Sincethe first reported case in 1971 of a patient with vestibular schwannoma who was treated using radiosurgery by Leksell,34GKS for the treatment of vestibular schwannoma has rapidly established itself as a viable alternative to microsurgical resection.7,28,29,32,47,53,57,61,77Because GKS rarely requires hospitalization, is relatively noninvasive, and requires minimal recovery time, it may seem the ideal method of treatment. However, it is not without risk. Radiosurgery for the treatment of vestibular schwannoma introduces risks to the facial nerve and hearing, as well as posttreatment complications such as balance disturbances, hydrocephalus, headaches, tinnitus, and other cranial neuropathies.17,49
A large volume of literature has been published to date describing the postradiation morbidity and mortality in patients with vestibular schwannoma. However, given that most of these studies are small- to modest-sized case series, frequently from single institutions, it may be difficult for the new individual practitioner to use those studies to develop his/her own approach to the management of these tumors.
For this reason, we report a comprehensive review of the English-language literature to evaluate and present results on morbidity and mortality in patients treated via GKS for vestibular schwannoma. Through this, we aim to provide a representation of the effect of dose on the overall rates of morbidity for patients undergoing GKS for vestibular schwannoma.
开云体育世界杯赔率
Article Selection
文学的全面审查cted on the morbidity and mortality of patients who were treated using GKS for vestibular schwannoma by pooling data from the existing English-language literature. Articles were identified via a PubMed search using Boolean searches with the key words “Gamma Knife,” “vestibular schwannoma radiosurgery AND morbidity,” “vestibular schwannoma radiosurgery AND mortality,” “acoustic neuroma radiosurgery AND morbidity,” and “Gamma Knife surgery AND mortality” alone and in combination. After reviewing these articles, we then reviewed all references in these papers. This search was performed multiple times, most recently on May 31, 2007 (Table 1).
A summary of studies included in our analysis*
| Authors & Year | Pub-Med ID | Sample Size | Dose (Gy) | |||
|---|---|---|---|---|---|---|
| Fractionated | Marginal | Max | ||||
| Hirsch et al., 1979 | 386705 | 9 | no | NA | 50 | |
| Hirsch & Norén, 1988 | 3051887 | 111 | no | 21.5 | 37.5 | |
| Kamereret al., 1988 | 3059942 | 110 | no | NA | 50 | |
| Thomsen et al., 1990 | 2240175 | 1 | no | NA | 26 | |
| Linskey et al., 1992 | 1436407 | 17 | no | 18 | 33.3 | |
| Oyama et al., 1994 | 7526251 | 13 | no | NA | 28.7 | |
| Foote et al., 1995 | 7607937 | 36 | no | 18 | NA | |
| Ogunrinde et al., 1995 | 7826279 | 31 | no | NA | 32.8 | |
| Pollock et al., 1995 | 7708162 | 78 | no | 16.3 | 31.2 | |
| Hirato et al., 1995 | 8532129 | 28 | no | 12.1 | 25.2 | |
| Kondziolka et al., 1998 | 17112219 | 462 | no | 15 | NA | |
| Miller et al., 1999 | 10030254 | 82 | no | 18 | NA | |
| Niranjan et al., 1999 | 10515468 | 29 | no | 14 | NA | |
| Schulder et al., 1999 | 10337979 | 1 | no | 14 | NA | |
| Spiegelmann et al., 1999 | 11370134 | 44 | no | 14 | NA | |
| Subach et al., 1999 | 10223445 | 40 | no | NA | 29.4 | |
| Unger et al., 1999 | 10672298 | 56 | no | 13 | NA | |
| Ito et al., 2000 | 10924974 | 125 | no | 15.4 | 29.8 | |
| Shirato et al ., 2000 | 11121639 | 65 | yes | 36 | 50 | |
| Tago et al., 2000 | 11143268 | 1 | no | 14 | 20 | |
| Roos et al., 2000 | 10849982 | 23 | no | 12 | 20 | |
| Prasad et al., 2000 | 10794287 | 153 | no | 13.3 | 34.3 | |
| Kida et al., 2000 | 10825525 | 20 | no | 13 | 26.8 | |
| Foote et al., 2001 | 11565866 | 149 | no | 14 | NA | |
| Shamisa et al., 2001 | 11354416 | 1 | no | NA | 27.5 | |
| Petit et al., 2001 | 11846928 | 47 | no | 12 | 24 | |
| Flickinger et al., 2001 | 11147876 | 190 | no | 13 | 26 | |
| Bertalanffy et al., 2001 | 11534689 | 40 | no | 12 | NA | |
| Karpinos et al., 2002 | 12459364 | 75 | no | 14.5 | NA | |
| Régis et al., 2002 | 12450031 | 104 | no | 13 | NA | |
| Rowe et al., 2003 | 12933938 | 96 | no | 15.2 | NA | |
| Watanabe et al., 2003 | 14609174 | 1 | no | 24 | NA | |
| Rowe et al., 2003 | 14617712 | 234 | no | 13 | NA | |
| Linskey et al., 2003 | 12691405 | 54 | no | 12 | NA | |
| 自制et al., 2003 | 12925242 | 51 | no | 12 | NA | |
| Flickinger et al., 2004 | 15337560 | 313 | no | 13 | 26 | |
| Wackym et al., 2004 | 15354007 | 29 | no | NA | 27.4 | |
| Wowra et al., 2004 | 15707030 | 111 | no | 13 | NA | |
| Chung et al., 2004 | 15234046 | 72 | no | 13 | 21.9 | |
| 有限公司mbs et al., 2005 | 16111574 | 106 | yes | NA 57.6 | ||
| Hasegawa et al., 2005 | 15658090 | 73 | no | 14.6 | 28.4 | |
| Hayhurst et al., 2005 | 16120523 | 2 | no | NA | NA | |
| Poetker et al., 2005 | 16272946 | 23 | no | NA | 27.47 | |
| Wowra et al., 2005 | 15662792 | 111 | no | NA | 31.1 | |
| 王et al., 2005 | 15697166 | 7 | no | 12 | 25.4 | |
| van Eck et al., 2005 | 15662811 | 78 | no | 13 | 20 | |
| Paek et al., 2005 | 15952200 | 25 | no | 12 | NA | |
| Myrseth et al., 2005 | 15854240 | 103 | no | 12.2 | 35.3 | |
| Lunsford et al., 2005 | 15662809 | 829 | no | 13 | NA | |
| Inoue, 2005 | 15662791 | 18 | no | 12 | NA | |
| Huang et al., 2005 | 16038371 | 45 | no | 11.5 | 23 | |
| Hasegawa et al., 2005 | 16094154 | 317 | no | 13.2 | 26.2 | |
| Chung et al., 2005 | 15662787 | 195 | no | 13 | 21.9 | |
| Pollock, 2006 | 16462477 | 208 | no | 13.5 | 27 | |
| Park et al., 2006 | 16397752 | 8 | no | 12 | NA | |
| Massager et al., 2006 | 16458446 | 82 | no | 12 | NA | |
| Hempel et al., 2006 | 16741754 | 123 | no | 13 | 22.7 | |
| 有限公司mbs et al., 2006 | 16464537 | 26 | no | 13 | NA | |
| Koh et al., 2007 | 17318817 | 60 | yes | NA | 50 | |
| Mathieu et al., 2007 | 17327790 | 62 | no | 14 | 27.5 | |
| Neuhaus et al., 2007 | 17310028 | 1 | no | NA | 26 | |
| Rutten et al., 2007 | 17182142 | 26 | no | 14 | NA | |
| Franco-Vidal et al., 2007 | 17159493 | 1 | no | 13 | NA | |
* All patients underwent GKS. Abbreviations: ID = identification; NA = not available.
Inclusion criteria for articles were that morbidity and/ or complication rates were reported specifically for GKS without other radiotherapy or radiosurgery modalities mixed in an aggregated fashion. Patients with neurofibromatosis Type 2 were also included. Studies of patients who underwent microsurgery as a definitive treatment or those that described other forms of radiation were excluded.
Data Extraction
Data from individual and aggregated cases were extracted from each paper as follows. For those studies that did not specifically state the morbidity rate, the complication rate was used. Facial nerve and hearing morbidities are not included in this study, but are reported in separate studies in our series.
Data were analyzed as a whole and stratified into 2 cohorts according to the mean marginal dose of radiation delivered: ≤ 13 Gy and > 13 Gy. The morbidities recorded in this review were all new morbidities, appearing after radiation treatment or exacerbations of symptoms present prior to radiosurgery. Short-term morbidities were those that lasted less than 3 months. All other morbidities were considered to be long term. Mortality was defined as death after GKS within 30 days of treatment.
All tumors included in this study were < 25 mm in their largest diameter. The median largest dimension and median tumor volume were not reportable as studies did not consistently report either value.
Statistical Analysis
The Pearson chi-square test was used for statistical evaluation of the data. The p value was considered significant at the 5% (0.05) level, after correcting for multiple comparisons with Bonferroni correction, using the 2-sided reading in each case.
Results
A total of 63 articles2–6,8–12,15–25,27,28,30,31,33,35,37–40,42,44–46,48,50–52,54,56,58–67,69,72–76,78,80–82,85,86describing 5631 patients provided some useable data and were included in estimates of overall incidence of these complications. A large number of articles represented repeat publications from the same investigators on the same patient cohort discussing other aspects of that cohort. When this conflict arose, we excluded all obviously duplicated cohorts except the largest published cohort from that institution, or the most recent, which we assumed would include all previously published patients from this group. Other excluded articles had to be eliminated from the analysis for reasons of missing data or unusable data presentation.
Of these patients, 3248 received a mean marginal radiation dose ≤ 13 Gy, while 2383 patients (42%) received > 13 Gy. The median follow-up time for the group receiving ≤ 13 Gy was 39.5 months, and the median follow-up time for the group receiving > 13 Gy was 36.5 months.
Cranial Nerve Neuropathy
Following radiosurgery, 135 patients (2.4%) were reported to have developed a new non-CN VII or non-CN VIII cranial neuropathy. The rate of neuropathies of individual CNs are summarized inTable 2. Trigeminal neuropathy, manifested by facial paresthesias or tingling, was by far the most common neuropathy, occurring over 28 times more frequently than the next most common neuropathy. Patients receiving > 13 Gy were significantly more likely to develop trigeminal nerve neuropathy than those receiving < 13 Gy (p < 0.001) (Table 2).
A summary of rates of various CN neuropathies in the reported literature*
| CN | % | p Value | ||
|---|---|---|---|---|
| Overall | >13 Gy | <13 Gy | ||
| I | 0.0 | 0.0 | 0.0 | NS |
| II | 0.0 | 0.0 | 0.0 | NS |
| III | 0.0 | 0.0 | 0.0 | NS |
| IV | 0.0 | 0.0 | 0.0 | NS |
| V | 2.30 | 3.15 | 1.63 | <0.001 |
| VI | 0.03 | 0.08 | 0.0 | NS |
| IX | 0.0 | 0.0 | 0.0 | NS |
| X | 0.0 | 0.0 | 0.0 | NS |
| XI | 0.0 | 0.0 | 0.0 | NS |
| XII | 0.08 | 0.0 | 0.15 | NS |
* NS = not significant.
Hydrocephalus
Hydrocephalus was reported in 48 patients (0.85%). Of these patients 36 (75%) required a shunt as the definitive form of treatment, and 12 patients (25%) were treated conservatively. Hydrocephalus was reported to have occurred in 24 (0.74%) of the 3248 patients receiving ≤ 13 Gy and in 24 (1.0%) of the 2383 patients receiving > 13 Gy. The reported incidence of hydrocephalus was not affected by marginal doses of radiation delivered to these patients (0.6% for both cohorts) (Fig. 1). However, patients with hydrocephalus who were receiving > 13 Gy appeared to have a higher rate of symptomatic hydrocephalus requiring shunt treatment than those receiving lower doses (96% [> 13 Gy] vs 56% [≤ 13 Gy], p < 0.001).
Bar graph showing a comparison of rates of hydrocephalus and symptomatic hydrocephalus between patients receiving > 13 Gy marginal radiation dose and those receiving ≤ 13 Gy. *p > 0.001.
Vertigo and Tinnitus
Eighty-four patients were reported to have experienced vertigo or balance disturbance after their treatment. In the group of 2383 patients that received marginal doses > 13 Gy, vertigo or balance disturbance occurred in 26 (1.1%). Of the 3248 patients in the group that was subjected to ≤ 13 Gy as their marginal dose of radiation, 58 (1.8%) were reported to have developed vertigo or balance disturbance. The rate of vertigo or balance disturbance in the lower-dose cohort was significantly higher than that in the higher-dose cohort (p = 0.001) (Fig. 2).
Bar graph showing a comparison of rates of vertigo and balance disturbance and tinnitus between patients receiving > 13 Gy marginal radiation dose and those receiving ≤ 13 Gy. *p > 0.001.
Twenty-five patients were reported to have tinnitus after treatment. In the group of 2383 patients that received marginal doses > 13 Gy, tinnitus occurred in 2 (0.1%). Of the 3248 patients in the group that was subjected to ≤ 13 Gy as their marginal dose of radiation, 23 patients (0.7%) reported tinnitus. The rate of tinnitus in the lower-dose cohort was significantly higher than that in the higher-dose cohort (0.1% [> 13 Gy] vs ≤ 13 Gy 0.7%, p = 0.001) (Fig. 2).
Discussion
Although the morbidity and mortality rates in patients undergoing radiosurgery for vestibular schwannoma have seen drastic improvements over the years, there has been wide variation in the published literature, with tumor control rates ranging from 60 to 100%.30,36Due to the rarity of certain morbidities, it has been hard for smaller studies to provide accurate information regarding rates of occurrence. A large number of investigators have published their results previously, but to date there have been few attempts to systematically summarize the literature about this topic. In this study, we performed a comprehensive review of the literature of the morbidity and mortality in a large population of patients with vestibular schwannomas who were treated via single-fraction GKS.
Our analysis revealed that patients treated with an average marginal dose of 13 Gy or less were less likely to develop symptomatic trigeminal neuropathy over the time period of reported follow-up, when compared with those who received higher doses of radiation. Furthermore, while there was no statistically significant difference in the incidence of hydrocephalus between those patients who received a mean marginal radiation dose of 13 Gy or less and those that received a higher dose, patients receiving the higher dose seemed to have more severe hydrocephalus and usually required a CSF diversion procedure.
Interestingly, we found that patients treated with lower marginal doses experienced a small, but significantly increased rate of vertigo and balance problems, as well as an increase in the rate of posttreatment tinnitus. The reason for this is unclear, but we hypothesize that perhaps patients treated with higher doses have more complete dysfunction of this nerve, while those treated with lower doses have enough function left to detect vertigo or tinnitus. This may result from more severe involvement of the vestibular nerve with higher doses. Other reviews of the radiosurgery literature found that increased marginal doses lead to higher rates of posttreatment CN VIII dysfunction.87Further work is needed to address this complex question.
More recently, fractionated radiosurgery has been used in an attempt to minimize injury to adjacent normal CNs using a linear accelerator or the CyberKnife (Accuray Systems).1,13,14,26,41,55,71,79,83,84While planning is often similar to GKS, the method of immobilization is different. Rather than a frame-based approach, the position of target structure is replicated daily using customized head molds and/or face masks while obtaining regular radiographs to confirm positioning. While some consider the degree of accuracy less with these methods than that with frame-based techniques, there is evidence that results can be comparable if done properly.43,68,70Further study is needed to assess whether fractionated radiotherapy has reduced morbidity when compared with radiosurgery.
我们的研究有一些局限性should be acknowledged. Most notably, our analysis is inherently limited by the quality and accuracy of the reported literature, and unpublished data, which cannot be included in an analysis of this type, might reveal different results than an analysis limited to published data. Additionally, given the importance of long-term follow-up in studies of radiosurgery, it is not uncommon for investigators to follow up a cohort for a long period of time and to publish serial reports about the outcomes of these same patients. While we made every effort to exclude duplicated patients, it is possible that in our effort to exclude these patients, some of the smaller, earlier reports from some groups included unique patients not included in later cohorts and, thus, were incorrectly excluded from our analysis. Without the primary data sets, we cannot determine if this occurred and correct for it. Similarly, because we do not have the treatment plans for these patients, we can only look at marginal dose and are not able to assess the dose delivered to important structures such as the cochlea and the vestibular apparatus. Thus, the effect of lower dose could, in part, be the result of improved conformality of treatment plans in recent years, when lower doses were used more frequently.
有限公司nclusions
我们代表ort our results from a large aggregated review of the English-language literature regarding radiosurgery for vestibular schwannoma. We hope that by using such a large data set, we are able to minimize the effect of individual institutions' bias to determine accurate outcome characteristics, specifically morbidity and mortality, for patients treated with radiosurgery to help physicians and patients determine the best approach for managing these tumors.
Disclosure
Dr. Sughrue was supported in part by a grant from the AANS Neurosurgery Research and Education Foundation (NREF). Dr. Yang was supported in part by the NIH National Research Service Award (NRSA) program. Dr. Kane was supported in part by a grant from the Howard Hughes Medical Institute. Dr. Parsa was supported by the Georgiana and Reza Khatib endowed chair for skull base tumor surgery.
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