The optimal management of VS remains a matter of debate. For small to medium-sized lesions, the options are radiosurgery, microsurgery or a “wait and scan” approach. Small to medium-sized (Koos grade I to III) symptomatic lesions can be treated either by surgery or by radiosurgery based on surgeon preference or availability of expertise. For small to medium-sized tumors, comparative studies suggest that GKRS might compare favorably with microsurgery, with a high degree of local tumor control, a much lower rate of facial nerve palsy, and a much higher rate of serviceable hearing preservation [
44,
46,
51,
52,
55]. Recent clinical trials have suggested pro-active radiosurgical treatment, even in small Koos grade I intracanalicular tumors [
57].
Large symptomatic VS are generally considered to be an indication for microsurgical excision, except in cases with significant co-morbidities contraindicating open surgery. The management remains challenging, especially with regard to facial and cochlear nerve outcomes. The expectations of the patients with large VS and their referral doctors have increased, especially in the current context of high-quality outcomes that are available for patients with smaller lesions treated with GKRS. Thus, patients with large VS are often referred to centers equipped with radiosurgery, expecting results comparable with those reported in patients with smaller lesions. The change in our treatment paradigm for the treatment of large VS was made specifically to address those issues.
In our series, only 32 out of 257 patients (12.4%) had Koos grade IV tumors, which may seem a comparably low percentage compared with other studies. However, if we look at recent studies with approaches comparable with ours, we may find an even lower percentage of Koos grade IV tumors. For example, in Iwai et al. [
29], which is a large series with a long-term follow-up, the percentage of Koos grade IV tumors is 10.5%. Thus, we believe that it will be less and less uncommon to have a low percentage of Koos grade IV tumors in modern series of VS, especially in teams offering radiosurgery in addition to combined approaches.
Facial nerve outcome in the management of large VS
For microsurgery of large VS, it has been well accepted that the size of the tumor is the main predictor for preservation of the facial nerve, both anatomically and functionally [
31,
64]. The risk for facial nerve dysfunction in patients with VS larger than 3 cm is 6-fold greater than in patients with smaller tumors [
73]. In Samii et al.’s series of large VS [
64], even though a facial nerve function considered excellent/good was achieved in 75%, subgroup analysis shows that only 25% of patients retained H–B I facial nerve function after surgery. Following total microsurgical resection of large VS (larger than 3 cm in size), facial nerve function preservation (H–B I or II) was achieved in 27–58% [
3,
31,
40,
62,
63,
79] in the major reported series.
A meta-analysis published by Gurgel et al. [
21] analyzed facial nerve outcomes after surgery for large VS depending on the type of surgical excision. They found that H–B I or II were reported in 65.2% of the 601 retrosigmoid approaches included in their study. Furthermore, facial nerve outcomes were not significantly different using translabyrinthine or retrosigmoid approaches, but showed statistically better outcome, compared with the extended translabyrinthine approach. In the same meta-analysis [
21], the authors found a strong and significant association between the degree of resection and outcome. Of the 80 patients with subtotal resection, 92.5% had good facial nerve outcomes, compared with 74.6% and 47.3% of those who received near-total resection and gross total resection respectively.
Subtotal resection achieves better preservation rates, between 82 and 88% (H–B I and II) [
37,
50], and even almost 100% in some reports [
27]. When using a combination of microsurgery and radiosurgery for large VS, authors reported facial nerve function preservation (H–B I and II) ranging between 85.7 to 95% [
15,
27,
49,
50,
69]. For example, in the series by Van de Langenberg et al. [
69], after planned subtotal resection, good facial nerve outcomes (H–B I or II) were reported in 94% of the cases after microsurgery and GKRS. In another series by Pan et al. [
49], outcomes were reported after intracapsular decompression (group I) or radical extracapsular resection (group II). For group I, the pre- and post-surgical tumor volumes were 17.5 ± 1.1 cm
3 and 9.35 ± 1.02 cm
3 respectively, and for the group II they were 16.4 ± 0.95 cm
3 and 1.1 ± 0.14 cm
3 respectively. For group I, 90% of the patients retained excellent facial function (H–B I or II). For group II, only 35% retained excellent facial nerve function (data statistically significant).
It is worth noting that most of the series reporting facial nerve function after microsurgical resection, “excellent” or “good” results usually include patients in H–B I or II (or sometimes reaching H–B I to III), which from the functional point of view and quality of life of the patients is not similar to “normal” facial nerve function (i.e., H–B I).
For small- to medium-sized VS (Koos grades I to III) treated with first-line GKRS, Regis et al. [
60] recently reported their experience in a very large cohort of 3,050 patients, with 2,336 having a minimum of 3 years’ follow-up, over a 20-year period of experience. Although the global rate of transient facial palsy was less than 0.5% in the entire series, there was a definite trend in improved facial nerve outcomes with experience and new technology. Since the introduction of GKRS robotization, facial nerve paresis has virtually disappeared in their series. This observation is in agreement with our experience in treating VS with GKRS, since the introduction and use of the Leksell Gamma Knife® Perfexion™ in Lausanne, with no permanent facial nerve impairment in our whole series.
Thus, our current results in patients with large VS, with 100% facial nerve functional preservation, H–B I outcome, and a high level of hearing preservation, compete favorably with the existing literature on the surgical management of large VS. This supports the assumption that our combined approach warrants strong consideration and further evaluation as a preferred option for those patients with larger tumors.
Hearing outcome in the management of large VS
The size of VS does not necessarily correlate with the presence of serviceable hearing at the time of presentation [
68]. Large tumors can also present with good hearing levels. Hearing preservation rates following microsurgical resection in large VS vary between 0 and 29% [
12‐
14,
25,
63,
64,
73]. In one of the publications by Samii et al. [
64], the probability of hearing preservation after total excision was estimated to be 11%. In a surgical series of 54 patients (75.9% total removal) with preserved hearing at the time of surgery and VS measuring ≥ 20 mm in extrameatal diameter (16 patients with ≥30 mm), hearing preservation was achieved in 53.7%, but only 31% had maintenance (or improvement) of hearing at the same level as before surgery [
71]. In a recent systematic review on VS surgery, Ansari et al. [
2] reported on 127 patients with tumors with a maximal diameter larger than 3 cm. This report did not provide the stratified data on the extent of tumor removal across the series. Nevertheless, hearing preservation was found to be possible in only 28.3% [
2]. Di Maio et al. reported on a series of 46 large tumors (≥ 30 mm); 28 patients had hearing preservation surgery and of these patients, 6 (21.4%) had hearing preservation after surgery [
10].
By comparison, for small to medium-sized tumors, radiosurgery data show a hearing preservation rate ranging between 38% and 94% [
6,
23,
34,
36,
38,
48,
56,
70,
74]. A recent meta-analysis of published literature on GKRS for VS included 28 studies published between 2007 and 2011, with 3,233 patients [
61]. The average prescription dose was 12.4 Gy. The preservation of serviceable hearing was on average 66.45%, with a mean follow-up of 51 months. The authors also made a comparison with similar studies [
45,
72,
75‐
78], showing the preservation of serviceable hearing in 20–57% of the patients. In a systematic review, Yang et al. [
77] included 45 articles, with 4,234 treated patients, and a median reported follow-up of 35 months. The mean GKRS dose was 14.2 ± 2.4 Gy. The overall hearing preservation rate was 51%, irrespective of radiation dose, tumor size or patient’s age. The authors concluded after a more detailed analysis that a marginal dose less than 13 Gy was associated with a higher rate of preserved hearing.
Recent literature reveals better hearing outcomes with the subtotal excision of large VS, with or without additional radiosurgery. Van de Langenberg et al. [
69] reported hearing preservation in only one of 4 patients with serviceable presurgical hearing. In another series of 11 patients who underwent intracapsular decompression of VS followed by GKRS, Pan et al. [
49] reported hearing to be preserved in all patients, even though surprisingly, they reported only 89% facial nerve preservation in the same series.
The results of our series are also in line with these reports, showing hearing preservation that is comparable with those results, or even better.
Tumor control
Vestibular schwannomas are known to have a small annual rate of growth [
65]. Despite this, recurrences may occur between 7 and 11% when surgical resection is considered to be total [
40,
62], and between 7 and 53% in subtotal resection [
19,
32,
33,
54]. There is a clear relationship between the residual tumor volume and further recurrence. This observation is further confirmed by a recent series by Vakilian et al. [
67], in which the authors found that all VS with a postsurgical volume greater than 2.5 cm
3 recurred.
Tumor control rates of GKRS in VS are reported to be as high as 97.5% of the cases, with a median decrease in size of 40% at 7 years’ follow-up [
60]. A recent meta-analysis of published literature on GKRS for VS, which included 28 studies published between 2007 and 2011 and 3,233 patients reported an average tumor control of 92.7%, after a mean follow-up of 51.24 months [
61]. The authors also made a comparison with similar studies [
45,
72,
75‐
78], showing 81–100% tumor control for tumors ranging from 2.7 to 4 cm
3.
The reported tumor control rate for combined approaches ranges between 79% and 100%, with our study reporting 91.6% (Table
3). In this sense, our local control is perfectly comparable with what has been published to date. Nevertheless, an analysis of actuarial tumor control rates would show lower rates (i.e., 90.7%, and actuarial rates of 94% at 1 year, 88% at 2 years, and 77% at 2.6 years, which further remained stable over time) than in large series of upfront GKRS for VS. However, at this stage of our analysis, the interpretation of the actuarial control rate for the current follow-up period, on a small sample size and a small number of failures (only 3 cases) should be cautiously interpreted. As there was no selection bias regarding the inclusion of patients treated with our combined approach, several other hypotheses may account for this finding. These large tumors could be biologically more aggressive, a fact that cannot yet be proven with standard neuropathological examinations. Although not performed systematically in our series, many pathological samples have been tested for Ki-67 or MIB1 indexes, and did not show any abnormal increase in cell proliferation with these markers (data not shown). Advances in pathological evaluation, searching for specific biological markers for the possible aggressive nature of VS, may help to better understand the specific situation of these failures. Another important factor could be the learning curve of the neurosurgical technique, from the point of view of the ability to have the thinnest and uniform residual capsule that is left in place covering the facial and cochlear nerves; the learning curve for the GKRS planning in its ability to achieve an optimal plan in these difficultly shaped target volumes could also be a factor of failure. Of note, the 3 cases of failures happened in patients treated early in this series (i.e., patients numbers 3, 9, and 11). Increased experience with subtotal excision and optimized planning radiosurgical strategies could reduce the incidence of treatment failures with this approach.
Table 3
Summary of the main series published in the literature
| 14 | 32 | 85.7 | NA | 79 |
| 8 | 68.8 | NA | NA | 100 |
| 61 | 53.7 | 95 | NA | 93.5 |
| 8 | 46 | 87.5 | NA | 100 |
Van de Langenberg et al. [ 69] | 50 | 33.8 | 94 | 25 (1/4) | 90 |
| 18 | 57 | 89 | 100 (11/11) | 100 |
| 40 | 66 | 95 | 42.9 (6/14) | 90 |
| 22 | 28 | 87 | NA | 100 |
Present study | 32 | 29 | 100 | 76.9 (10/13) | 91.6 |
Combination of surgery and GKRS for large VS
Surgery for large VS is currently considered the gold standard. The number of patients presenting with large VS is decreasing, as imaging diagnosis and management are performed earlier in smaller tumors. For example, in our series, when all consecutive patients managed in our center were considered, only 25 patients out of 217 (11.5%) presented with VS too large for upfront GKRS, and underwent planned subtotal surgical excision as part of a combined approach. This low number reflects the incidence of large VS in a skull-base neurosurgical center rather than low recruitment, as almost 90% of our patients could be treated with upfront radiosurgery, and VS represent more than 25% of our GKRS activity.
Although it seems that planned partial resection followed by radiosurgery has become an increasingly popular approach in the neurosurgical community, very few centers have reported their results, as recently reviewed by Iwai et al. [
28]. Pan et al. [
49] compared two groups of patients with large VS, namely partial excision followed by GKRS (group 1 with 18 patients) versus total excision (group 2 with 17 patients). An excellent facial nerve outcome (H–B I or II) was achieved in 89% in group I and in 35% in group II; hearing preservation was 100% in group I and 0% in group 2. In Van de Langenberg’s series of 50 patients with the same surgical strategy [
69], an excellent facial nerve outcome (H–B I or II) was achieved in 94% and hearing was preserved in 1 out of 4 patients. A recent systematic review by Brokinkel et al. [
4] analyzed 6 studies of GKRS following subtotal resection. There were 159 patients with a tumor diameter more than 2 cm. After a mean follow-up of 15 months, good facial nerve function (H–B I or II) was achieved in 94%, whereas serviceable hearing preservation was achieved in 11.6%. Tumor growth control was achieved in 93.8%. Recently, Radwan et al. [
53] have presented their results in a series of 22 patients treated with planned subtotal resection. Seventeen of them had radiosurgery and 5 wanted to undergo a “wait-and-scan” strategy for the remnant. Immediately after surgery, 68% of the patients had good and moderate facial nerve function; however, 32% had significant facial weakness (H–B IV or even higher). After a mean postoperative follow-up period of 28 months, 86.4% presented excellent facial nerve function, the former still including, however, H–B grades I and II. Regarding hearing preservation, 36% had serviceable hearing, including 6 patients with G–R 2 and 2 patients with G–R 1; one had decreased hearing function at 6 months after radiosurgery (passing from G–R 2 to G–R 4). Facial numbness was encountered in 18% immediately after surgery, showing improvement within the follow-up course; 9% experienced temporary dysphagia and dysarthria. The mean time between surgery and radiosurgery was 9.5 months. In this series, the radiosurgery management was heterogeneous, with 9 cases undergoing GKRS and 7 hypofractionated regimens [
53].
Again, compared with those results, our series of 32 patients with large VS provides optimal results, with a normal facial nerve function (H–B I) outcome in 100% of the cases, and a high rate of hearing preservation (77.8% of the patients in G–R 1 preoperatively remained at G–R 1, and 92% of the patients with residual hearing G–R 1–3 preoperatively remained in G–R 1–3 postoperatively).
Achieving the optimal residual tumor volume for radiosurgery after microsurgical resection is not always easy, especially when cochlear nerve function preservation is the goal. This is exemplified in our series, where we found in 3 patients that the residual volume was too large for safe GKRS and we therefore decided on a second planned subtotal surgery. The facial nerve outcome was identical after the second surgery and GKRS (H–B I), but 1 patient lost hearing. However, the benefit of a staged resection needs to be balanced with the morbidity associated with a second hospitalization and craniotomy. If a single-stage excision can achieve the same outcome, this situation remains preferable [
22]. In our experience, the 3 patients who needed staged surgery clearly reflect the learning curve of the technique that we have developed.
The inherent philosophy of combining surgery with radiosurgery needs a good understanding of both the therapeutic steps and its respective safety–efficacy evaluation. Although the microsurgeon can avoid direct dissection between the tumor capsule and the facial and cochlear nerves and improve the functional outcome of resection with a “nerve-centered” tumor surgery approach, the GKRS surgeon needs to appreciate that treatment planning may be more difficult because of the modification of local conditions as a result of surgery, to achieve a treatment plan that allows for the best functional outcome, as for smaller tumors. Both the extent of the planned microsurgical resection and the radiosurgical management, including its timing, are key to the success of this approach. There are 2 strategies for the subtotal resection of large VS. One consists in a planned subtotal resection in which the neurosurgeon focuses the technique on cranial nerve preservation and on resecting only the amount of tumor that is needed to render the residual tumor volume compatible with radiosurgery. This yields to the best functional outcome, as recently reviewed by Iwai et al. [
28] and reported in our series. Another approach consists in performing a near-total extirpation, aiming to leave only a small tumor remnant, usually at the level of the internal acoustic porus, considering that it is the location in which the facial nerve is particularly at risk for injury and functional impairment. This approach, whose goal is also a better functional outcome, has proven to be less favorable. For example, in the recent publication by Jeltema et al. [
30], aimed at near total extirpation of large VS with salvage radiosurgery only when the remnant is showing growth, normal facial nerve function (H–B I) was achieved in only 57.7% of the cases, whereas 32.7% of the patients had mild (H–B II–III) facial function impairment after surgery, and 9.6% had severe (H–B IV–V) impairment; there was no mentioning of the hearing status. Thus, this later approach does not represent a “real” planned subtotal extirpation, and functional results might have been better if a larger residual tumor had been left in place. The subsequent, and related, issue concerns the timing of radiosurgery after subtotal resection of VS. Although Jeltema et al. [
30] are in favor of salvage radiosurgery only when the remnant is growing, arguing that it was needed in only 13% of their series, we and others [
28] believe that in planned subtotal resection, when a larger piece of VS is left in place, GKRS should take place in the months following surgery, as part of a combined approach. We consider that the residual tumor is at a high risk for further regrowth and we prefer to perform GKRS when the residual VS has a volume and anatomical relationship that is suitable for optimal radiosurgery dosimetry planning and treatment.
Study limitations
There are several limitations of the present study. The first is the short follow-up period following surgery and GKRS; there is a need for further evaluation and re-confirmation of the current clinical and neuroimaging results presented in this study. Second, owing to the small sample size, the statistical power is limited. Third, there was a relatively short interval between the surgical resection and GKRS targeting, which may not have offered enough time for good visualization of the tumor and thus allow optimal GKRS targeting. Fourth, there is an ongoing debate concerning the regrowth of the residual tumor after surgery and the possible need for further irradiation. In our center, the current strategy is to offer a combined treatment to the patient from the very beginning, including both a planned subtotal surgery and further GKRS on the residual tumor several months later.