Journal of Clinical Neuroscience 21 (2014) 2077–2082
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Review
Gamma Knife radiosurgery following subtotal resection of vestibular schwannoma Benjamin Brokinkel a,⇑, Cristina Sauerland c, Markus Holling a, Christian Ewelt a, Gerhard Horstmann b, Albertus T.C.J. van Eck b, Walter Stummer a a b c
Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany Gamma Knife Center Krefeld, Krefeld, Germany Institute of Biostatistics and Clinical Research, University Hospital Münster, Münster, Germany
a r t i c l e
i n f o
Article history: Received 21 November 2013 Accepted 29 March 2014
Keywords: Acoustic neuroma Cerebellopontine angle tumor Gamma Knife radiosurgery Microsurgery Operative surgical procedures Vestibular schwannoma
a b s t r a c t During treatment of large vestibular schwannomas, incomplete resection (IR) followed by Gamma Knife surgery (GKS; Elekta AB, Stockholm, Sweden) possibly offers tumor growth control and good clinical outcome, and is being discussed as an alternative to complete tumor removal with its inherent risks, especially for facial nerve function. However, available data for this concept are limited due to the small number of published studies. To analyze the effects of combined therapy in a larger cohort, we reviewed the currently available data. Six studies comprising 159 patients with a tumor diameter of at least 2 cm were included (median volume 19.95 cm3 in four studies, n = 137). GKS was performed on average 6 months postoperatively with a mean marginal dose of 11.88 Gy (mean target volume 4.42 cm3, mean diameter 18.45 mm). Preoperatively facial nerve function was serviceable (House and Brackmann Grades I+II) in 158 of 159 patients (99.4%) and in 125 of 151 patients (82.8%, 95% confidence interval [CI] 76–88%) postoperatively. Hearing was serviceable in 29 of 151 patients (19.2%) preoperatively and in 16 of 79 patients postoperatively (20.2%, 95%CI 12–31%). Within a mean follow-up time of 50 months (range 12–102 months), facial nerve function and hearing after IR remained serviceable in 142 of 151 (94.0%, 95%CI 89–97%) and 15 of 129 patients (11.6%, 95%CI 7–18%). Tumor growth control was achieved in 149 of 159 patients (93.8%). Six patients were subjected to repeated therapy. Minimal complications were reported for microsurgery and GKS. Combined therapy was shown to be beneficial regarding both tumor control and adverse side effects among all analyzed studies. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Treatment modalities in vestibular schwannoma (VS) are controversial when analyzing the available literature. Although small tumors can often be managed expectantly, VS with a diameter >2 cm or with mass effect usually require radiosurgical, radiotherapeutical or microsurgical (MS) treatment [1–4]. Complete tumor resection has been widely accepted as it provides both mass reduction and excellent local tumor control. However, despite technical advances, including intraoperative monitoring, recently published data revealed a postoperative facial nerve palsy
⇑ Corresponding author. Tel.: +49 251 83 43931; fax: +49 251 83 45646. E-mail address: [email protected] (B. Brokinkel). http://dx.doi.org/10.1016/j.jocn.2014.03.037 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
rate between 8 and 68.8% (mean, 34%) with the risk related to tumor size [5–8]. Conversely, incomplete tumor resections (IR) usually result in better facial nerve outcome at the expense of local tumor control [9–13]. As Gamma Knife surgery (GKS; Elekta AB, Stockholm, Sweden) has shown efficient local tumor control and minor adverse side effects in both recurrent and primary VS of limited size [1,14–16], this raises the question of whether the combination of IR and GKS in large VS might unite the beneficial aspects of both regimes. Although encouraging results have been reported in several retrospective studies over the past decade, these analyses partially focused on individual aspects and included only small numbers of patients [17–22]. To depict the adverse and beneficial effects of combined IR and GKS in VS in a larger collective, we conducted an extensive literature search for this review.
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2. Methods and materials 2.1. Article selection A PubMed search using the key words ‘‘vestibular schwannoma’’, ‘‘acoustic neuroma’’, ‘‘gamma knife’’, ‘‘radiosurgery’’, ‘‘surgery’’ and ‘‘resection’’ alone or in combination yielded seven retrospective studies published between 2002 and 2012. Studies which encompassed a combination of IR and subsequent GKS for VS as the primary, intended treatment were included. Of the seven analyses identified, one was excluded since cases of GKS for residual tumor were not distinguishable from radiosurgery for tumor recurrence according to the explanation proffered in the manuscript [23]. Thus, six studies including two subgroup analyses [19,20] were included in this review. 2.2. Data extraction If available, clinical data were assessed before and after IR and after GKS during long-term follow-up. Facial nerve function was classified according to the House and Brackmann scale (H+B) [19]. Accordingly, function was specified as ‘‘serviceable’’ in H+B Grades I and II, while Grades III–VI were defined as ‘‘not serviceable’’. Hearing was analyzed in five studies and assessed by varying classification systems but was not investigated in one study [20]. Hearing was considered serviceable when speech repetition or pure tone audiogram values were less than 50 dB and the speech discrimination score was >50% (according to Gardner and Robertson Scale Grades I and II in three studies [17,18,22] and American Academy of Otolaryngology – Head and Neck Surgery Guidelines Grades A and B in one study) [21]. Radiological follow-up was performed by MRI in all studies with varying thresholds for tumor progression depending on whether they employed two or three-dimensional measurement systems. Radiological progression was defined as an increasing tumor volume of more than 20% [19], increasing tumor diameter of more than 19.7% [21], or growth progression of more than 1 mm in two dimensions or 2 mm in any dimension [22]. No explicit definitions were given in three studies [17,18,20]. Clinical progression was defined in case of additional salvage therapy (GKS, MS) due to symptomatic tumor regrowth in two studies [21,22]. 2.3. Statistical analyses Descriptive analyses and tables were created using Excel (Microsoft, Redmond, WA, USA). If parameters, such as facial nerve function or hearing, had been recorded in the same way in different studies, data were combined for statistical analyses as noted in the text. For rates of serviceable hearing and facial function, 95% confidence intervals (CI) for binominal distributions were calculated using the Java-using Münster Biometry Online-system, provided by the Institute of Biostatistics and Clinical Research, University Hospital, Münster, Germany. 3. Results 3.1. Patient characteristics and radiological imaging The studies included in this review reported on 159 patients with VS who were treated by intended incomplete MS tumor resection and additional GKS between 1994 and 2009. Since combined treatment was only applied to a subgroup of patients in one study and the patient characteristics were not documented separately, data on sex and median age were only available in five studies comprising 151 patients. This group was comprised of 80
females (52.9%) and 71 males (47.1%) with a median age of 48.6 years (female:male ratio of 1.2). Neurofibromatosis (NF) was an exclusion criterion in half of the publications; however, since there were only two patients with NF in the remaining studies, these patients were included in this review (1.3%) but not investigated separately. Since clinical presentation was variably recorded among the included studies, initial symptoms were available for a subset of patients and classified as described below. Thus, symptoms at the time of presentation included trigeminal hypoesthesia- and paresthesia in 23 of 72 (31.9%) patients, cerebellar signs in 25 of 90 (27.7%), and tinnitus and vertigo in 22 and 24 of 90 patients (24.4% and 26.7%, respectively). Data on initial hearing and facial nerve function were available in 151 and 159 patients, respectively (Table 1). Among these patients, hearing and facial nerve function was serviceable in 19.2% (29 patients, 95%CI 13.2–26.4%) and 99.4% (158 patients, 95%CI 96.5–99.9%), respectively, while extent of facial weakness was not documented in one patient [21]. Signs of increased intracranial pressure were present in seven of 72 patients (9.7%) with preoperative ventriculo-peritoneal shunting and lumbar drainage in one patient each. 3.2. Radiological imaging and follow-up Tumor size was available for all studies but was obtained from different two and three-dimensional measurements (Table 2). In five of the six studies, initial tumor diameter was at least 2 cm. Follow-up MRI revealed tumor regrowth in 10 patients (6.2%), while tumor size remained unchanged or decreased in 149 patients (93.8%). In eight patients, tumor growth was less than 1 mm in one direction or 2 mm in any direction and was therefore not classified as progression by the authors (Table 2) [22]. 3.3. Surgical procedures and GKS Table 3 summarizes both surgical and radiosurgical conditions of the different studies. Information regarding the surgical approach was available in 90 patients and included a retrosigmoidal approach in 64 patients, a translabyrinthine approach in 25 and a transpetrosal transtentorial approach in one patient (71.1%, 27.7% and 1.1%, respectively). Intraoperative facial nerve monitoring was explicitly described in four of the six studies (63.5%). Since grades of IR (for example, partial versus subtotal removal) were inconstantly described and determined among the included studies, these data were not analyzed for this review. However, postoperative target volume and diameter for GKS were available for all patients and ranged from 0.22 to 15.5 cm3 (mean 4.42 cm3) and 9 to 36.1 mm (mean 18.45 mm), respectively. Tumor marginal dose was given in five of the six studies and ranged from 9–14.1 Gy (mean 11.88 Gy). In five studies, which included 151 patients, the mean interval between MS and GKS was 6 months. 3.4. Clinical follow-up The mean follow-up was 50 months and was available for all patients (Table 1, range 12–102 months). Rates of serviceable hearing were similar preoperatively (19.2%, 29 of 151 patients) and postoperatively (20.2%, 16 of 79 patients, 95%CI 12.0–30.7%) and decreased to 11.6% (15 of 129 patients, 95%CI 6.6–18.4%) following GKS. Among patients with data on facial nerve function, rates of serviceable nerve function decreased from 99.4% at the time of presentation to 82.8% (125 of 151 patients, 95%CI 75.7–88.4%) after MS. However, facial nerve function had recovered to a serviceable state after GKS in 94.0% (142 of 151 patients, 95%CI 88.9–96.8%) at the time of last follow-up.
Table 1 Basic clinical data and hearing and facial nerve function at the time of presentation, following MS and at long-term follow up after GKS Study
Iwai et al. 2003 [18]
Park et al. 2006* [20]
Fuentes et al. 2008 [17]
van de Langenberg et al. 2011 [21]
Pan et al. 2012* [19]
Total
14
8
61
8
50
18
159
Median age, years
47
n.r.
41
53
52
50
44
Median follow-up, months
32
69
54
46
34
58
44
Hearing Serviceable§ Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable§ Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable§ Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable# Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable– Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable Not serviceable Facial nerve function Serviceable** Not serviceable
Preoperative
Postoperative
After GKS
n
n
n
%
%
n.r.
n.r.
3 11
21.4 78.6
14 0 n.r.
100 0
8 0
100.0 0.0
10 51
16.4 83.6
5 56
8.2 91.8
3 58
4.9 95.1
61 0
100.0 0.0
58 3 n.r.
95.0 5.0
58 3 n.r.
95.1 4.9
1 7
12.5 87.5
8 0
100.0 0.0
7 1 n.r.
87.5 12.5
7 1
87.5 12.5
4 46
8.0 92.0
1 49
2.0 98.0
49 1à
98.0 2.0
n.r. 34 16
68.0 32.0
47 3
94.0 6.0
11 7
61.1 38.9
11 7
61.1 38.9
11 7
61.1 38.9
18 0
100.0 0.0
16 2
89.0 11.0
18 0
100.0 0.0
29 122
19.2 80.8
16 63
20.2 79.7
15 114
11.6 88.3
158 1
99.4 0.6
125 26
82.8 17.2
142 9
94.0 6.0
n.r. 10 4à n.r.
71.4 28.6
n.r.
12 2 n.r.
Recurrent treatment
%
n
%
GKS MS None
0 1 13
7.1 92.9
GKS MS None
0 0 8
0.0 0.0 100.0
GKS MS None
1 0 60
1.6 0.0 98.4
GKS MS None
0 0 8
0.0 0.0 100.0
GKS MS None
3 1 46
6.0 2.0 92.0
GKS MS None
0 0 18
0.0 0.0 100.0
GKS MS None
4 2 153
2.5 1.3 96.2
85.7 14.3
n.r.
B. Brokinkel et al. / Journal of Clinical Neuroscience 21 (2014) 2077–2082
Yang et al. 2008 [22]
Patients. n
GKS = Gamma Knife surgery (Elekta AB, Stockholm, Sweden), MS = microsurgery, n.r. = not recorded. * Subgroup analyses. ** According to House and Brackmann Grades 1 and 2. – Speech repetition threshold/pure tone audiogram 50 n.r.
6 (43) 2 (14) n.r.
36.4
26.80
n.r.
4.6
n.r.
0 (0)
n.r.
61
n.r.
20.60
13.5– 55.1 4.1–44.4
n.r.
Yang et al. 2008 [22]
30– 47.2 n.r.
n.r.
n.r.
3.65
à
Fuentes et al. 2008 [17]
35 40 45 n.r.
2 (25) 5 (62.5) 1 (13.5) 50
40
35–45
n.r.
n.r.
18
9–20
1.16
0.52– 15.5 0.31–2.2
35
26–54
14.90
4.1–36.1
n.r.
n.r.
3.34
4 (8)
n.r.
n.r.
n.r.
n.r.
17.50
n.r.
n.r.
n.r.
9.35
0.22– 11.8 n.r.
van de Langenberg et al. 2011 [21] *
Pan et al. 2012 [19]
3 (4.9)
0 (0)
0 (0)
GKS = Gamma Knife surgery (Elekta AB, Stockholm, Sweden), n.r. = not recorded. * Subgroup analyses. According to the target volume/size before GKS. à Slightly enlarged tumors were not classified as radiological progression in one study.
Surgical complications were described in all but one study [22], including 61 patients. In another study comparing different grades of tumor resection, one patient died after MS. However, this did not occur in the subgroup of patients with subtotal resection and GKS which were analyzed for this review [20]. Since further surgical complications were not clearly assignable to the subgroups of different treatments in this study, surgical complications of four studies including 90 patients were finally analyzed. Among these, low rates of MS complications with no death or cerebrospinal fluid fistulas were reported. In a series of 18 patients described by Iwai et al., trochlear nerve palsy following MS occurred in one patient while initial symptoms such as ataxia, trigeminal neuropathy and signs of increased intracranial pressure resolved completely [18]. Correspondingly, a lack of surgical complications and improvement of symptoms due to cerebellar or brainstem compression was also reported by Fuentes et al. [17]. Rates of surgical complications in another series included hemorrhage in one patient with a coagulation disorder requiring two subsequent surgical interventions and resulting in hemiparesis (2%), hydrocephalus with either ventriculo-peritoneal shunting or lumbar drain in two patients (4%), temporary dysfunction of the cranial nerves (CN) VI or IX and X in two (4%) and three patients (6%), respectively, and one patient (2%) with persisting CN IX and X dysfunction requiring percutaneous endoscopic gastrostomy [21]. Comparing 18 patients who received intracapsular tumor resection and subsequent GKS with 17 patients who received radical tumor removal and GKS in one study, one case of postoperative hydrocephalus requiring
ventriculo-peritoneal shunting occurred in each group (5.6% and 5.9%, respectively). However, in contrast to the group with incomplete resection, one case of lower CN deficit was observed following radical tumor resection [19]. Low rates of radiosurgical complications were described in all six studies. No adverse side effects after GKS were reported in four studies including 91 patients [17,18,20,22]. Van de Langenberg et al. described transient facial palsy (H+B Grade II) in 4%, transient trigeminal hypoesthesia in 2% and persisting facial spasm in 2% (two, one and one of 50 patients, respectively). In this series, one death from cardiac arrest, presumably unrelated to treatment, occurred 5 years after GKS [21]. In the comparative analysis by Pan et al., among the 18 patients who received IR and GKS, one patient suffered from transient hearing loss, which improved to serviceable hearing after administration of steroids. Correspondingly, the authors reported significantly reduced mean returnto-work times (2.4 versus 33.4 weeks, p < 0.001) and improvement of quality of life according to the 36-Item Short Form Health Survey (p < 0.001) [19]. Data on recurrence rates and subsequent treatments were available for all studies (Table 1). Among 10 patients with radiological tumor progression, further treatment after neurological deterioration was indicated in six patients and included GKS alone in three (1.9%), MS in two (1.3%) and GKS following MS in one patient suffering from NF (0.6%). Thus, clinical tumor control was achieved in 153 of 159 patients (96.2%) with treatment for recurrence in six individuals (3.8%). Predictors for tumor control
Table 3 Basic treatment data including surgical approaches, facial nerve monitoring and interval from microsurgery to Gamma Knife surgery, as well as tumor marginal doses Study
Surgical approach, n (%)
Iwai et al. 2003 [18] *
Park et al. 2006 [20] Fuentes et al. 2008 [17] van de Langenberg et al. 2011 [21] Pan et al. 2012* [19] Yang et al. 2008 [22]
Retrosigmoid Transpetrosal transtentorial n.r. Retrosigmoid Retrosigmoid Translabyrinthe Retrosigmoid n.r.
13 (92.8) 1 (7.2) 8 (100) 25 (50) 25 (50) 18 (100)
Facial nerve monitoring
Interval from MS to GKS, months (mean; range)
Tumor marginal dose, Gy (mean; range)
Yes
2.9; 1–6
12.1; 10–14.1
n.r. Yes n.r.
n.r.; 1–6 9; 6–12 8.5; 2–24
12; n.r. 11.8; 11–13 11; 9.4–11.9
Yes Yes
3.6; n.r. 5.8; 0.3–95.7
n.r. 12.5; 9–14
GKS = Gamma Knife surgery (Elekta AB, Stockholm, Sweden), MS = microsurgery, n.r. = not recorded. * Subgroup analyses.
B. Brokinkel et al. / Journal of Clinical Neuroscience 21 (2014) 2077–2082
were analyzed in two studies, revealing no impact of patient age or sex, tumor laterality or pre- or postoperative size, radiological features such as cystic components, or time between MS and GKS. However, Yang et al. reported a favorable response to treatment in patients with cystic VS which approached significance (p = 0.089) [21,22]. The rate of preserving serviceable facial nerve function was inversely correlated with extent of tumor removal in two studies [19,20].
4. Discussion A combined treatment regime was able to provide both sufficient local tumor control and excellent facial nerve function preservation among all aforementioned studies. The cumulative preservation of serviceable facial nerve function in the analyzed series was 94% on long-term follow-up, which outstrips most reported rates following MS (ranging from 31.4% to 92.8% in recent studies), with even lower rates after complete resection of tumors exceeding 3 cm (27–58% in 11 studies) [5,21]. Thus, although the influence of the extent of tumor removal on postoperative facial nerve function is still controversial, the conclusion that reduced mechanical stress during IR might help maintain neural function appears reasonable. Accordingly, conflicting data reporting high rates of impaired facial nerve function after subtotal tumor removal are partially explained by delayed abandonment of the resection after abnormalities in intraoperative facial nerve monitoring, encouraging a more restrictive surgical intention [5,19]. Notably, comparing rates of serviceable nerve function after MS and after GKS (82.8% versus 94%), the recovery of facial nerve function appeared to not be impaired by GKS. This effect was noted in each single analysis, arguing against an effect of cumulative observations, which might have partially obscured increased rates in smaller studies. Low rates of preserved serviceable hearing were reported among most included studies (mean preservation rate of 11.6%). As one possible explanation, comparison of pre and post-intervention (both MS and GKS) hearing function revealed heavily impaired function even at the time of clinical presentation (8.0–21.4% in four of five studies). Although hardly calculable, these data suggest additional hearing deterioration to a non-serviceable state in only a few patients. This thesis is supported by results from Pan et al., who reported excellent preservation of initial serviceable hearing (61.1%) with no further deterioration after MS and GKS in 18 patients [19]. While preservation of serviceable hearing was reported in 0–30% for complete resection of large VS in several studies [19,21], recently published data revealed an inverse correlation of hearing preservation with the extent of MS removal [5,19]. Although restrictive tumor resection is further encouraged by these results, the authors are aware of the limitations of this review, including a unique evaluation of hearing in all patients and in terms of considering surgical approaches. With no reported death, wound infection or cerebrospinal fluid fistula, the rates of complications following MS were found to be considerably lower compared to most rates published for complete resection in large VS (up to 1.9%, 1.1% and 27.0%, respectively) [21]. However, this should be considered in the context of the small number of patients and the varying surgical centers and surgeons in this review. Only marginal adverse side effects of GKS were reported and included mainly transient dysfunction of CN V, VII and VIII (four of 159 patients, 2.5%), while persisting facial spasm only occurred in a single patient (0.6%). With some limitations due to the varying definitions of tumor growth, radiological tumor control was achieved in 93.8% with further treatment indicated in six individuals (3.8%), which is comparable to a broad spectrum of published recurrence rates
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following MS [5,21,24]. Predictors of treatment failure in terms of regrowth or the indication for second line treatment were not elaborated in detail since these were only analyzed in single cases or studies. However, NF was present in two of three patients with radiological tumor progression in one study [18]. Van de Langenberg et al. found that neither patient-related characteristics nor radiological features (for example, tumor size, enhancement or cystic components) correlated with tumor progression [21]. Contrarily, Yang et al. showed higher rates of tumor control in cystic VS, challenging currently published data of reduced tumor control after GKS in cystic VS, although this was not statistically significant [22]. Concerning the six analyzed studies, results of a combined treatment strategy were comparable to conventional and hypofractionated stereotactic radiotherapy (SRT) in recently published studies, where local tumor control was achieved in 90–100% with preservation of facial nerve function in up to 100%. Although hearing preservation, when reported, was over 90%, tumor sizes differed widely among these studies and tumors were smaller compared to most of the analyses included in this review [3,4,25]. Investigations on larger tumors exceeding 3 cm in diameter treated by SRT showed controversial results with increasing risk of facial palsy and further CN deficits in some series [26–29]. Since local tumor control following SRT seems to decrease with increasing tumor size [26], the role of SRT alone and in combination with previous MS in treating larger VS remains to be elucidated in further studies. The range of postoperative tumor volumes or diameters was large among the studies included in this analysis and no correlation was observed between treatment failures after surgery and GKS and tumor size. Intuitively, higher control rates would have been expected with smaller residual tumor volumes, which did not appear to be the case in the present analysis. Nevertheless, large tumors after surgery and GKS have been observed to be particularly difficult to handle if surgery again becomes necessary [30]. For this reason, surgeons should still strive to minimize residual tumor load even if secondary GKS is planned. The authors are aware of several limitations of this work. Results of the single studies are consistently based on small (eight to 61 patients) cohorts. The analyzed criteria and study methods differed widely in some cases. Moreover, this review could only include a subselection of data due to inconsistencies among the individual publications. Since the study design was retrospective in each analysis, it is evident that further prospective randomized studies are needed. In our mind the appropriate prospective comparison would be between MS alone and the combined treatment strategy of IR and radiosurgery. We are presently contemplating such a study in a multicenter setting. Nevertheless, with the aforementioned limitations, the combined treatment modality of MS and radiosurgery appears to be a safe and effective approach for treating large VS. With apparently good clinical outcomes and local tumor control, these data suggest that a restrictive MS (IR) approach incorporating safe maximum tumor reduction followed by GKS may be a feasible option for VS patients and we strongly encourage further investigation in prospective clinical trials. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Milligan BD, Pollock BE, Foote RL, et al. Long-term tumor control and cranial nerve outcomes following gamma knife surgery for larger-volume vestibular schwannomas. J Neurosurg 2012;116:598–604.
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[17] Fuentes S, Arkha Y, Pech-Gourg G, et al. Management of large vestibular schwannomas by combined surgical resection and gamma knife radiosurgery. Prog Neurol Surg 2008;21:79–82. [18] Iwai Y, Yamanaka K, Ishiguro T. Surgery combined with radiosurgery of large acoustic neuromas. Surg Neurol 2003;59:283–9 [discussion 289–1]. [19] Pan HC, Sheehan J, Sheu ML, et al. Intracapsular decompression or radical resection followed by Gamma Knife surgery for patients harboring a large vestibular schwannoma. J Neurosurg 2012;117:69–77. [20] Park CK, Jung HW, Kim JE, et al. Therapeutic strategy for large vestibular schwannomas. J Neurooncol 2006;77:167–71. [21] van de Langenberg R, Hanssens PE, van Overbeeke JJ, et al. Management of large vestibular schwannoma. Part I. Planned subtotal resection followed by Gamma Knife surgery: radiological and clinical aspects. J Neurosurg 2011;115: 875–84. [22] Yang SY, Kim DG, Chung HT, et al. Evaluation of tumour response after gamma knife radiosurgery for residual vestibular schwannomas based on MRI morphological features. J Neurol Neurosurg Psychiatry 2008;79:431–6. [23] 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]. [24] Sughrue ME, Kaur R, Rutkowski MJ, et al. Extent of resection and the long-term durability of vestibular schwannoma surgery. J Neurosurg 2011;114:1218–23. [25] Puataweepong P, Dhanachai M, Dangprasert S, et al. Linac-based stereotactic radiosurgery and fractionated stereotactic radiotherapy for vestibular schwannomas: comparative observations of 139 patients treated at a single institution. J Radiat Res 2013;55:351–8. [26] Aoyama H, Onodera S, Takeichi N, et al. Symptomatic outcomes in relation to tumor expansion after fractionated stereotactic radiation therapy for vestibular schwannomas: single-institutional long-term experience. Int J Radiat Oncol Biol Phys 2013;85:329–34. [27] Mandl ES, Meijer OW, Slotman BJ, et al. Stereotactic radiation therapy for large vestibular schwannomas. Radiother Oncol 2010;95:94–8. [28] Kalapurakal JA, Silverman CL, Akhtar N, et al. Improved trigeminal and facial nerve tolerance following fractionated stereotactic radiotherapy for large acoustic neuromas. Br J Radiol 1999;72:1202–7. [29] Lederman G, Lowry J, Wertheim S, et al. Acoustic neuroma: potential benefits of fractionated stereotactic radiosurgery. Stereotact Funct Neurosurg 1997; 69:175–82. [30] Gerganov VM, Giordano M, Samii A, et al. Surgical treatment of patients with vestibular schwannomas after failed previous radiosurgery. J Neurosurg 2012; 116:713–20.
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Review
Gamma Knife radiosurgery following subtotal resection of vestibular schwannoma Benjamin Brokinkel a,⇑, Cristina Sauerland c, Markus Holling a, Christian Ewelt a, Gerhard Horstmann b, Albertus T.C.J. van Eck b, Walter Stummer a a b c
Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany Gamma Knife Center Krefeld, Krefeld, Germany Institute of Biostatistics and Clinical Research, University Hospital Münster, Münster, Germany
a r t i c l e
i n f o
Article history: Received 21 November 2013 Accepted 29 March 2014
Keywords: Acoustic neuroma Cerebellopontine angle tumor Gamma Knife radiosurgery Microsurgery Operative surgical procedures Vestibular schwannoma
a b s t r a c t During treatment of large vestibular schwannomas, incomplete resection (IR) followed by Gamma Knife surgery (GKS; Elekta AB, Stockholm, Sweden) possibly offers tumor growth control and good clinical outcome, and is being discussed as an alternative to complete tumor removal with its inherent risks, especially for facial nerve function. However, available data for this concept are limited due to the small number of published studies. To analyze the effects of combined therapy in a larger cohort, we reviewed the currently available data. Six studies comprising 159 patients with a tumor diameter of at least 2 cm were included (median volume 19.95 cm3 in four studies, n = 137). GKS was performed on average 6 months postoperatively with a mean marginal dose of 11.88 Gy (mean target volume 4.42 cm3, mean diameter 18.45 mm). Preoperatively facial nerve function was serviceable (House and Brackmann Grades I+II) in 158 of 159 patients (99.4%) and in 125 of 151 patients (82.8%, 95% confidence interval [CI] 76–88%) postoperatively. Hearing was serviceable in 29 of 151 patients (19.2%) preoperatively and in 16 of 79 patients postoperatively (20.2%, 95%CI 12–31%). Within a mean follow-up time of 50 months (range 12–102 months), facial nerve function and hearing after IR remained serviceable in 142 of 151 (94.0%, 95%CI 89–97%) and 15 of 129 patients (11.6%, 95%CI 7–18%). Tumor growth control was achieved in 149 of 159 patients (93.8%). Six patients were subjected to repeated therapy. Minimal complications were reported for microsurgery and GKS. Combined therapy was shown to be beneficial regarding both tumor control and adverse side effects among all analyzed studies. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Treatment modalities in vestibular schwannoma (VS) are controversial when analyzing the available literature. Although small tumors can often be managed expectantly, VS with a diameter >2 cm or with mass effect usually require radiosurgical, radiotherapeutical or microsurgical (MS) treatment [1–4]. Complete tumor resection has been widely accepted as it provides both mass reduction and excellent local tumor control. However, despite technical advances, including intraoperative monitoring, recently published data revealed a postoperative facial nerve palsy
⇑ Corresponding author. Tel.: +49 251 83 43931; fax: +49 251 83 45646. E-mail address: [email protected] (B. Brokinkel). http://dx.doi.org/10.1016/j.jocn.2014.03.037 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
rate between 8 and 68.8% (mean, 34%) with the risk related to tumor size [5–8]. Conversely, incomplete tumor resections (IR) usually result in better facial nerve outcome at the expense of local tumor control [9–13]. As Gamma Knife surgery (GKS; Elekta AB, Stockholm, Sweden) has shown efficient local tumor control and minor adverse side effects in both recurrent and primary VS of limited size [1,14–16], this raises the question of whether the combination of IR and GKS in large VS might unite the beneficial aspects of both regimes. Although encouraging results have been reported in several retrospective studies over the past decade, these analyses partially focused on individual aspects and included only small numbers of patients [17–22]. To depict the adverse and beneficial effects of combined IR and GKS in VS in a larger collective, we conducted an extensive literature search for this review.
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2. Methods and materials 2.1. Article selection A PubMed search using the key words ‘‘vestibular schwannoma’’, ‘‘acoustic neuroma’’, ‘‘gamma knife’’, ‘‘radiosurgery’’, ‘‘surgery’’ and ‘‘resection’’ alone or in combination yielded seven retrospective studies published between 2002 and 2012. Studies which encompassed a combination of IR and subsequent GKS for VS as the primary, intended treatment were included. Of the seven analyses identified, one was excluded since cases of GKS for residual tumor were not distinguishable from radiosurgery for tumor recurrence according to the explanation proffered in the manuscript [23]. Thus, six studies including two subgroup analyses [19,20] were included in this review. 2.2. Data extraction If available, clinical data were assessed before and after IR and after GKS during long-term follow-up. Facial nerve function was classified according to the House and Brackmann scale (H+B) [19]. Accordingly, function was specified as ‘‘serviceable’’ in H+B Grades I and II, while Grades III–VI were defined as ‘‘not serviceable’’. Hearing was analyzed in five studies and assessed by varying classification systems but was not investigated in one study [20]. Hearing was considered serviceable when speech repetition or pure tone audiogram values were less than 50 dB and the speech discrimination score was >50% (according to Gardner and Robertson Scale Grades I and II in three studies [17,18,22] and American Academy of Otolaryngology – Head and Neck Surgery Guidelines Grades A and B in one study) [21]. Radiological follow-up was performed by MRI in all studies with varying thresholds for tumor progression depending on whether they employed two or three-dimensional measurement systems. Radiological progression was defined as an increasing tumor volume of more than 20% [19], increasing tumor diameter of more than 19.7% [21], or growth progression of more than 1 mm in two dimensions or 2 mm in any dimension [22]. No explicit definitions were given in three studies [17,18,20]. Clinical progression was defined in case of additional salvage therapy (GKS, MS) due to symptomatic tumor regrowth in two studies [21,22]. 2.3. Statistical analyses Descriptive analyses and tables were created using Excel (Microsoft, Redmond, WA, USA). If parameters, such as facial nerve function or hearing, had been recorded in the same way in different studies, data were combined for statistical analyses as noted in the text. For rates of serviceable hearing and facial function, 95% confidence intervals (CI) for binominal distributions were calculated using the Java-using Münster Biometry Online-system, provided by the Institute of Biostatistics and Clinical Research, University Hospital, Münster, Germany. 3. Results 3.1. Patient characteristics and radiological imaging The studies included in this review reported on 159 patients with VS who were treated by intended incomplete MS tumor resection and additional GKS between 1994 and 2009. Since combined treatment was only applied to a subgroup of patients in one study and the patient characteristics were not documented separately, data on sex and median age were only available in five studies comprising 151 patients. This group was comprised of 80
females (52.9%) and 71 males (47.1%) with a median age of 48.6 years (female:male ratio of 1.2). Neurofibromatosis (NF) was an exclusion criterion in half of the publications; however, since there were only two patients with NF in the remaining studies, these patients were included in this review (1.3%) but not investigated separately. Since clinical presentation was variably recorded among the included studies, initial symptoms were available for a subset of patients and classified as described below. Thus, symptoms at the time of presentation included trigeminal hypoesthesia- and paresthesia in 23 of 72 (31.9%) patients, cerebellar signs in 25 of 90 (27.7%), and tinnitus and vertigo in 22 and 24 of 90 patients (24.4% and 26.7%, respectively). Data on initial hearing and facial nerve function were available in 151 and 159 patients, respectively (Table 1). Among these patients, hearing and facial nerve function was serviceable in 19.2% (29 patients, 95%CI 13.2–26.4%) and 99.4% (158 patients, 95%CI 96.5–99.9%), respectively, while extent of facial weakness was not documented in one patient [21]. Signs of increased intracranial pressure were present in seven of 72 patients (9.7%) with preoperative ventriculo-peritoneal shunting and lumbar drainage in one patient each. 3.2. Radiological imaging and follow-up Tumor size was available for all studies but was obtained from different two and three-dimensional measurements (Table 2). In five of the six studies, initial tumor diameter was at least 2 cm. Follow-up MRI revealed tumor regrowth in 10 patients (6.2%), while tumor size remained unchanged or decreased in 149 patients (93.8%). In eight patients, tumor growth was less than 1 mm in one direction or 2 mm in any direction and was therefore not classified as progression by the authors (Table 2) [22]. 3.3. Surgical procedures and GKS Table 3 summarizes both surgical and radiosurgical conditions of the different studies. Information regarding the surgical approach was available in 90 patients and included a retrosigmoidal approach in 64 patients, a translabyrinthine approach in 25 and a transpetrosal transtentorial approach in one patient (71.1%, 27.7% and 1.1%, respectively). Intraoperative facial nerve monitoring was explicitly described in four of the six studies (63.5%). Since grades of IR (for example, partial versus subtotal removal) were inconstantly described and determined among the included studies, these data were not analyzed for this review. However, postoperative target volume and diameter for GKS were available for all patients and ranged from 0.22 to 15.5 cm3 (mean 4.42 cm3) and 9 to 36.1 mm (mean 18.45 mm), respectively. Tumor marginal dose was given in five of the six studies and ranged from 9–14.1 Gy (mean 11.88 Gy). In five studies, which included 151 patients, the mean interval between MS and GKS was 6 months. 3.4. Clinical follow-up The mean follow-up was 50 months and was available for all patients (Table 1, range 12–102 months). Rates of serviceable hearing were similar preoperatively (19.2%, 29 of 151 patients) and postoperatively (20.2%, 16 of 79 patients, 95%CI 12.0–30.7%) and decreased to 11.6% (15 of 129 patients, 95%CI 6.6–18.4%) following GKS. Among patients with data on facial nerve function, rates of serviceable nerve function decreased from 99.4% at the time of presentation to 82.8% (125 of 151 patients, 95%CI 75.7–88.4%) after MS. However, facial nerve function had recovered to a serviceable state after GKS in 94.0% (142 of 151 patients, 95%CI 88.9–96.8%) at the time of last follow-up.
Table 1 Basic clinical data and hearing and facial nerve function at the time of presentation, following MS and at long-term follow up after GKS Study
Iwai et al. 2003 [18]
Park et al. 2006* [20]
Fuentes et al. 2008 [17]
van de Langenberg et al. 2011 [21]
Pan et al. 2012* [19]
Total
14
8
61
8
50
18
159
Median age, years
47
n.r.
41
53
52
50
44
Median follow-up, months
32
69
54
46
34
58
44
Hearing Serviceable§ Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable§ Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable§ Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable# Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable– Not serviceable Facial nerve function Serviceable** Not serviceable Hearing Serviceable Not serviceable Facial nerve function Serviceable** Not serviceable
Preoperative
Postoperative
After GKS
n
n
n
%
%
n.r.
n.r.
3 11
21.4 78.6
14 0 n.r.
100 0
8 0
100.0 0.0
10 51
16.4 83.6
5 56
8.2 91.8
3 58
4.9 95.1
61 0
100.0 0.0
58 3 n.r.
95.0 5.0
58 3 n.r.
95.1 4.9
1 7
12.5 87.5
8 0
100.0 0.0
7 1 n.r.
87.5 12.5
7 1
87.5 12.5
4 46
8.0 92.0
1 49
2.0 98.0
49 1à
98.0 2.0
n.r. 34 16
68.0 32.0
47 3
94.0 6.0
11 7
61.1 38.9
11 7
61.1 38.9
11 7
61.1 38.9
18 0
100.0 0.0
16 2
89.0 11.0
18 0
100.0 0.0
29 122
19.2 80.8
16 63
20.2 79.7
15 114
11.6 88.3
158 1
99.4 0.6
125 26
82.8 17.2
142 9
94.0 6.0
n.r. 10 4à n.r.
71.4 28.6
n.r.
12 2 n.r.
Recurrent treatment
%
n
%
GKS MS None
0 1 13
7.1 92.9
GKS MS None
0 0 8
0.0 0.0 100.0
GKS MS None
1 0 60
1.6 0.0 98.4
GKS MS None
0 0 8
0.0 0.0 100.0
GKS MS None
3 1 46
6.0 2.0 92.0
GKS MS None
0 0 18
0.0 0.0 100.0
GKS MS None
4 2 153
2.5 1.3 96.2
85.7 14.3
n.r.
B. Brokinkel et al. / Journal of Clinical Neuroscience 21 (2014) 2077–2082
Yang et al. 2008 [22]
Patients. n
GKS = Gamma Knife surgery (Elekta AB, Stockholm, Sweden), MS = microsurgery, n.r. = not recorded. * Subgroup analyses. ** According to House and Brackmann Grades 1 and 2. – Speech repetition threshold/pure tone audiogram 50 n.r.
6 (43) 2 (14) n.r.
36.4
26.80
n.r.
4.6
n.r.
0 (0)
n.r.
61
n.r.
20.60
13.5– 55.1 4.1–44.4
n.r.
Yang et al. 2008 [22]
30– 47.2 n.r.
n.r.
n.r.
3.65
à
Fuentes et al. 2008 [17]
35 40 45 n.r.
2 (25) 5 (62.5) 1 (13.5) 50
40
35–45
n.r.
n.r.
18
9–20
1.16
0.52– 15.5 0.31–2.2
35
26–54
14.90
4.1–36.1
n.r.
n.r.
3.34
4 (8)
n.r.
n.r.
n.r.
n.r.
17.50
n.r.
n.r.
n.r.
9.35
0.22– 11.8 n.r.
van de Langenberg et al. 2011 [21] *
Pan et al. 2012 [19]
3 (4.9)
0 (0)
0 (0)
GKS = Gamma Knife surgery (Elekta AB, Stockholm, Sweden), n.r. = not recorded. * Subgroup analyses. According to the target volume/size before GKS. à Slightly enlarged tumors were not classified as radiological progression in one study.
Surgical complications were described in all but one study [22], including 61 patients. In another study comparing different grades of tumor resection, one patient died after MS. However, this did not occur in the subgroup of patients with subtotal resection and GKS which were analyzed for this review [20]. Since further surgical complications were not clearly assignable to the subgroups of different treatments in this study, surgical complications of four studies including 90 patients were finally analyzed. Among these, low rates of MS complications with no death or cerebrospinal fluid fistulas were reported. In a series of 18 patients described by Iwai et al., trochlear nerve palsy following MS occurred in one patient while initial symptoms such as ataxia, trigeminal neuropathy and signs of increased intracranial pressure resolved completely [18]. Correspondingly, a lack of surgical complications and improvement of symptoms due to cerebellar or brainstem compression was also reported by Fuentes et al. [17]. Rates of surgical complications in another series included hemorrhage in one patient with a coagulation disorder requiring two subsequent surgical interventions and resulting in hemiparesis (2%), hydrocephalus with either ventriculo-peritoneal shunting or lumbar drain in two patients (4%), temporary dysfunction of the cranial nerves (CN) VI or IX and X in two (4%) and three patients (6%), respectively, and one patient (2%) with persisting CN IX and X dysfunction requiring percutaneous endoscopic gastrostomy [21]. Comparing 18 patients who received intracapsular tumor resection and subsequent GKS with 17 patients who received radical tumor removal and GKS in one study, one case of postoperative hydrocephalus requiring
ventriculo-peritoneal shunting occurred in each group (5.6% and 5.9%, respectively). However, in contrast to the group with incomplete resection, one case of lower CN deficit was observed following radical tumor resection [19]. Low rates of radiosurgical complications were described in all six studies. No adverse side effects after GKS were reported in four studies including 91 patients [17,18,20,22]. Van de Langenberg et al. described transient facial palsy (H+B Grade II) in 4%, transient trigeminal hypoesthesia in 2% and persisting facial spasm in 2% (two, one and one of 50 patients, respectively). In this series, one death from cardiac arrest, presumably unrelated to treatment, occurred 5 years after GKS [21]. In the comparative analysis by Pan et al., among the 18 patients who received IR and GKS, one patient suffered from transient hearing loss, which improved to serviceable hearing after administration of steroids. Correspondingly, the authors reported significantly reduced mean returnto-work times (2.4 versus 33.4 weeks, p < 0.001) and improvement of quality of life according to the 36-Item Short Form Health Survey (p < 0.001) [19]. Data on recurrence rates and subsequent treatments were available for all studies (Table 1). Among 10 patients with radiological tumor progression, further treatment after neurological deterioration was indicated in six patients and included GKS alone in three (1.9%), MS in two (1.3%) and GKS following MS in one patient suffering from NF (0.6%). Thus, clinical tumor control was achieved in 153 of 159 patients (96.2%) with treatment for recurrence in six individuals (3.8%). Predictors for tumor control
Table 3 Basic treatment data including surgical approaches, facial nerve monitoring and interval from microsurgery to Gamma Knife surgery, as well as tumor marginal doses Study
Surgical approach, n (%)
Iwai et al. 2003 [18] *
Park et al. 2006 [20] Fuentes et al. 2008 [17] van de Langenberg et al. 2011 [21] Pan et al. 2012* [19] Yang et al. 2008 [22]
Retrosigmoid Transpetrosal transtentorial n.r. Retrosigmoid Retrosigmoid Translabyrinthe Retrosigmoid n.r.
13 (92.8) 1 (7.2) 8 (100) 25 (50) 25 (50) 18 (100)
Facial nerve monitoring
Interval from MS to GKS, months (mean; range)
Tumor marginal dose, Gy (mean; range)
Yes
2.9; 1–6
12.1; 10–14.1
n.r. Yes n.r.
n.r.; 1–6 9; 6–12 8.5; 2–24
12; n.r. 11.8; 11–13 11; 9.4–11.9
Yes Yes
3.6; n.r. 5.8; 0.3–95.7
n.r. 12.5; 9–14
GKS = Gamma Knife surgery (Elekta AB, Stockholm, Sweden), MS = microsurgery, n.r. = not recorded. * Subgroup analyses.
B. Brokinkel et al. / Journal of Clinical Neuroscience 21 (2014) 2077–2082
were analyzed in two studies, revealing no impact of patient age or sex, tumor laterality or pre- or postoperative size, radiological features such as cystic components, or time between MS and GKS. However, Yang et al. reported a favorable response to treatment in patients with cystic VS which approached significance (p = 0.089) [21,22]. The rate of preserving serviceable facial nerve function was inversely correlated with extent of tumor removal in two studies [19,20].
4. Discussion A combined treatment regime was able to provide both sufficient local tumor control and excellent facial nerve function preservation among all aforementioned studies. The cumulative preservation of serviceable facial nerve function in the analyzed series was 94% on long-term follow-up, which outstrips most reported rates following MS (ranging from 31.4% to 92.8% in recent studies), with even lower rates after complete resection of tumors exceeding 3 cm (27–58% in 11 studies) [5,21]. Thus, although the influence of the extent of tumor removal on postoperative facial nerve function is still controversial, the conclusion that reduced mechanical stress during IR might help maintain neural function appears reasonable. Accordingly, conflicting data reporting high rates of impaired facial nerve function after subtotal tumor removal are partially explained by delayed abandonment of the resection after abnormalities in intraoperative facial nerve monitoring, encouraging a more restrictive surgical intention [5,19]. Notably, comparing rates of serviceable nerve function after MS and after GKS (82.8% versus 94%), the recovery of facial nerve function appeared to not be impaired by GKS. This effect was noted in each single analysis, arguing against an effect of cumulative observations, which might have partially obscured increased rates in smaller studies. Low rates of preserved serviceable hearing were reported among most included studies (mean preservation rate of 11.6%). As one possible explanation, comparison of pre and post-intervention (both MS and GKS) hearing function revealed heavily impaired function even at the time of clinical presentation (8.0–21.4% in four of five studies). Although hardly calculable, these data suggest additional hearing deterioration to a non-serviceable state in only a few patients. This thesis is supported by results from Pan et al., who reported excellent preservation of initial serviceable hearing (61.1%) with no further deterioration after MS and GKS in 18 patients [19]. While preservation of serviceable hearing was reported in 0–30% for complete resection of large VS in several studies [19,21], recently published data revealed an inverse correlation of hearing preservation with the extent of MS removal [5,19]. Although restrictive tumor resection is further encouraged by these results, the authors are aware of the limitations of this review, including a unique evaluation of hearing in all patients and in terms of considering surgical approaches. With no reported death, wound infection or cerebrospinal fluid fistula, the rates of complications following MS were found to be considerably lower compared to most rates published for complete resection in large VS (up to 1.9%, 1.1% and 27.0%, respectively) [21]. However, this should be considered in the context of the small number of patients and the varying surgical centers and surgeons in this review. Only marginal adverse side effects of GKS were reported and included mainly transient dysfunction of CN V, VII and VIII (four of 159 patients, 2.5%), while persisting facial spasm only occurred in a single patient (0.6%). With some limitations due to the varying definitions of tumor growth, radiological tumor control was achieved in 93.8% with further treatment indicated in six individuals (3.8%), which is comparable to a broad spectrum of published recurrence rates
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following MS [5,21,24]. Predictors of treatment failure in terms of regrowth or the indication for second line treatment were not elaborated in detail since these were only analyzed in single cases or studies. However, NF was present in two of three patients with radiological tumor progression in one study [18]. Van de Langenberg et al. found that neither patient-related characteristics nor radiological features (for example, tumor size, enhancement or cystic components) correlated with tumor progression [21]. Contrarily, Yang et al. showed higher rates of tumor control in cystic VS, challenging currently published data of reduced tumor control after GKS in cystic VS, although this was not statistically significant [22]. Concerning the six analyzed studies, results of a combined treatment strategy were comparable to conventional and hypofractionated stereotactic radiotherapy (SRT) in recently published studies, where local tumor control was achieved in 90–100% with preservation of facial nerve function in up to 100%. Although hearing preservation, when reported, was over 90%, tumor sizes differed widely among these studies and tumors were smaller compared to most of the analyses included in this review [3,4,25]. Investigations on larger tumors exceeding 3 cm in diameter treated by SRT showed controversial results with increasing risk of facial palsy and further CN deficits in some series [26–29]. Since local tumor control following SRT seems to decrease with increasing tumor size [26], the role of SRT alone and in combination with previous MS in treating larger VS remains to be elucidated in further studies. The range of postoperative tumor volumes or diameters was large among the studies included in this analysis and no correlation was observed between treatment failures after surgery and GKS and tumor size. Intuitively, higher control rates would have been expected with smaller residual tumor volumes, which did not appear to be the case in the present analysis. Nevertheless, large tumors after surgery and GKS have been observed to be particularly difficult to handle if surgery again becomes necessary [30]. For this reason, surgeons should still strive to minimize residual tumor load even if secondary GKS is planned. The authors are aware of several limitations of this work. Results of the single studies are consistently based on small (eight to 61 patients) cohorts. The analyzed criteria and study methods differed widely in some cases. Moreover, this review could only include a subselection of data due to inconsistencies among the individual publications. Since the study design was retrospective in each analysis, it is evident that further prospective randomized studies are needed. In our mind the appropriate prospective comparison would be between MS alone and the combined treatment strategy of IR and radiosurgery. We are presently contemplating such a study in a multicenter setting. Nevertheless, with the aforementioned limitations, the combined treatment modality of MS and radiosurgery appears to be a safe and effective approach for treating large VS. With apparently good clinical outcomes and local tumor control, these data suggest that a restrictive MS (IR) approach incorporating safe maximum tumor reduction followed by GKS may be a feasible option for VS patients and we strongly encourage further investigation in prospective clinical trials. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Milligan BD, Pollock BE, Foote RL, et al. Long-term tumor control and cranial nerve outcomes following gamma knife surgery for larger-volume vestibular schwannomas. J Neurosurg 2012;116:598–604.
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