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. 2021 Aug 13;8(6):639–651. doi: 10.1093/nop/npab052

Assessing the long-term safety and efficacy of gamma knife and linear accelerator radiosurgery for vestibular schwannoma: A systematic review and meta-analysis

Sergio W Guadix 1, Alice J Tao 1, Anjile An 2, Michelle Demetres 3, Umberto Tosi 4, Swathi Chidambaram 4, Jonathan P S Knisely 5, Rohan Ramakrishna 4, Susan C Pannullo 4,✉
PMCID: PMC8579095  PMID: 34777833

Abstract

Background

Differences in long-term outcomes of single-fraction stereotactic radiosurgery (SRS) between gamma knife (GK) and linear accelerator (LINAC) systems for vestibular schwannoma (VS) management remain unclear. To investigate differences in safety and efficacy between modalities, we conducted a meta-analysis of studies over the past decade.

Methods

MEDLINE, EMBASE, and Cochrane databases were queried for studies with the following inclusion criteria: English language, published between January 2010 and April 2020, cohort size ≥30, and mean/median follow-up ≥5 years. Odds ratios (OR) compared rates of tumor control, hearing preservation, and cranial nerve toxicities before and after SRS.

Results

Thirty-nine studies were included (29 GK, 10 LINAC) with 6516 total patients. Tumor control rates were 93% (95% CI 91-94%) and 94% (95% CI 91-97%) for GK and LINAC, respectively. Both GK (OR 0.06, 95% CI 0.02-0.13) and LINAC (OR 0.47, 95% CI 0.29-0.76) reduced odds of serviceable hearing. Neither GK (OR 0.71, 95% CI 0.41-1.22) nor LINAC (OR 1.13, 95% CI 0.64-2.00) impacted facial nerve function. GK decreased odds of trigeminal nerve (TN) impairment (OR 0.55, 95% CI 0.32-0.94) while LINAC did not impact TN function (OR 1.45, 95% CI 0.81-2.61). Lastly, LINAC offered decreased odds of tinnitus (OR 0.15, 95% CI 0.03-0.87) not observed with GK (OR 0.70, 95% CI 0.48-1.01).

Conclusions

VS tumor control and hearing preservation rates are comparable between GK and LINAC SRS. GK may better preserve TN function, while LINAC decreases tinnitus rates. Future studies are warranted to investigate the efficacy of GK and LINAC SRS more directly.

Keywords: acoustic neuroma, gamma knife, linear accelerator, radiosurgery, vestibular schwannoma

Vestibular schwannoma (VS), also termed acoustic neuroma, is the most common tumor of the cerebellopontine angle with an incidence of 0.2-1.7 in 100 000.1,2 It is a benign nerve sheath tumor, originating from the Schwann cells of the vestibular portion of cranial nerve (CN) VIII.3,4 More than half of VS will grow after 5 years3 and, if left untreated, patients can present with symptoms due to compression of the fourth ventricle and brainstem, leading to obstructive hydrocephalus along with trigeminal nerve (TN) and facial nerve (FN) dysfunction.5

Intervention for VS is generally offered to address tumor growth causing progression of symptoms (eg, facial weakness, dizziness, tinnitus, progressive hearing loss) and to maintain quality of life for patients.1,6–19 Stereotactic radiosurgery (SRS) is a well-established treatment modality for VS that utilizes stereotactic tumor localization and precise dose conformality to deliver beams of radiation to tumor margins.20 The safety and efficacy of SRS for VS have been demonstrated in numerous retrospective and prospective studies. In particular, SRS for small- to medium-sized VS without significant mass effect (<3 cm or Koos Grades I-III) compares favorably to microsurgery in terms of CN preservation,21–25 rates of hearing preservation,21,22,24–26 and quality of life.21,24 Greater decreases in tumor volume are also seen at 5 years after SRS compared with observation alone.27

SRS is most commonly administered with either gamma knife (GK) or linear accelerator (LINAC) systems. GK models utilize approximately 200 spatially fixed Cobalt-60 radiation sources that combine collimated beams to deliver a high radiation dose to a single target point. LINAC radiosurgery uses a moving megavoltage x-ray source with multiple skull entry points to deliver highly collimated beams of radiation.15,28 Sequential patient positional shifts, durations of time that irradiation is being delivered, and precisely specified radiation beam geometries permit the entire tumor’s volume to receive a therapeutic dose.29 The fundamental engineering decisions employed in the design of these radiosurgery platforms have downstream effects on how each device can precisely deliver focal high-dose radiation to tumor sites. These differences necessitate modified clinical practices to achieve optimal dose-planning and radiosurgical technique.15 Despite these differences, studies have traditionally investigated the efficacy of each modality independently with little examination of the comparative safety or effectiveness of LINAC and GK SRS systems.30 Given the paucity of evidence, current guidelines are unable to remark on the superiority or non-inferiority of one SRS delivery system over another.30 This systematic review and meta-analysis seeks to address this significant gap in the literature by compiling evidence on long-term tumor control, hearing preservation, and CN toxicities from studies of large patient cohorts receiving GK or LINAC SRS published in the past decade (2010-2020).

Methods

Literature Search Protocol

This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.31 In adherence to these guidelines, a protocol was registered in PROSPERO, an international prospective registry of systematic reviews (registration # CRD42020178627).

Comprehensive searches (Supplementary Figure 1) were run on April 6, 2020 in the following databases: Ovid MEDLINE (1946 to present); Ovid EMBASE (1974 to present); and Cochrane Library (Wiley). Search terms included all subject headings and associated keywords for the concepts of “vestibular schwannoma” and “stereotactic radiosurgery.”

Study Selection and Eligibility Criteria

Abstract and full-text reviews were performed in the online Covidence systematic review screening software (Veritas Health Innovation, Melbourne, Australia) by 2 independent reviewers. After duplicate results were removed, titles and abstracts were reviewed against pre-defined inclusion/exclusion criteria listed below. Full text was then pulled for 791 selected studies for a second round of eligibility screening. Reference lists and articles citing included studies were pulled from Scopus (Elsevier) and also screened. The full PRISMA flow diagram is displayed in Figure 1.

Figure 1.

Figure 1.

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PRISMA flow diagram of study identification, screening, and selection. Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

We included peer-reviewed publications meeting the following major inclusion criteria: (1) English-language studies published from January 2010 to April 2020, (2) single-fraction SRS used as the primary treatment modality, as opposed to other fractionation techniques, (3) cohorts with ≥30 patients, (4) median or mean reported patient follow-up ≥5 years, (5) studies reporting primarily on adult patients, and (6) studies reporting on functional outcomes, rather than quality of life measures.

Studies were restricted to the past decade to reflect contemporary practice and capture publications with more standardized reporting methods, which have become increasingly prevalent over time.32–34 The median/mean follow-up criterion of 5 years was implemented to lower the likelihood of pseudoprogression33,34 artificially affecting results of the included studies.

To further reduce heterogeneity, as done in previous reviews,13 studies were excluded if they only focused on a particular subgroup of patients (eg, only large VS, neurofibromatosis type 2 [NF2] patients, recurrent VS, etc.). This approach safeguarded against one SRS system including significantly higher proportions of these specific patient populations, potentially biasing results. Additionally, studies were excluded if they did not differentiate between patients receiving GK or LINAC.

Outcomes of Interest

Primary outcomes were rates of tumor control (most often defined by <10% increase in tumor volume at follow-up and no need for surgical intervention), serviceable hearing, and nonauditory morbidity including FN and TN impairment. Secondary outcomes included tinnitus and postoperative hydrocephalus, with or without the need for ventriculoperitoneal shunting.

Data Extraction

Data from included studies were extracted manually and stored in Microsoft Excel (Microsoft Office, 2018). Relevant study characteristics extracted were authors, publication year, study design, median and/or mean follow-up, and number of patients treated with SRS. Patient variables extracted were age, prior surgical or radiation therapy, and NF2 status. Tumor volume and control rates were noted. Treatment characteristics included SRS device type (GK vs LINAC) and fractionation regimen (median dose, dosage range, isodose line). Adverse events associated with SRS included rates of serviceable hearing (defined as Gardner-Robertson Scale I or II), TN and FN impairment, tinnitus, and hydrocephalus. We broadly defined CN dysfunction given the considerable heterogeneity with which studies reported TN and FN symptoms. However, FN impairment was most often assessed with the House-Brackmann scale.

Statistical Analysis

Meta-analyses for complication odds ratios (OR) were conducted for studies using GK and LINAC SRS. Statistical heterogeneity was tested through the Cochrane Q test and a P value ≤0.20 was used to indicate the presence of heterogeneity. Statistical heterogeneity was also assessed by the inconsistency statistic (I2). However, regardless of the heterogeneity test P value or I2 statistic percentage, a random-effects analysis was used to calculate the pooled ORs. To assess complication proportions, the results of each study were expressed as binary proportions with 95% confidence intervals (CIs). For studies with pre- and post-radiosurgery complication proportions, we conservatively treated the pre- and post-groups as independent to facilitate an OR computation. The results of each study were expressed as an OR comparing the post-radiosurgery proportion to the pre-radiosurgery proportion with 95% CIs. A continuity correction of 0.5 was used in studies with zero cell frequencies.

For each analysis of complication type, the presence of publication bias was evaluated through a funnel plot, displayed as a scatter plot of the complication proportions/ORs estimated from individual studies vs a measure of study size or precision. The Egger’s test was used to statistically assess the presence of publication bias. All analyses were conducted with the use of R Version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Study Selection and Characteristics

Our systematic review revealed no randomized controlled trials (RCTs) assessing outcomes of GK vs LINAC SRS for VS treatment. Only one 2-arm study35 included patients stratified by SRS device type, though patient stratification was not randomized and ultimately the results were not stratified by SRS system. Out of a total of 39 studies included, 29 primarily utilized GK SRS for VS, and 10 used LINAC SRS. Overall, these included data from over 6516 patients: 5788 GK, 728 LINAC. SRS was delivered as a single fraction. Overall, the median dose ranged from 11 to 13 Gy at the 57% isodose line for GK and 12 to 18 Gy at the 80% isodose line for LINAC. Relevant patient characteristics (age, prior therapy, NF2 status, tumor volume, SRS dose received) and treatment outcomes (tumor control, CN impairment, hearing preservation, tinnitus, hydrocephalus) are summarized for GK (Table 1) and LINAC (Table 2).

Table 1.

Gamma Knife (GK) Studies and Patient Characteristics

First Author, Year N Median SRS Dose (Gy); Range (Isodose) Age Mean/Median; Range (yr) Prior Therapy NF2 Median Tumor Volume; Range (cm3) Mean f/u; Range (mo) Median f/u; Range (mo) Tumor Control at f/u CN V Deficit CN VII Deficit Serviceable Hearing Tinnitus Post-SRS Hydrocephalus
Pre- SRS Post- SRS Pre- SRS Post- SRS Pre- SRS Post- SRS Pre-SRS Post- SRS
Nagano, 2010a 87 12;10.5-13 (52.2%) 58.6/59; 29-80 27/87 (31.0%) N/A 1.9; 0.1-13.2 90; 60-133.2 85.2; 60-133.2 78/87 (89.7%) 17/87 (19.5%) 10/87 (11.5%) N/A 14/87 (16.1%) N/A N/A N/A N/A N/A
Nakaya, 2010b 202 13 (50%) 61;18-95 0/202(0%) 0/202(0%) 3.9; 0.76-38.6 65; 12-179 196/202 (97%) N/A N/A N/A 7/200(3.5%) 12/202(5.9%) 9/186(4.8%) N/A N/A N/A
Wackym, 2010a 59 12.84;11.7-14(50.6%) N/A 7/59(11.9%) 0/59(0%) N/A 63.76; 9-109 65.5; 9-109 N/A 9/59 (15.3%) 8/59 (13.6%) 6/59 (10.2%) 5/59(8.5%) 38/59(64.4%) N/A 29/59(49.2%) 26/59 (44.1%) N/A
Sun, 2012b 190 13;6-14.4 (45%) 50.6;10-77 56/190 (29.5%) 0/190(0%) 3.6; 0.3-27.3 109;8-195 170/190 (89.5%) 10/190 (5.3%) 2/190 (1.1%) 53/190 (27.9%) 68/190 (35.8%) 22/190(11.6%) 18/190(9.5%) 124/190 (65.3%) 69/190 (36.3%) 6/190 (3.2%)
Yomo, 2012b 154 12.1;9-14 (51.1%) 54.1;24-76 0/154(0%) 0/154(0%) 0.73; 0.03-5.37 60;6-132 142/154 (92.2%) N/A 2/154 (1.3%) N/A 1/154 (0.65%) 105/154 (68.2%) 64/154 (41.6%) N/A N/A N/A
Carlson, 2013b 44 12;12-13 (N/A) 56.9/58; 36-72 0/44(0%) 0/44(0%) 0.715; 0.153-12 99.6; 60-168 111.6; 60-168 N/A N/A N/A N/A N/A 44/44(100%) 8/44(18.2%) N/A N/A N/A
Hasegawa, 2013b 427 12.8;10-18 (50%) 55; 7-86 93/427 (21.8%) 13/427(3%) 2.8; 0.07-36.7 150; N/A 396/427 (92.7%) N/A N/A 20/347 (5.8%) 5/430(1.2%) 117/117(100%) 56/117(47.9%) N/A N/A 25/427 (5.9%)
Kim, 2013b 58 12.2;11.5-13 (50.7%) 49.6;21-69 0/58(0%) 0/58(0%) 0.34; 0.03-1 61.5; 36-141 51/58 (87.9%) N/A N/A N/A N/A 60/60(100%) 34/60(56.7%) 32/60(53.3%) N/A N/A
Massager, 2013b 139 12;12-14 (N/A) N/A N/A N/A 1.1; 0.01-8.3 78;60-138 126/139 (90.6%) N/A N/A N/A N/A N/A N/A N/A N/A N/A
Mindermann, 2013b 235 12.9(N/A) 57.3 20/235 (8.51%) 0/235(0%) 1.85 62.4; N/A 214/235 (91.1%) N/A N/A N/A N/A N/A N/A N/A N/A N/A
Anderson, 2014b 48 12.5;9.7-16 (N/A) N/A 11/48 (22.9%) 1/48(2.1%) 0.66 83.6; N/A 47/48 (97.0%) 18/48 (37.5%) 18/48 (37.5%) 13/48 (27.1%) 10/48 (20.8%) 12/12(100%) 7/12(58.3%) 18/48 (37.5%) 14/48 (29.2%)
Bir, 2014b 82 12;12-13 (50%) 62;14-89 20/82(24%) N/A 3.24; 0.24-16 60;6-144 74/82 (90.2%) 0/82(0%) 3/82(3.7%) 16/82 (19.5%) 5/82(6.1%) N/A N/A 12/82(14.6%) 9/82 (11.0%) 1/82(1.2%)
Boari, 2014b 379 13;11-15 (50%) 59/61; 23-85 0/379(0%) 0/379(0%) 1.2; 0.013-14.3 75.7/69.5; 36-157 368/379 (97.1%) 37/379 (9.8%) 24/379 (6.3%) 29/379 (7.7%) 11/379(2.9%) 187/379 (49.3%) 47/96(49%) 150/379 (39.6%) 142/379 (37.5%) 20/379 (5.3%)
Wangerid, 2014b 128 12.3 (mean); 11-16(50-60%) 64;23-89 0/128(0%) 0/128(0%) 1.65 (mean); 0.1-8.4 96;11-165 113/123 (91.9%) N/A 3/128 (2.3%) 1/128 (0.78%) 4/128 (3.13%) N/A N/A 52/128 (40.6%) N/A 4/123 (3.3%)
Akpinar, 2016b 88 12.5;11.5-13 (N/A) 47;20-71 0/88(0%) 0/88(0%) 0.72; 0.11-12.8 75;12-169 82/88 (93%) 3/88(3.4%) N/A 3/88(3.4%) 3/88(3.4%) 88/88(100%) 67/88(76.1%) 56/88(63.6%) N/A N/A
Klijn, 2016b 420 11.1;8.8-13 (62%) 57.6;15-86 0/420(0%) 0/420(0%) 1.4; 0.01-17.7 61.2; 2.4-144 375/420 (89.3%) 65/420 (15.5%) 13/420 (3.1%) N/A N/A 71/71(100%) 43/71(60.6%) N/A N/A 5/420 (1.2%)
Mousavi, 2016b 166 12.5; 12-13 (N/A) 49;20-71 0/166(0%) 0/166(0%) 0.8; 0.1-12.8 65;12-183 153/166 (92.2%) 0/166(0%) 0/166(0%) 1/166 (0.60%) 1/166 (0.60%) 166/166(100%) 112/166 (67.5%) 89/166 (53.6%) N/A 0/166(0%)
Watanabe, 2016b 180 14.8; 13-18 (60%) 56;11-80 56/183 (30.6%) 10/183 (5.5%) 2; 0.05-26.2 114; IQR 73-144 158/180 (87.8%) 6/183 (3.3%) 6/183 (3.3%) N/A N/A 74/183(40.4%) 23/66(34.8%) N/A N/A 11/183 (6.0%)
Lin, 2017b 100 12;12-13(50%) 50.1 (mean) 0/100(0%) N/A Divided into size clusters 78;36-120 85/100 (85.0%) N/A N/A 7/100(7%) N/A 100/100(100%) 61/100(61%) 70/100 (70.0%) N/A N/A
Pan, 2017b 93 12(50%) 58; 57.7-15.1 0/93(0%) 0/93(0%) 3.14(mean) 76.3 N/A 9/93(9.7%) N/A 5/93(5.4%) 4/93(4.3%) 64/64(100%) 12/64(18.8%) 46/93(49.5%) 36/93 (38.7%) 1/93(1.1%)
Tveiten, 2017b 247 12 Gy(50%) 58.2 0/247(0%) 0/247(0%) Divided into size clusters 92.4 N/A N/A N/A 4/247 (1.6%) 9/247(3.6%) N/A N/A N/A N/A N/A
Wu, 2017b 187 12;11-13 (N/A) 52.2; 20.4-82.3 0/187(0%) 0/187(0%) 2; 0.1-16.2 60.8; 24-128.9 170/187 (90.9%) N/A N/A N/A N/A N/A N/A N/A N/A N/A
Hasegawa, 2018b 92 12;10.4-16.8 (50%) 54;17-77 1/92(1%) 0/92(0%) 1.5;0.1-14.5 106; 36-262 90/92 (97.8%) 4/92(4.3%) 1/92(1.1%) 1/92(1.1%) 0/92(0%) 92/92(100%) 49/92(53.3%) N/A N/A N/A
Milner, 2018b 45 12-13(50%) 55.8;34-75 0/45(0%) 0/45(0%) 1.75;0.012-9.504 69.6; 19-209 N/A N/A N/A N/A N/A 27/45(60%) 4/43(9.3%) N/A N/A N/A
Johnson, 2019b 871 13;8-25 (N/A) 57;19-95 0/871(0%) 0/871(0%) 0.9;0.02-36 62.4; 12-300 844/871 (96.9%) N/A N/A N/A N/A 326/326(100%) 196/326 (60.1%) 536/871 (61.5%) 510/817 (62.4%) N/A
Johnson, 2019 b 307 12.5;12-15 (N/A) 52;20-85 0/307(0%) 0/307(0%) 0.7;0.02-16.7 91.2; 12-276 291/307 (94.8%) N/A 18/307 (5.9%) N/A 0/307(0%) 307/307(100%) 186/307 (60.6%) N/A N/A 1/307 (0.33%)
Langenhuizen, 2019b 311 11.9;9.5-13.6(55%) 59;24-85 0/311(0%) 0/311(0%) 1.16;0.06-12.18 60;19-159 276/311 (88.7%) N/A N/A N/A N/A N/A N/A N/A N/A N/A
Tucker, 2019b 52 12.5;12-16 (50%) 59.8/63.7; 19.4-84.2 6/52(11.5%) 0/52(0%) 2.41;0.09-12.8 69;12-192 51/52 (98.1%) N/A N/A N/A N/A N/A N/A N/A N/A 1/52(1.9%)
Shinya, 2019b 397 13(N/A) 56 88/397 (22%) 0/397(0%) 2 103 373/397 (94.0%) N/A 12/422 (2.8%) N/A N/A 181/422 (42.9%) 91/422 (21.6%) N/A N/A 15/397 (3.8%)
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Abbreviations: CN, cranial nerve; f/u, follow-up; GK, gamma knife; IQR, interquartile range; N/A indicates not reported, excluded from analysis, or unable to determine; NF2, neurofibromatosis type 2; SRS, stereotactic radiosurgery.

aProspective study.

bRetrospective study.

A total of 29 studies investigating the long-term outcomes of GK SRS were included. GK SRS was most commonly delivered as a single fraction with a median of 11-13 Gy at the 57% isodose line. Relevant patient characteristics (age, prior therapy, NF2, tumor volume) and treatment outcomes (tumor control, CN impairment, hearing preservation, tinnitus, hydrocephalus) are summarized.

Table 2.

Linear Accelerator (LINAC) Studies and Patient Characteristics

First Author, Year N Median SRS Dose (Gy); Range (Isodose) Age Mean or Median; Range (yr) Prior Therapy NF2 Median Tumor Volume; Range (cm3) Mean f/u; Range (mo) Median f/u; Range (mo) Tumor Control at 5-yr f/u CN V Deficit CN VII Deficit Serviceable Hearing Tinnitus Post-SRS Hydrocephalus
Pre- SRS Post- SRS Pre- SRS Post- SRS Pre- SRS Post- SRS Pre- SRS Post- SRS
Hsu, 2010a 75 14; 12-20 (80%) 52.4; 21-77 N/A N/A 1.5; 0.1-23.7 97.8; 60-163 69/75 (92.0%) N/A N/A N/A N/A N/A N/A N/A N/A N/A
Roos, 2011a 102 12; 12-14 (70-90%) 60;19-83 6/102(5.9%) 5/102 (4.9%) N/Ac 65; 10-184 99/102 (97.0%) 19/102 (18.6%) 15/102 (14.7%) 7/102 (6.9%) 9/102 (8.8%) 50/97(51.5%) 19/97 (19.6%) N/A N/A 4/102 (3.9%)
Tsai, 2013a 117 18;(79%) 57.3; 24-90 24/117 (20.5%) N/A 4.7; 0.023-20.0 61.1; 18-87 116/117 (99.1%) N/A N/A N/A N/A 65/117 (55.6%) 53/65 (81.5%) N/A N/A N/A
Puataweepong, 2014a 39 12; 12-13 (80%) 47;16-71 25/39 (64.1%) 2/39 (5.1%) 0.96; 0.08-0.92 61; 12-143 37/39 (94.8%) N/A N/A 17/39 (43.6%) 17/39 (43.6%) 4/39(10.3%) 1/39(2.6%) N/A N/A 0/39(0%)
Ellenbogen, 2015b 50 12.5(80%) 59;15-79 7/50(14%) 1/50 (2.0%) 2.4; 0.24-10.59 69.6; 16.8-110.4 47/49 (95.9%) 0/50(0%) 2/50 (4.0%) 1/50 (2.0%) 2/50 (4.0%) 10/45(22.2%) 5/45(11.1%) 19/50 (38.0%) 0/50(0%) 0/50(0%)
Matsuo, 2015a 44 14; 10-16 (80%) 58;21-76 N/A N/A 2.38; 0.4-8.99 165.6; 66-234 40/44 (90.9%) N/A N/A N/A N/A N/A N/A N/A N/A N/A
Tu, 2015a 61 12 (80%) 65;24-80 N/A 0/61 (0%) N/A 160; 108-216 52/61 (85.2%) N/A 7/61 (11.5%) N/A 0/61 (0%) N/A N/A N/A 1/61 (1.6%) 2/61 (3.3%)
Kessel, 2016a 56 12; 12-20 (80%) 63;16-85 0/56 (0%) 0/56 (0%) 1.03; 0.09-5.36 90; 0-172.8 N/A 6/56 (10.7%) 9/56 (16.1%) 6/56 (10.7%) 6/56 (10.7%) 19/56(33.9%) 10/56(17.9%) 37/56 (66.1%) 39/56 (69.6%) N/A
Lo, 2018a 136 12(80%) 65;28-91 N/A 5/136 (3.7%) 2.9; 0.1-13.9 79.2 126/136 (92.6%) 28/136 (20.6%) 32/136 (23.5%) 26/136d (11.8%) N/Ad 17/153 (11.1%) N/A 76/136 (55.9%) 19/136 (14.0%) 6/136 (4.4%)
Anselmo, 2020a 48 16.5; 13-20 (90%) 61.5; 23-83 13 (27%) N/A 1.7; (0.09-7.4) 144; 24-192 44/48(91.7%) 6/48 (12.5%) 17/48 (35.4%) N/A N/A 23/48(47.5%) 21/46 (45.7%) 8/48 (16.7%) 0/48(0%) 1/48 (2.1%)
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Abbreviations: f/u, follow-up; N/A indicates not reported, excluded from analysis, or unable to determine; NF2, neurofibromatosis type 2; SRS, stereotactic radiosurgery.

aRetrospective study.

bProspective study.

cTumor size given in diameter.

dHB scale > 1; post-SRS HB scale not reported.

A total of 10 studies investigating long-term outcomes of LINAC SRS were included. SRS was delivered as a single fraction with a median of 12-18 Gy at an 80% isodose line. Relevant patient characteristics (age, recurrent tumor, NF2, tumor volume) and treatment outcomes (tumor control, cranial nerve impairment, hearing preservation, tinnitus, hydrocephalus) are summarized.

Primary Outcomes

Twenty-five studies reported tumor control rates at a median or mean follow-up of >5 years for GK and 9 studies for LINAC. 5721 patients received GK SRS and 671 received LINAC SRS. Rates of tumor control were similar between the 2 modalities with GK and LINAC studies achieving an overall tumor control rate of 93% (95% CI 91-94%) and 94% (95% CI 91-97%), respectively (Figure 2A and B). Heterogeneity between studies was significant amongst the GK (I2 = 76%; P < .01) and LINAC studies (I2 = 59%; P = .01). Among the included studies, Johnson et al36 (N = 871) and Lo et al37 (N = 136) contributed the most patients for each SRS modality and therefore contributed most to the overall results.

Figure 2.

Figure 2.

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Long-term tumor control for GK and LINAC SRS. (A) Twenty-five GK studies reported VS tumor control at a mean or median follow-up of >5 years. Overall tumor control at patient follow-up post-SRS was 93% (95% CI 91-94%). Heterogeneity of included studies was 76% (P < .01), indicating substantial methodological variation among included studies. (B) Nine LINAC studies reported VS tumor control. Overall tumor control at patient follow-up post-SRS was 94% (95% CI 91-97%). Heterogeneity of included studies was 59% (P = .01), indicating substantial methodological variation among included studies. Abbreviations: CI, confidence interval; GK, gamma knife; LINAC, linear accelerator; SRS, stereotactic radiosurgery; VS, vestibular schwannoma.

The odds of serviceable hearing before and after SRS were pooled for 19 GK and 6 LINAC studies (Figure 3A and B), totaling 3022 and 402 patients, respectively. There was a significantly decreased odds of post-SRS serviceable hearing for both modalities. The odds of serviceable hearing after GK SRS were estimated at 0.06 (95% CI 0.02-0.13), while the odds were 0.47 (95% CI 0.29-0.76) for LINAC SRS. There was marked heterogeneity among the GK studies (I2 = 92%; P < .01) that was not as substantial for the LINAC studies (I2 = 48%; P = .09). The largest contributors to the reported estimates were Johnson et al36 (N = 326) and Tsai et al38 (N = 117) for GK and LINAC, respectively.

Figure 3.

Figure 3.

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Rates of serviceable hearing preservation after GK and LINAC SRS. (A) Nineteen GK studies reported serviceable hearing rates before and after GK SRS at a mean or median follow-up of >5 years. Odds ratios (OR) are displayed, denoting the odds of serviceable hearing at patient follow-up after receiving GK SRS. Overall odds of hearing preservation at patient follow-up post-SRS were 0.06 (95% CI 0.02-0.13). Heterogeneity of included studies was 92% (P < .01), indicating substantial methodological variation among included studies. (B) Six LINAC studies reported serviceable hearing rates before and after LINAC SRS. Overall odds of hearing preservation at patient follow-up post-SRS were 0.47 (95% CI 0.29-0.76). Heterogeneity of included studies was 48% (P = .09). Abbreviations: CI, confidence interval; GK, gamma knife; LINAC, linear accelerator; Pre-RDT, pre-radiation; Post-RDT, post-radiation; SRS, stereotactic radiosurgery.

The included studies inconsistently reported on nonauditory morbidity for patients at long-term follow-up, including FN and TN dysfunction. Thus, data on these outcomes were limited for both modalities. 12 GK studies and 4 LINAC studies reported on FN impairment. Neither GK (OR 0.71, 95% CI 0.41-1.22) nor LINAC (OR 1.13, 95% CI 0.64-2.00) demonstrated a significant change in the odds of FN dysfunction post-SRS (Figure 4A and B).

Figure 4.

Figure 4.

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Rates of facial nerve impairment after GK SRS. (A) Twelve GK studies reported facial nerve (FN) impairment before and after GK SRS at a mean or median follow-up of >5 years. Odds ratios (OR) are displayed, denoting the odds of FN impairment at patient follow-up after receiving GK SRS. Overall odds of FN impairment at patient follow-up post-SRS were 0.71 (95% CI 0.41-1.22). Heterogeneity of included studies was 63% (P < .01), indicating substantial methodological variation among included studies. (B) Four LINAC studies reported FN impairment before and after LINAC SRS. Overall odds of FN impairment at patient follow-up post-SRS were 1.13 (95% CI 0.64-2.00). Heterogeneity of included studies was 0% (P = .94), indicating methodological homogeneity among included studies. Abbreviations: CI, confidence interval; FN, facial nerve; GK, gamma knife; LINAC, linear accelerator; Pre-RDT, pre-radiation; Post-RDT, post-radiation; SRS, stereotactic radiosurgery.

Data on TN dysfunction were analyzed for the reported totals of 1706 and 392 GK and LINAC patients, respectively. Pooled estimates from the 10 GK studies revealed a decreased odds of TN impairment at patient follow-up (Figure 5A and B), with an OR of 0.55 (95% CI 0.32-0.94). Conversely, though not statistically significant, there was slight trend towards increased odds of TN impairment among the 5 LINAC studies included (OR 1.45, 95% CI 0.81-2.61).

Figure 5.

Figure 5.

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Rates of trigeminal nerve impairment after GK SRS. (A) Ten GK studies reported trigeminal nerve (TN) impairment before and after GK SRS at a mean or median follow-up of >5 years. Odds ratios (OR) are displayed, denoting the odds of TN impairment at patient follow-up after receiving GK SRS. Overall odds of TN impairment post-SRS were 0.55 (95% CI 0.32-0.94). Heterogeneity of included studies was 60% (P < .01), indicating substantial methodological variation among included studies. (B) Five LINAC studies reported TN impairment. Overall odds of TN impairment post-SRS were 1.45 (95% CI 0.81-2.61). Heterogeneity of included studies was 45% (P < .12), indicating relative methodological consistency among included studies. Abbreviations: CI, confidence interval; GK, gamma knife; LINAC, linear accelerator; Pre-RDT, pre-radiation; Post-RDT, post-radiation; SRS, stereotactic radiosurgery.

Secondary Outcomes

A total of 13 GK and 6 LINAC studies reported on rates of hydrocephalus post-SRS. In total, these included 3317 GK patients and 435 patients receiving LINAC SRS. Rates of hydrocephalus were identical between the 2 modalities with 2% (95% CI 1.0-4.0%) of GK patents and 2% of LINAC patients (95% CI 1.0-4.0%) experiencing hydrocephalus at follow-up. Tinnitus was the least reported endpoint of interest with only 7 GK studies (N = 1722 patients) and 4 LINAC studies (N = 290 patients) reporting rates of patients with tinnitus before and after SRS. While GK patients did not experience changes in tinnitus post-SRS (OR 0.70, 95% CI 0.48-1.01) LINAC patients did demonstrate a significantly decreased odds of tinnitus after treatment (OR 0.15, 95% CI 0.03-0.87).

Publication Bias

Egger’s test revealed no publication bias for the majority of studies reporting on our primary and secondary outcomes of interest (Supplementary Figures 1–4). However, GK studies reporting long-term rates of serviceable hearing did appear to display significant publication bias (Supplementary Figure 2A). This signifies methodological variations in study design among this group of studies, most notably including variations in sample size.

Discussion

Outcomes from GK and LINAC SRS have often been reported interchangeably despite differences in dose delivery and patient positioning. Although previous systematic reviews have discussed rates of morbidity and tumor control after radiosurgery for VS, there have been few efforts to systematically review long-term outcomes in cohorts stratified by SRS device type.2 Attempting to address this gap and inform contemporary practice, we compiled results from retrospective and prospective studies published in the past decade on the long-term safety and efficacy of GK and LINAC SRS for VS management.

Context in the Literature

Up to 70% of VS begin to show significant radiographic evidence of growth after approximately 1-2 years.39 To account for the natural history of VS we only included studies with follow-up of ≥5 years. This resulted in an average follow-up period of roughly 7 years for GK and 8 years for LINAC SRS.

Our findings of 93% and 94% overall tumor control for GK and LINAC are consistent with other meta-analyses investigating the efficacy of these modalities independently.29,40,41 Thus, both SRS modalities continue to offer outstanding tumor control. Using a multivariable logistic regression, a study by Wowra et al35 found that SRS device type did not significantly impact the odds of tumor control at patient follow-up. This conclusion is further supported by our results.

Both LINAC and GK SRS were associated with decreased odds of serviceable hearing at long-term follow-up in our analysis. While hearing preservation rates for LINAC patients in our study are similar to other publications on LINAC radiotherapy,41,42 the odds of serviceable hearing post-GK was 94% lower compared to pre-GK in this meta-analysis, which is notably lower than expected. Several factors may explain this discrepancy. First, several studies intentionally elected for GK SRS in those patients with the lowest likelihood of hearing preservation rather than alternative treatment plans such as observation or fractionated radiotherapy. Second, different operative definitions of serviceable hearing were used in the eligible studies; these included Gardner-Robertson Scale < II and inter-aural pure tone average threshold <50 dB. This variation in objective outcome measurement likely contributed to significant heterogeneity and bias of hearing preservation results for the included GK studies. Third, the long-term follow-up of patients included in our study may simply reflect decreased hearing preservation over time not captured by studies with shorter follow-up periods.43

We found that CN morbidity and rates of tinnitus were inconsistently reported in the literature, including in previous systematic reviews. However, our findings suggest that, while both systems similarly impact the FN, GK may be less likely to cause TN impairment post-SRS, while odds of tinnitus were lower for LINAC patients in the study period. It is unclear what underlies these differences. The higher median dosing range of LINAC SRS (12-18 Gy) compared with GK (11-13 Gy) observed in our study may provide an underlying explanation for the slightly higher TN morbidity in the pooled LINAC studies. Additional contributing factors may include variations in dose homogeneity, use of stereotactic frame, and real-time adjustment to patient movement required for each SRS modality.

Of note, our review identified over 2 times as many GK SRS studies compared with LINAC studies (29 vs 10). This likely reflects a shift in the use of these SRS modalities, with LINAC garnering more popularity in recent years. Although practitioners often utilize more varied fractionation techniques with LINAC,44,45 our results suggest that LINAC may be comparable to GK when delivered as SRS.

Overall, the major utility and novelty of this meta-analysis lie in the stratification of both GK and LINAC studies during the same decade of publication. Given that patients may be differentially offered GK or LINAC depending on their geographic location or other factors, such as whether they receive care at an academic vs nonacademic institution, it is important to be aware of the risks and benefits of each SRS modality,46 especially as both techniques continue to evolve. Our results thus offer a glimpse at the relative similarities and differences in outcomes that may be expected with use of GK and LINAC SRS for VS in contemporary practice.

Limitations and Future Directions

We found significant heterogeneity within pooled studies investigating the long-term safety and efficacy of GK and LINAC for VS in large patient cohorts. This is a common issue encountered by systematic reviews in the VS literature. There are several reasons for this observation. First, although there were large numbers of patients for most outcomes of interest, the majority of studies included in this meta-analysis were retrospective. Sample sizes and outcome measures were highly variable as methods for data collection were likely not prescribed until long after patients began receiving SRS. Second, outcomes such as FN and TN dysfunction were sometimes measured using different methods; studies often inconsistently applied the House-Brackmann scale or used differing thresholds within the scale to define CN dysfunction. Additionally, outcomes such as tinnitus and hydrocephalus were reported much less frequently than tumor control or hearing preservation in the extant literature. We also excluded studies reporting outcomes of SRS only in particular patient cohorts (eg, large, cystic, and NF2). Thus, further characterization of GK and LINAC SRS outcomes in these populations may be warranted. Finally, we did not address the role of fractionation given that GK treatments have been historically single fraction; however, a meta-analysis on this topic has been recently published.44

The most significant limitation of this meta-analysis is the absence of RCTs and 2-arm studies.35 This fundamentally limits the ability to make direct statistical comparisons between these 2 preeminent SRS modalities. Although there are many practical obstacles hindering RCTs in this arena, including cost and accessibility, single- and multicenter prospective studies deploying both GK and LINAC with standardized data collection and symptom assessments could help further characterize their differences in long-term safety and efficacy, which would be beneficial for clinicians and hospital systems in managing the treatment of patients with VS.

Conclusion

In this meta-analysis, we systematically reviewed the long-term safety and efficacy of GK and LINAC SRS for VS over the past decade using large retrospective and prospective patient cohorts. Rates of tumor control, hearing preservation, and hydrocephalus were similar over the observation period between SRS modalities. However, our results indicate that GK may better preserve TN function, while LINAC may offer decreased rates of tinnitus. These findings underscore the importance of conducting future 2-arm studies with standardized outcome reporting to investigate the efficacy of GK and LINAC SRS more directly.

Funding

A.A., MPH, was partially supported by the National Center for Advancing Translational Science of the National Institute of Health under award number UL1TR002384.

Conflict of interest statement. The authors do not have any personal or institutional financial interest in drugs, materials, or devices described in this submission.

Supplementary Material

npab052_suppl_Supplementary_Figure_S1
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npab052_suppl_Supplementary_Figure_S2
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npab052_suppl_Supplementary_Figure_S3
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npab052_suppl_Supplementary_Figure_S4
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npab052_suppl_Supplementary_Data
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Associated Data

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Supplementary Materials

npab052_suppl_Supplementary_Figure_S1
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npab052_suppl_Supplementary_Figure_S2
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npab052_suppl_Supplementary_Figure_S3
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npab052_suppl_Supplementary_Figure_S4
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npab052_suppl_Supplementary_Data
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