranial neuropathies such as facial spasm have also been noted after radiosurgery for VS.4,5,23,37,42–47 Surgical shunting and cerebrospinal fluid diversion may be required to address the late hydrocephalus complication.4,5,23,47,48 Despite the availability of published data that highlights the clinical, radiographic, and biological parameters when managing VS patients with radiosurgery, predicting hearing preservation after radiosurgery remains a challenge for practitioners.14,36,40,49–52 This difficulty may result from most studies having been small to modest in size, frequently from a single institution, and lacking statistical power and freedom from potential practitioner bias to draw
* Corresponding author. Tel.: +1 415 353 2629. E-mail address: [email protected] (A.T. Parsa). 0967-5868/$ - see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.jocn.2008.09.023
firm conclusions. In our review we found impressive variations in reported hearing preservation outcomes for VS patients treated with radiosurgery. Because of the numerous variables associated with assessing hearing preservation after radiosurgery in the literature, the hearing preservation rate after radiosurgery is not well defined.37,53,54 The reported rates of hearing preservation vary between 11% and 77%, with most recent reports between 50% and 70% range.4,11,18,28–30,35,39,44,46,53–64 Clearly, the reported outcomes do not provide the clinician with a consensus estimate of expected hearing preservation outcomes when counseling patients. The factors implicated in affecting post-radiation hearing preservation after radiosurgery are the dose of radiation delivered, tumor volume and patient age. We performed an extensive review of the English literature to analyze the results of patients with VS treated with radiosurgery. Using an aggregated database of patients from our systematic analysis, we investigated specific variables that may influence hearing preservation rates after radiosurgery for VS. 2. Methodology 2.1. Article selection Articles were identified via Boolean PubMed searches using the key words ‘‘radiosurgery”, ‘‘acoustic neuroma,” ‘‘hearing,” ‘‘vestibular schwannoma,” and ‘‘hearing preservation,” alone and
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in combination. This query identified 254 papers from which all quantifiable and assessable data regarding patients treated with radiosurgery were analyzed for satisfying our inclusion criteria. The inclusion criteria for articles were that: (i) hearing preservation rates were reported specifically for VS; (ii) hearing status was reported using the American Association of Otolaryngology – Head and Neck Surgery (AAO–HNS) or the Gardner–Robertson (GR) classification; (iii) tumor growth rate was monitored by serial MRIs; and (iv) initial tumor size was documented. Papers up to and before the current year were included in this analysis. In all papers ‘‘tumor size” was defined as the largest measurable diameter of the tumor. Stereotactic radiosurgery was defined as the precise application of radiation to a defined target in a limited number of sessions less than or equal to five, which was clarified by the American Association of Neurological Surgeons, Congress of Neurological Surgeons, and the American Society for Therapeutic Radiology and Oncology.65
the data based on their tumor volume with a cut-off of 1.5 cm3. The final cluster analysis divided the data based on patient age, with a cut-off of 65 years. 2.3. Statistical analysis We compared between-group rates of hearing preservation using the Fisher exact test and unpaired t-tests when appropriate. We compared initial tumor size between hearing preserved and non-preserved patients using the Wilcoxon rank-sum test. Correlation analyses between length of follow-up, rates of hearing preservation, and rate of growth were performed using the Pearson’s correlation test. For all tests, the p value was considered significant at p < 0.05. Unless otherwise stated, all continuous values presented were mean ± standard deviation (SD). 3. Results
2.2. Data extraction
3.1. Systematic analysis
Data from individual and aggregated cases were extracted from each paper. Only patients who had AAO–HNS class A or B or patients who had GR I or II at their last follow-up visit were defined as having their hearing preserved in our analysis. For those articles that quoted an overall hearing preservation rate for their series only, without giving further specific patient data, the rates were used as described. Patients who had lost hearing prior to radiosurgery (AAO–HNS class C, D or GR class III, IV, or V) were excluded. All VS patients treated with recent microsurgery were also excluded. We contacted the authors to accumulate non-aggregated data when necessary. When multiple articles by the same center from different time frames reported patients, each center’s patients and experience were counted once. In order to limit redundancy, duplicate patients and cases when ascertained were not added to our analysis. Data were analyzed as a whole and stratified into three cohorts. The first comprehensive analysis divided the data according to the average marginal dose of radiation delivered (i.e. whether the dose was 612.5 Gy or >12.5 Gy). The second cohort analysis segregated
A total of 74 articles, involving 5,825 patients, met the criteria of the established protocol and were evaluated (Supplementary Table 1),2,4,5,10,17,19,26,29,35,41,43–46,53,56–58,60,62–64,66–93 and the overall rate of hearing preservation in these studies was 57% (Table 1).1,11–13,28,39,47,55,62,63,94–112 The age range of patients treated with radiosurgery varied from 20 years to 73.5 years, with an average of 53.6 years (±10.7 years) and an average follow-up time of 41.2 months (±27.1 months). Similarly, the median length of follow-up in our analysis was 34.3 months. The average radiation dose used to treat patients was 16.0 Gy. 3.2. The effect of dosage on hearing preservation A total of 401 patients were cited receiving an average marginal dose of 612.5 Gy whereas 1241 patients received an average marginal dose of >12.5 Gy. The group receiving the lower doses of radiosurgery had superior hearing preservation rates (59% vs. 53%, p = 0.0285 [Fig. 1]), which suggests that hearing preservation is significantly affected by radiation dose. Patients receiving the
Table 1 Data summary of articles evaluated for the systematic review of hearing preservation after stereotactic radiosurgery for vestibular schwannoma. Total no. of articles
Total no. patients
Total no. patients with intact hearing
Average patient age (years)
Average marginal dose (Gy)
Average tumor volume (cm3)
Mean tumor control rate (%)
Average follow-up (months)
Overall hearing preservation rate (%)
74
5825
2083
53.6
16.0
4.05
94
41.2
57
Fig. 1. Hearing preservation analyzed by average marginal radiation dose of radiosurgery (612.5 Gy vs. >12.5 Gy) (p value indicated) showing improved hearing preservation in the low radiation dose group.
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Fig. 2. Hearing preservation analyzed by tumor volume (61.5 cm3 vs. >1.5 cm3) (p value indicated) showing similar hearing outcomes in small and large tumors.
Fig. 3. Hearing preservation analyzed as a function of age with an age cut-off of older or younger than 65 years (p value indicated) showing similar hearing preservation in both older and younger patients.
lower radiation dose still had excellent tumor control rates (average 94% ± 3%). An analysis of the follow-up times in regards to hearing preservation using a Pearson correlation calculation found that hearing preservation rates did not vary with follow-up time (r = 0.09, p = 0.451).
the older population (tumor volume 3.65 cm3 ± 2.7 cm3 vs. 6.57 cm3 ± 7.5 cm3, p < 0.0001) despite the similar hearing preservation rates.
3.3. The effect of tumor volume on hearing preservation
Hearing preservation continues to be an important concern of patients undergoing radiosurgery for VS. Few investigators have combined the published research to achieve the statistical power needed to accurately characterize hearing preservation outcome in radiosurgery treatment for VS. We performed an aggregated systematic analysis of hearing preservation in a large population of patients who have undergone radiation treatment for VS. Our analysis revealed that patients treated with an average marginal dose of 12.5 Gy or less were more likely to preserve their hearing after radiosurgery compared to those patients who received higher doses of radiation. This was true irrespective of tumor size in our analysis, so patients who had larger tumors treated with lower doses of radiation had improved hearing preservation. Higher doses of radiation are associated with higher rates of cranial nerve toxicity.61,89,112,113 Low dose radiosurgery has a favorable efficacy to toxicity ratio as compared to higher doses,4,5,23,40,44,72,78,79 and doses of 12.5 Gy or less carry a lower risk for cranial neuropathy.40 Earlier radiosurgery treatments used higher rates of radiation, but more modern treatments have used lower dose radiosurgery with similar rates of tumor control. Our systematic analysis confirms the safety of utilizing a lower radiation dose of 12.5 Gy with good tumor control (average 94% ± 3%) at an average follow-up of 41.2 months (median 34.3 months). In our comprehensive analysis, radiosurgery treatment of patients with an average tumor volume of 1.5 cm3 or less had similar
A total of 140 patients in our analysis had an average tumor volume of 1.5 cm3 or less, and 738 patients had an average tumor volume of >1.5 cm3. Patients with smaller tumors had similar hearing preservation rates (64% vs. 69%, p = 0.3228 [Fig. 2]). This statistically non-significant difference suggests that tumor volume may not be a critical clinical prognostic factor for hearing preservation in all patients undergoing radiosurgery for VS. Patients with the smaller tumors received a higher average radiation dosage of 17.8 Gy (±6.6 Gy) and had worse hearing preservation, whereas patients with larger tumors received a lower average radiation of 15.0 Gy (±4.9 Gy) and had improved hearing preservation (p < 0.0001). 3.4. The effect of age on hearing preservation A total of 1681 patients were reported with an average age of younger than 65 years, and 85 patients were reported with an average age of 65 years or older at the time of radiosurgery. Younger patients (<65 years) had similar hearing preservation as patients who were older than 65 years of age (58% vs. 62%, p = 0.4317 [Fig. 3]). This difference was not statistically significant, which suggested that age may not be an important prognostic factor for hearing preservation. Tumor size was on average significantly larger in
4. Discussion
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hearing preservation rates compared to studies with tumors of larger volumes (64% vs. 69%, p = 0.3228 [Fig. 2]). These data suggest that tumor size is not an important risk factor for hearing preservation with radiosurgery treatment. Patients with smaller tumors received a higher average radiation dosage of 17.8 Gy (±6.6 Gy) than those with larger tumors who received a lower average radiation of 15.0 Gy (±4.9 Gy), and had inferior hearing preservation with the higher radiation (p < 0.0001). This suggests that tumor size may not be an important prognostic factor for hearing preservation after radiosurgical treatment for VS, but that radiation dose may be a more critical prognostic factor for hearing preservation. Although the mechanism for this is unclear, larger tumors may have less cochlear involvement with radiosurgical treatment and may allow radiosurgical planning with less and lower radiation exposure to the cochlear nerve, leading to improved hearing outcomes in patients with larger VS. Furthermore, larger tumors may allow for less radiation dose to the cochlear nerve by having a greater displacement of the nerve. This may explain why larger tumors had improved hearing preservation with lower radiation doses. Lastly, lower radiation doses to larger tumors decreases the radiation susceptibility of adjacent nerves, which improves the likelihood of hearing preservation after radiosurgery. Older patients typically have higher rates of co-morbid conditions which may preclude them from open surgery. Despite these co-morbidities, patients older than 65 years had similar hearing preservation rates as younger patients. Age was not an important prognostic factor for hearing preservation in our analysis. Furthermore, older patients were more likely to have a significantly larger average tumor size treated with radiosurgery (tumor volume 3.65 cm3 ± 2.7 cm3 vs. 6.57 cm3 ± 7.5 cm3, p < 0.0001). This statistically significant difference suggests that older patients with large VS can be treated with radiosurgery with similar rates of hearing preservation despite older age and larger VS. Advanced age and larger tumor size does not appear to be a critical prognostic factor in hearing preservation outcomes in patients treated with radiosurgery for VS. The variability of data presentation reported in the papers precluded us from further analysis in stratifying the data to determine if statistically significant cut-off points existed. These reported studies typically represent the experience at academic centers that may have a more uniform standard of care for radiosurgical treatment. Community medical centers may have radiosurgical treatment standards that vary even further than the data reported by most academic centers. Hence, determining the significant prognostic factors is critical for determining an improved and uniform standard of care that will improve patient outcomes. Although actuarial time-dependant data would be ideal, this was not possible with a retrospective systematic analysis as performed, and is an inherent limitation in our study. Hearing preservation in this retrospective study could be assessed only through last follow-up, which had an average of 41.2 months and a median of 34.3 months. Furthermore, use of a Pearson correlation analysis found that hearing preservation rates did not vary with follow-up time (r = 0.09, p = 0.451). Future prospective studies should provide further insight into the relationship between these prognostic variables and hearing preservation, perhaps with fewer patients or lower statistical power than the present study. This aggregated systematic analysis is the first reported investigation of the available English literature to evaluate the overall impact of radiosurgery for VS on hearing preservation. We report our results from a large aggregated systematic analysis of hearing outcomes in patients with VS treated with radiosurgery. Utilizing this large data set from the available published literature minimizes the effect of bias from individual institutions
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in determining accurate and overall hearing preservation prognostic characteristics for these patients. Our analysis suggests that radiation dose is the most important prognostic factor for hearing preservation irrespective of tumor size or age in VS patients treated with radiosurgery. Our data reveal that patients treated with 612.5 Gy have improved hearing outcomes and that patients with larger tumor sizes also have improved hearing preservation when treated with lower radiation doses. Although older patients are more likely to have larger tumors treated with radiosurgery, older patients had similar hearing preservation outcomes as younger patients. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jocn.2008.09.023. References 1. Delbrouck C, Hassid S, Massager N, et al. Preservation of hearing in vestibular schwannomas treated by radiosurgery using Leksell Gamma Knife: preliminary report of a prospective Belgian clinical study. Acta Otorhinolaryngol Belg 2003;57:197–204. 2. Karpinos M, Teh BS, Zeck O, et al. Treatment of acoustic neuroma: stereotactic radiosurgery vs. microsurgery. Int J Radiat Oncol Biol Phys 2002;54:1410–21. 3. Kaylie DM, McMenomey SO. Microsurgery vs gamma knife radiosurgery for the treatment of vestibular schwannomas. Arch Otolaryngol Head Neck Surg 2003;129:903–6. 4. Kondziolka D, Lunsford LD, McLaughlin MR, et al. Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med 1998;339:1426–33. 5. Kondziolka D, Subach BR, Lunsford LD, et al. Outcomes after gamma knife radiosurgery in solitary acoustic tumors and neurofibromatosis Type 2. Neurosurg Focus 1998;5:e2. 6. Noren G. Long-term complications following gamma knife radiosurgery of vestibular schwannomas. Stereotact Funct Neurosurg 1998;70:65–73. 7. Pellet W, Regis J, Roche PH, et al. Relative indications for radiosurgery and microsurgery for acoustic schwannoma. Adv Tech Stand Neurosurg 2003;28:227–82; discussion 282–4. 8. Pogodzinski MS, Harner SG, Link MJ. Patient choice in treatment of vestibular schwannoma. Otolaryngol Head Neck Surg 2004;130:611–6. 9. Regis J, Delsanti C, Roche P, et al. Preservation of hearing function in the radiosurgical treatment of unilateral vestibular schwannomas. Preliminary results. Neurochirurgie 2002;48:471–8. 10. 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. 11. Unger F, Walch C, Papaefthymiou G, et al. Radiosurgery of residual and recurrent vestibular schwannomas. Acta Neurochir (Wien) 2002;144:671–6; discussion 676–7. 12. Unger F, Walch C, Schrottner O, et al. Cranial nerve preservation after radiosurgery of vestibular schwannomas. Acta Neurochir Suppl 2002;84: 77–83. 13. Unger F, Walch C, Haselsberger K, et al. Radiosurgery of vestibular schwannomas: a minimally invasive alternative to microsurgery. Acta Neurochir (Wien) 1999;141:1281–5; discussion 1285–6. 14. Friedman WA, Foote KD. Linear accelerator-based radiosurgery for vestibular schwannoma. Neurosurg Focus 2003;14:e2. 15. Shoshan Y, Wygoda M, Umansky F. Stereotactic radiosurgery and fractionated stereotactic radiotherapy: background, definitions, applications. Isr Med Assoc J 2005;7:597–9. 16. Battista RA, Wiet RJ. Stereotactic radiosurgery for acoustic neuromas: a survey of the American Neurotology Society. Am J Otol 2000;21:371–81. 17. 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; discussion 224–9. 18. Sekhar LN, Gormley WB, Wright DC. The best treatment for vestibular schwannoma (acoustic neuroma): microsurgery or radiosurgery? Am J Otol 1996;17:676–82; discussion 683–9. 19. Kamerer DB, Lunsford LD, Moller M. Gamma knife: an alternative treatment for acoustic neurinomas. Ann Otol Rhinol Laryngol 1988;97:631–5. 20. Lunsford LD, Kamerer DB, Flickinger JC. Stereotactic radiosurgery for acoustic neuromas. Arch Otolaryngol Head Neck Surg 1990;116:907–9. 21. Wiet RJ, Micco AG, Bauer GP. Complications of the gamma knife. Arch Otolaryngol Head Neck Surg 1996;122:414–6. 22. Ramsay HA, Luxford WM. Treatment of acoustic tumours in elderly patients: is surgery warranted? J Laryngol Otol 1993;107:295–7. 23. Mendenhall WM, Friedman WA, Buatti JM, et al. Preliminary results of linear accelerator radiosurgery for acoustic schwannomas. J Neurosurg 1996;85: 1013–9.
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