OR I G I N A L AR T I C L E

Image-guided robotic radiosurgery for glomus jugularetumors—Multicenter experience and review of theliterature

Felix Ehret MD1 | Markus Kufeld MD1 | Christoph Fürweger PhD1,2 |

Alfred Haidenberger MD1 | Christian Schichor MD, MHBA3 |

Ralph Lehrke MD4 | Susanne Fichte MD5 | Carolin Senger MD6 |

Martin Bleif MD7 | Daniel Rueß MD2 | Maximilian Ruge MD2 |

Jörg-Christian Tonn MD3 | Alexander Muacevic MD1 | John-Martin Hempel MD8

1European Cyberknife Center, Munich,Germany2Department of Stereotaxy and FunctionalNeurosurgery, Center for Neurosurgery,University Hospital Cologne, Cologne,Germany3Department of Neurosurgery, Ludwig-Maximilians-University Munich, CampusGrosshadern, Munich, Germany4German CyberKnife Center, Soest,Germany5CyberKnife Center Mitteldeutschland,Erfurt, Germany6Charité CyberKnife Center, Charité –Universitätsmedizin Berlin, Berlin,Germany7Radiochirurgicum/CyberKnife Südwest,Göppingen, Germany8Department of Otorhinolaryngology andHead and Neck Surgery, Ludwig-Maximilians-University Munich, CampusGrosshadern, Munich, Germany

CorrespondenceFelix Ehret, European Cyberknife Center,Max-Lebsche-Platz 31, Munich 81377,Germany.Email: felix.ehret@campus.lmu.de

Funding informationMunich Medical Research School,Ludwig-Maximilians-University Munich

Section Editor: Martin Hullner

Abstract

Background: Glomus jugulare tumors (GJTs) are challenging to treat due to

their vascularization and location. This analysis evaluates the effectiveness and

safety of image-guided robotic radiosurgery (RRS) for GJTs in a multicenter

study and reviews the existing radiosurgical literature.

Methods: We analyzed outcome data from 101 patients to evaluate local con-

trol (LC), changes in pretreatment deficits, and toxicity. Moreover, radio-

surgical studies for GJTs have been reviewed.

Results: After a median follow-up of 35 months, the overall LC was 99%.

Eighty-eight patients were treated with a single dose, 13 received up to 5 frac-

tions. The median tumor volume was 5.6 cc; the median treatment dose for

single-session treatments is 16 Gy, and for multisession treatments is 21 Gy.

Fifty-six percentage of patients experienced symptom improvement or recov-

ered entirely.

Conclusions: RRS is an effective primary and secondary treatment option for

GJTs. The available literature suggests that radiosurgery is a treatment option

for most GJTs.

KEYWORD S

CyberKnife, glomus jugulare, paraganglioma, radiosurgery, review

This manuscript will not be presented at any meeting.

Received: 7 May 2020 Revised: 14 July 2020 Accepted: 14 August 2020

DOI: 10.1002/hed.26439

Head & Neck. 2020;1–13. wileyonlinelibrary.com/journal/hed © 2020 Wiley Periodicals LLC 1

1 | INTRODUCTION

With an estimated incidence of around one per 1.3 millionpeople, glomus jugulare tumors (GJTs) are rare, well-vascularized neuroendocrine tumors arising from the adven-titial chemoreceptor tissue of the jugular bulb.1 They areusually of benign histology but are capable of locally infil-trating adjacent tissue like the lower cranial nerves and thetemporal bone. In rare cases, GJTs can secret catechol-amines and metastasize to lymph nodes and distant organs,which significantly worsens the disease prognosis.2-4 Due totheir location close to the jugular foramen, common symp-toms are lower cranial nerve palsies, which lead to dyspha-gia, dysarthria, pulsatile tinnitus, hearing loss, vertigo, anddysphagia. In hormone-secreting tumors, tachycardia andlabile blood pressures are typical findings.4

Even with the development of microsurgical tech-niques, surgical tumor resection remains a challenge forsurgeons given the location of the tumor, vascularizationand adjacent nerves, and vessels.5-7 Despite the lack oftreatment guidelines, fractionated radiotherapy andsingle-session radiosurgery (RS) are alternative treatmentoptions, especially for patients not suitable for surgery.6-8

Due to the rarity of the tumor, many studies investigatingRS for the management of GJTs comprised only a smallnumber of patients, additionally included other head andneck paragangliomas, and did not stratify the outcomesfor primary and secondary RS. Only a few studiesreported long-term follow-up results and only a limitednumber of studies on the use of image-guided roboticradiosurgery (RRS) are available. To overcome this lackof knowledge and to improve clinical decision making forthe primary or postoperative irradiation of GJTs, we con-ducted a retrospective multicenter study including sixcenters investigating the use of image-guided RRS for thetreatment of GJTs. We also reviewed the radiosurgical lit-erature and compared our results with published data.

2 | MATERIALS AND METHODS

2.1 | Patients

One hundred and one patients with GJTs from six dedi-cated CyberKnife (CK) centers were treated with RRSbetween July 2005 and March 2019 and included in thisretrospective multicenter study. Patient informationincluding medical history, previous treatments, andfollow-up data were stored at each center in the respec-tive electronic health records or patient files. Duringfollow-up appointments, patients were evaluated for clin-ical symptoms, adverse effects, complications, and treat-ment response by clinical examination and by magnetic

resonance imaging (MRI). Appointments took place 6 and12 months after treatment delivery. Follow-up was doneafter 6 months and in 12 months intervals, thereafter if noacute complications occurred. Only patients with at leastone completed radiographic and clinical follow-up6 months after treatment delivery were included in thisanalysis. GJT diagnosis was either based on histopatholog-ical examination (39 patients) or radiographic findings aswell as clinical appearance of the patient (62 patients). Forradiographic diagnosis, thin-sliced computed tomography(CT), MRI, as well as contrast-enhanced MR angiography(CE-MRA) imaging were used. This study was approvedby the respective institutional review board.

2.2 | Treatment procedure and outcome

For treatment planning and delivery, thin-sliced, contrast-enhanced CT and MRI scans were used for every patient.Imaging sequences included gadolinium-enhanced T1 andT2 sequences and vessel-focused Time of Flight series.Resulting CT and MRI imaging data were overlaid fortreatment planning. Various software tools (MultiPlan,Precision, Accuray Inc., Sunnyvale, California) were usedfor inverse treatment planning. All patients were treatedwith single- or multisession (up to 5 fractions) stereotacticRRS in an outpatient setting using a CyberKnife RRS sys-tem (Accuray Inc., Sunnyvale, California). During treat-ment delivery, custom-fitted thermoplastic face maskswere used for non-invasive fixation. Tumor volume mea-surement was done directly with the above-mentionedsoftware assessing the tumor volume on available thin-sliced MRI imaging data before treatment and at last avail-able follow-up. Radiographic assessment of the treatmentoutcome was defined as follows: Tumor volume reduction(TVR), tumor volume decrease of at least 20%, progressivedisease (PD), increase of the overall tumor volume of atleast 20%, with local control (LC) defined as no evidenceof PD during follow-up imaging. Tumors with volumechanges ±20% were considered unchanged. To determinepotential prognostic factors, logistic regression modelswere used following a backward selection approach. Fornormally distributed and paired data, a paired student'st test was conducted. Data were analyzed using STATA16.0 (StataCorp, College Station, Texas). P-values equal toor less than .05 were considered significant.

2.3 | Literature review

We used various combinations of keywords includingradiosurgery, stereotactic, cyberknife, gamma knife,LINAC, paraganglioma, chemodectoma, glomus jugulare,

2 EHRET ET AL.

TABLE 1 Patient characteristics, pretreatment deficits, and pretreatments

Patient characteristics

Total number of patients included 101

Sex (male/female, %) 35 (35) 66 (65)

Median Mean Range

Age (years) 56.0 57.6 18.8-87.3

Pretreatment Karnofsky performance score (%) 100 91.3 70-100

Follow-up (months) 35.0 44.0 6.0-160.8

Total tumor volume all patients (cc) 5.6 7.5 0.2-42.0

Total tumor volume primary treatment patients (cc) 6.1 8.2 0.4-42.0

Total tumor volume secondary treatment patients (cc) 3.9 6.3 0.2-31.6

Side of the tumor (left/right, %) 61 (60) 40 (40) —

Number of patients treated in single session 88

Dose (Gy) single session 16.0 15.6 12.0-18.0

Prescription isodose (%) single session 70 70.7 60-80

Number of patients treated in multisession 13

Number of fractions 3 4 5

Number of patients 8 1 4

Dose (Gy) multisession 21.0 23.1 19.5-30.0

Prescription isodose (%) multisession 70 70 63-77

Pretreatment deficits All patients Untreated Pretreated

Number of patients 101 62 39

Patients without deficits 5 1 4

Patients with deficits 96 61 35

Pulsatile tinnitus 52 35 17

Partial hearing loss 47 32 15

Dysphagia 35 19 16

Dysarthria 33 19 14

Vertigo 30 18 12

Total hearing loss 19 8 11

Facial nerve palsy (all degrees) 15 4 11

Feeling of pressure around tumor side 11 9 2

Spinal accessory nerve palsy (all degrees) 11 7 4

Dysesthesia 10 5 5

Pain 9 5 4

Horner syndrome 4 3 1

Cardiovascular complications 2 2 0

Epiphora 1 1 0

Pretreatments Number of patients

Patients with pretreatments 39

Single surgery 18

Single surgery plus tumor embolization 10

Multiple surgeries 6

Multiple surgeries plus tumor embolization 3

Multiple surgeries plus tumor embolization plus fractionated radiotherapy 1

(Continues)

EHRET ET AL. 3

and glomus jugulare tumor to search published studiesfor GJTs in the National Library of Medicine databasethrough May 1, 2020. Only studies which reported theprimary or secondary radiosurgical treatment of GJTswith up to five fractions were reviewed. Studies whichincluded the treatment of tumor entities other than GJTswere excluded. If an institution or authors had publishedmultiple studies, only the report with the largest samplesize was reviewed. Only studies with full-body texts inEnglish were included. To maintain comparability inregard to technological advancements, only studies publi-shed after January 1, 2000 were included in this review.

3 | RESULTS

3.1 | Patient characteristics andtreatment parameters

The median age at treatment delivery was 56 years. Mostof the treated patients were female (65%) and most of thetumors were located on the left side (60%). The mediantumor size was 5.6 cc. Sixty-two out of the 101 (61%)included patients received the treatment as their primarytherapy and the majority, 88 out of 101 (87%), were treatedin a single session. The median dose for primary and sec-ondary single-session treatments was 16 Gy; the mediandose for multisession treatments was 21 Gy in three to fivesessions. The median prescription isodose was 70%throughout primary and secondary treatments. The mostcommon pretreatment deficits included pulsatile tinnitus(51%), partial hearing loss (46%), dysphagia (34%), dysar-thria (32%), and vertigo (29%). At treatment delivery, fivepatients (5%) did not show clinical symptoms caused bytheir GJT. Thirty-nine patients underwent secondary RRSof their tumor. Thirty-eight of them underwent primarysurgical resection of their tumor, 10 patients had multiplesurgeries up to a maximum of five resections. A summaryof the baseline characteristics, treatment parameters, andpretreatment deficits is provided in Table 1.

3.2 | Treatment results

The median follow-up time was 35 months (range 6-160).At last follow-up, 23 (24%) patients recovered from their

symptoms and 31 (32%) experienced symptom improve-ment, whereas 35 (34%) reported no significant changesconcerning their pretreatment deficits. Five patients (5%)reported a transient worsening of their symptoms beforereturning to their pretreatment condition at the last avail-able follow-up. Two patients (2%) experienced a persis-tent worsening caused by one House-Brackmann gradeIV facial nerve palsy and one new pulsatile tinnitus aftertreatment delivery. All patients without pretreatment def-icits remained asymptomatic throughout their follow-up,whereas symptom control and improvement between pri-marily (91%) and secondarily (94%) treated patients wereconsistent. The overall LC rate was 99%. One patientdeveloped lymph node metastases 4 months after treat-ment. The primary tumor lesion was controlled at thetime of distant failure. Another patient suffered from alocal recurrence (PD) after 70.8 months. The recurrenttumor lesion was treated with proton radiotherapy andis controlled since treatment delivery. At last follow-up,42 tumors (41%) remained unchanged in size, whereas57 (56%) showed a TVR. Overall, the median and meanvolume reduction were 1.77 and 0.8 cc, respectively.These absolute reductions equal median and mean per-centage changes of 22% and 24%, respectively. Pairedstudent's t tests among all, primarily treated and second-arily treated patients showed a significant decrease intumor volume for the three groups at last follow-up(Table 2). The calculated progression free survival was97%, 97%, and 93% after 3, 5, and 7 years, respectively. Adetailed summary of the treatment results is provided inTable 2.

3.3 | Complications and toxicity

Seven patients (7%) showed potential toxicity after treat-ment delivery. Four reported headaches, vertigo, andnausea. One patient described moderate pain irradiatingto the mandibula, neck, and ear on the side of the tumor.All patients were treated with glucocorticoids in an out-patient setting and six of them entirely recovered shortlyafter. Two patients experienced persistent worsening(House-Brackmann grade IV facial nerve palsy, pulsatiletinnitus). No patient experienced radiation necrosis, sei-zures, acute bleedings, or radiation-inducedmalignancies.

TABLE 1 (Continued)

Patient characteristics

Radiosurgery plus single surgery plus tumor embolization 1

Note: cc, cubic centimeter, Gy, gray.

4 EHRET ET AL.

3.4 | Prognostic factors

Multivariate linear and logistic regression analyses wereused to assess prognostic factors for TVR, and symptomimprovement, defined as full recovery or pretreatmentdeficit improvement, as well as toxicity. Pretreatmenttumor size was found to be a significant predictor oftumor volume at last follow-up (F[6, 94], R2 = 0.31,P < .01). TVR in cc increased by 0.24 cc for each pre-treatment cc of tumor (Table 3). None of the analyzedfactors including age at treatment delivery, sex, pre-treatment and posttreatment tumor volumes, indication,dose, prescription isodose, and number of fractionsreached statistical significance for symptom improvement(Table 3). Moreover, no significant factors for the occur-rence of toxicity after treatment delivery were found(Table 3). Here, a number of fractions were omitted inthe analysis as a dependency among the independent var-iables in the model was identified.

3.5 | Literature review

A total of 29 studies have been identified.9-37 One studywas a multicenter trial with 132 patients and was countedas a separate publication even though parts of the datahad already been reported elsewhere. The data were

heterogeneous and besides follow-up, doses and LC notstandardized. Twenty-one studies out of 29 investigatedthe use of Gamma Knife (GK), only 8 reported the use oflinear accelerator- (LINAC) and CK-based RS. Themedian and mean follow-up ranged from 9.7 to 132 and25.4 to 86.4 months, respectively. Most studies (22/29)exclusively reported the use of single-session RS. Themedian dose used for single-session treatments rangedfrom 12 to 18 Gy, with the majority utilizing 15 Gy. Mostpatients were primarily treated with RS (64%, 508/788patients). Throughout all studies, LC rates between 69%and 100% were reported. The overall LC was 93.6%(725/774 patients), with only a minor difference betweenGK and LINAC/CK studies (94.2% and 91.6%, respec-tively). Data reporting for acute and long-term complica-tions, LC, as well as symptom control rates—defined asstable or improved pretreatment deficits—was heteroge-neous and prevented inclusion of all studies for exactdata calculation. Some authors reported results withvarying symptom outcome measurements, whereas otherstudies analyzed clinical outcomes for each pretreatmentdeficit separately. Moreover, some studies utilized classi-fication systems like the House-Brackmann score oraudiogram results. Symptom control rates after RS variedfrom 22% to 100% throughout the reviewed studies, with88.8% of patients achieving symptom control at lastfollow-up. Complications of RS were reported in 20 out

TABLE 2 Tumor volume changes, local control, and clinical outcomes of patients at last follow-up

Tumor volume changes (pretreatment vs last follow-up)

Patient groupMeanreduction (cc)

Medianreduction (cc)

Mean percentage volumereduction (%)

Medianpercentagevolumereduction (%) P-value

All patients (n = 101) 1.77 0.80 24 22 <.001

Primary treatmentpatients (n = 62)

1.51 0.71 20 20 <.001

Secondary treatmentpatients (n = 39)

2.19 0.89 29 27 .0013

Local control (%) 99

Clinical outcome of symptomatic patients at last follow-up

Clinical outcome No symptoms Symptomimprovement

Unchanged Transientworsening

Symptomworsening

Newsymptoms

Number of patients(n = 96)

23 31 35 5 1 1

Primary treatmentpatients (n = 61)

14 21 21 4 0 1

Secondary treatmentpatients (n = 35)

9 10 14 1 1 0

Note: n = number of patients, cc = cubic centimeter.

EHRET ET AL. 5

of 29 studies (68%) with complication rates ranging from2% to 28% in treated patients. The nine studies withoutreporting complications had only 20 or fewer patientsincluded. Overall, 8.8% (70/788 patients) experienced tox-icity and complications after treatment delivery, with aslightly higher rate found in LINAC/CK studies (12.7%and 7.9%, respectively), which might be explained by thelarger tumor volumes treated in LINAC/CK studies(Table 4). A summary of the literature review is providedin Table 4.

4 | DISCUSSION

Herein, we report the first multicenter study on the roleof image-guided RRS in the management of GJTs and thesecond-largest published radiosurgical series of patientstreated for GJTs. The results demonstrate that RRSachieves high rates of tumor and symptom control

throughout an intermediate follow-up time. These find-ings are consistent for primarily and secondarily treatedGJTs patients. Moreover, acute complications after treat-ment delivery are rare and no treatment-related mortalityhas been observed.

4.1 | Local control

As GJT recurrence can occur even after decades, long-term follow-up is needed to determine if our initiallyreported LC with this sample size is reliable and last-ing.5,38,39 Many reports showed radiosurgical LC ratesover 90% with an even more extensive follow-upperiod.12,14,19,20,24 Of these studies, Sheehan and col-leagues published the first multicenter RS study for GJTwith the data of the North American Gamma Knife Con-sortium. To date, it is the most extensive radiosurgicalseries available. They included 132 patients with 134 GJTs

TABLE 3 Prognostic factors for

tumor volume reduction, symptom

improvement, and toxicity by

multivariate linear and logistic

regression analyses

Tumor volume reduction (absolute, in cc)

Factor Coefficient P-value 95% confidence interval

Age −0.12 .53 −0.05-0.27

Sex 0.91 .12 −0.26-2.10

Pretreatment tumor volume 0.24 <.01 0.15-0.33

Indication −1.05 .07 −2.20-0.09

Dose −0.13 .46 −0.48-0.22

Isodose 0.95 .44 0.85-1.07

Fractions −0.05 .93 −1.24-1.14

Symptom improvement

Factor Odds ratio P-value 95% confidence interval

Age 1.00 .68 0.97-1.04

Sex 1.32 .58 0.48-3.57

Posttreatment tumor volume 1.03 .76 0.95-1.12

Indication 0.89 .82 0.33-2.14

Dose 1.06 .69 0.78-1.44

Isodose 0.92 .30 0.80-1.06

Fractions 0.62 .40 0.20-1.88

Toxicity

Age 0.95 .14 0.89-1.01

Sex 1.37 .72 0.23-7.89

Pretreatment tumor volume 1.01 .34 0.91-1.14

Indication 0.57 .51 0.10-3.03

Dose 0.66 .16 0.37-1.18

Isodose 1.07 .49 0.87-1.30

Note: Sex represents male vs female; indication represents primary vs secondary treatments; ccrepresents cubic centimeter.

6 EHRET ET AL.

TABLE

4Literature

review

Auth

orNumbe

rof

patients

Mod

ality

PrimaryTx

(numbe

rof

patients)

Seco

ndaryTx

(numbe

rof

patients)

Follow-uptime

(mon

ths)

Tumor

size

(cc)

Fx

Dose(G

y)LC(%

)Sy

mptom

control

(%)

Com

plica

tion

san

dtoxicity

(%)

Tripa

thie

tal,

2019

910

GK

100

Mean:3

9Mean:2

9.9

2-3

2fraction

smean:

11.2,3

fraction

smean:7

.64

100

100%

Twopa

tien

ts(20%

),on

ewith

spinal

accessorynerve

palsy,

onewithheada

che.

Giglio

ttietal,

2018

1016

LIN

AC

106

Median:4

4Median:1

1.7

1-5

Median:2

588

81.2

Twopa

tien

ts(12.5%

),on

ewith

vertigo,

onewithheada

che.

Salla

banda

etal,20181

130

LIN

AC,

CK

1416

Mean:5

5.2

Median:5

61-3

Median:1

4.0

9797

Fou

rpa

tien

ts(13.3%

)withlow-

grad

etoxicities.

Hafez

etal,

2018

1240

GK

400

Mean:8

4Mean:6

.51

Meanmarginal:1

5.0

9292.5

Threepa

tien

ts(7.5%)withnew

cran

ialn

erve

deficits.

Sharmaet

al,

2018

1342

GK

3012

Median:6

2.3

Mean:5

.01

Medianmarginal:

15.0

6980.9%

Eightpa

tien

ts(19%

)withlow-

grad

etoxicities.

Pateletal,

2018

1460

GK

3525

Median:6

6Median:1

1.6

1Meanmaxim

al:3

2,meanmarginal:1

691.7

96.6(hearingda

taexcluded)

Twopa

tien

ts(3.3%)withvocalcord

paralysis.

Ibrahim

etal,

2017

1575

GK

4728

Medianclinical:3

8.5,

median

radiograph

ic:5

1.5

Median:7

.01-2

Medianmarginal:1

893.4

84Twopa

tien

ts(2.6%),on

ewithvocal

cord

paralysis,on

ewithfacial

nerve

palsy.

Wak

efield

etal,

2017

1617

GK

89

Median:1

23Median:9

.81

Median:1

5.0

9494

Non

e.

Winford

etal,

2017

1738

(33with

follo

w-up

imaging)

GK

344

Mean

radiograph

ic:3

9.1

Median:5

.81

Meanmarginal:1

3.2

8894

forpa

tien

tswith

pretreatmen

tnerve

deficits

Total

of10

patien

ts(26.3%

),four

withvertigo,

fourwithpa

in,two

withtran

sien

ttastedisturban

ce,

twowithdy

sphagia,o

newith

necrosis.

Dob

berpuh

let

al,20161

812

GK

120

Mean:2

7.6

Median:8

.41

Medianmarginal:1

5100

100forlower

cran

ialn

erve

palsies,66.7%forpu

lsatile

tinnitus

Non

e.

ElM

ajdo

ubet

al,20151

927

LIN

AC

1314

Medianclinical:1

32,

median

radiograph

ic:1

15

Median:9

.51

Median:1

5100

96.2

Onepa

tien

t(3.7%)witha

persistentfacial

nerve

palsy.

Gan

día-

Gon

zález

etal,20142

0

58GK

4018

Mean:8

6.4,

median:

76.6

Median:9

.3,m

ean:1

21

Meanmaxim

al:2

5.2,

meanmarginal:

13.6

94.8

91.4

Twopa

tien

ts(3.4%)withnew

hearingloss.

Sageret

al,

2014

2121

LIN

AC

165

Median:4

9Mediandiam

eter:

17mm

1Median:1

5100

22to

62.5,d

epen

dingon

pre-

clinical

deficits

Sixpa

tien

ts(28.5%

),tw

opa

tien

tswithnau

sea,vomiting,

heada

che,threepa

tien

tswith

tran

sien

tfacial

numbn

ess,on

epa

tien

twithtongu

eweakn

ess.

Hurmuz

etal,

2013

2214

CK

131

Median:3

9Median:1

5.8

1-5

Median:2

5100

NR(8

patien

tswithcomplete

clinical

improvem

ent)

Non

e.

DeAndrad

eet

al,20132

315

LIN

AC

132

Mean:3

5.4

Mean:1

8.5

1-5

Meanmarginal:1

4100

100

Onepa

tien

t(6.6%)withtran

sien

tfacial

nerve

palsy.

Sheehan

etal,

2012

24132(123

with

follo

w-up

imaging)

GK

7557

Median:5

0.5

Median:5

.5,m

ean:7

.81

Median:1

593.0

85forcran

ialn

erve

deficits

Fifteen

patien

ts(11.3%

)with

worseningcran

ialn

erve

deficits

despitetumor

control.

Chen

etal,

2010

2515

GK

114

Mean:4

3.2

Mean:7

.31

Meanmarginal:1

4.6

80.0

88.8

Onepa

tien

t(6.6%)experien

ced

worseningdy

sarthria,dizziness,

andheada

che.

Gen

çet

al,

2010

2618

GK

711

Median:4

1.5,

mean:

52.7

Median5.54,m

ean

13.5

1Meanmarginal:1

5.6

94.4

94Non

e.

Navarro

Martín

etal,20102

710

GK

28

Median:9

.7Median:4

.01

Medianmarginal:

14.0

100

100

Non

e.

Gan

z&

Abd

elka

rim,

2009

28

14GK

113

Mean:2

8Mean:1

4.2

1Mean:1

3.6

100

100

Onepa

tien

t(7.1%)withtran

sien

tfacial

nerve

palsy.

Miller

etal,

2009

295

GK

05

Mean:3

4Mean:4

.14

1Meanmarginal:1

5.0

100

100

Non

e.

Sharmaet

al,

2008

3013

GK

76

Mean:2

5.4

Mean:5

.71

Meanmarginal:1

6.5

100

Symptom

improvem

entin

46%

ofpa

tien

tswith≥6mon

ths

offollow

-up.

Onepa

tien

t(7.6%)withtrigem

inal

neu

ralgia.

Lim

etal,

2007

3118

LIN

AC,

CK

144

Medianclinical:3

5,median

radiograph

ic:3

0

Meandiam

eter:

3.04

cm1-3

Median:2

0100

100

Threepa

tien

ts(16.6%

)experien

ced

tran

sien

tworseningof

cran

ial

nerve

deficits.

16GK

511

Median:1

8.5

Median:9

.81

100

100

Non

e.

(Con

tinue

s)

EHRET ET AL. 7

from eight institutions and reported progression-free sur-vival (PFS) rates of 98%, 90%, and 88% at 1, 3, and5 years, respectively.24 The actual LC was 93% at amedian follow-up of 50.5 months.24 Five-year LC ratesaround 90%-95% seem to be achievable with RS (Table 4).Similar PFS rates have been reported.14,15,24 Moreover,recent studies including this report have investigatedprognostic factors for LC or tumor progression-freesurvival.11,13,15,17,20,24

Sheehan and colleagues found significant factors intheir multivariate analysis. In their study, a higher num-ber of isocenters and the absence of trigeminal nerve dys-functions at the time of treatment delivery wereassociated with progression-free tumor survival.24 Also,Winford and colleagues identified an increased risk ofprogression with increased margin treatment doses.17

Herein, we found that pretreatment tumor volume signif-icantly influences posttreatment tumor size changes.However, identifying prognostic factors remains a diffi-cult task given the rarity and delay of local recurrences.Such factors might unmask with more extensive follow-up periods and more detailed as well as structuredpatient assessments. We expect to see more recurrencesin our study cohort within the next years.

Besides, the present LC rates for primary and second-ary GJT treatments are comparable with the radiosurgicaldata available, even though most of the data is from GK-based studies due to the availability and history of thisradiation technique (Table 4). Past studies have used vari-ous definitions of tumor progression, which might com-promise comparability. This effect can also be increasedby varying tumor volume measurement methods. Giventhe provided study data and reviewed literature, thereseem to be no significant differences in LC in regard tothe radiosurgical treatment modality (GK, LINAC, andCK) and number of fractions. Past surgical series mighthave focused on peripheral GJTs, including those exten-ding to the lower neck. Therefore, comparing our find-ings with surgical series is challenging due toheterogeneous patient selection and different surgicaltechniques. LC seems to be at least similar or slightly bet-ter for radiosurgical patients compared with surgery.5,7

Large surgical series with more than 60 patients includedreport LC rates between 76% and 93%.5,7,40-42 Ultimately,authors have argued that only a full surgical re-section may achieve complete cure.7 Nevertheless, not allstudies provide sufficient details regarding the follow-uptime, hindering comparability between RS, fractionatedradiotherapy and surgery. Furthermore, the data hetero-geneity of GJT patients in past studies makes it difficultto determine patients who would benefit from primarymicrosurgical resection or fractionated radiotherapy,especially considering recent advancements in surgeryT

ABLE

4(Con

tinue

d)

Auth

orNumbe

rof

patients

Mod

ality

PrimaryTx

(numbe

rof

patients)

Seco

ndaryTx

(numbe

rof

patients)

Follow-uptime

(mon

ths)

Tumor

size

(cc)

Fx

Dose(G

y)LC(%

)Sy

mptom

control

(%)

Com

plica

tion

san

dtoxicity

(%)

Bitaraf

etal,

2006

32Medianmarginal:

18.0

Feigl

&Horstman

n,

2006

33

12GK

75

Mean:3

3Mean:9

.41

Meanmarginal:1

7.0

100

92Twopa

tien

ts(16.6%

),on

ewith

tran

sien

tfacial

spasm,o

newith

tran

sien

thoarsen

ess.

Gerosaet

al,

2006

3420

GK

128

Mean:5

0.8

Mean:7

.03

1Meanmarginal:1

7.3

100

90Non

e.

Pozn

anovic

etal,20063

58

LIN

AC

80

Mean:1

5.6

Mean:7

.21

Median:1

5.0

100

87.5

Twopa

tien

ts(25%

),on

epa

tien

texperien

cedacute

vertigo,

one

patien

tsuffered

from

acute

nau

sea,vomitingan

dtran

sien

tcran

ialn

erve

neu

ropa

thy.

Eustacchio

etal,20023

619

GK

109

Median:8

6.4

Median:5

.22

1Medianmarginal:

14.0

94.7

100

Non

e.

Saringeret

al,

2001

3713

GK

49

Mean:5

0Mean:9

.03

1Medianmarginal:1

2100

100

Twopa

tien

ts(15.3%

),on

ewith

tran

sien

tdy

sphagia

andon

ewithfacial

nerve

palsy.

Mod

ality

Num

berof

stud

ies

Num

berof

patien

tsPrim

aryTx

(num

berof

patien

ts,%

)

Seconda

ryTx

(num

berof

patien

ts,%

)

Follow-uptimerange

(medianan

dmean,m

onths)

Tum

orsize

range

(medianan

dmean

combined,cc)

Fx(m

edian,

range)

Dose(m

edianan

dmeanmarginal

combined,G

y)

LC(%

,patientswith

follo

w-upim

aging

available)

Symptom

control

(%,o

nly

overallreporteddeficits

included)

Com

plicationan

dtoxicity

rate

(%)

All

29788

508(64.4%

)280(35.6%

)9.7-132

4-56

1,1-5

11.2-25

93.6(725/774)

88.8(442/498)

8.8%

(70/788)

GK

21639

407(63.7%

)232(36.3%

)9.7-123

4-29.6

1,1-3

11.2-18

94.2(593/629)

86.9(334/384)

7.9%

(51/639)

CK,L

INAC

8149

101(67.8%

)48

(32.2%

)15.6-132

7.2-56

1,1-5

14-25

91.6(132/149)

94.7(108/114)

12.7%(19/149)

Abb

reviations:

cc,cubiccentimeter;CK,CyberKnife;

Fx,

num

berof

fraction

s;GK,Gam

maKnife;

LC,localcontrol;LIN

AC,lin

earaccelerator;

mm,millim

eter;NR,not

repo

rted;Tx,

treatm

ent.

8 EHRET ET AL.

and cranial nerve management.43,44 Besides, fractionatedradiotherapy has shown to achieve comparable LC ratesand may play an important role for patients not suitablefor RS.5,7 Here, doses up to 45 Gy achieve good clinicalresults with a limited risk of adverse effects.7

Even though treatment guidelines including surgicaland radiosurgical options have been proposed by col-leagues, consensus guidelines for the treatment of GJTare still lacking.5,7 Still, surgical tumor resection is atreatment option which must be considered, especiallyfor rapidly growing and hormone-secreting tumors.Moreover, some authors emphasized on a more passiveapproach and suggested to follow a “wait and scan” strat-egy more frequently.45 This option is also supported bydata showing that even throughout an extensive follow-up of more than 5 years, 45% of patients experiencetumor stability or regression without treatment.45,46

Finally, radiobiological studies suggest paragangliomas tobe relatively radioresistant given the expression of knownmarkers of radioresistance (NOTCH, ZEB1) and down-regulation of cellular pathways fostering radiosensitivity(miR-200c, mir-34b/c).47-49 This might support a morepassive treatment approach. Overall, the decision fortreatment must be carefully evaluated and in agreementwith the patient's preferences, clinical status and personalwishes.

4.2 | Symptom control and quality of life

GJTs often account for considerable morbidity and signif-icantly impact the quality of life (Qol).50 Thus, patient-reported outcomes and projected symptom control arecrucial when determining the most suitable treatmentoption for patients besides overall performance statusand patients' preferences. In this study, 93% of the treatedpatients, regardless of undergoing primary or secondaryRRS, experienced symptom control or improvements intheir pretreatment deficits. Considering the sample sizeand follow-up time, this proportion underlines the effec-tiveness of RRS and demonstrates the equivalence inregard to GK-based treatments (Table 4). However,reported data are heterogeneous and some authors exam-ined the changes in pretreatment deficits for every symp-tom separately as well as used quantitative assessmentslike audiograms. Most studies analyzed in our literaturereview reported symptom control rates of ≥80%, with anestimated overall rate of 88.8% (442/498 patients,Table 4). Notably, these rates were mostly consistentregardless of sample size, tumor volume, follow-upperiod and radiation modality (Table 4). Thus, RSachieves reliable clinical results, especially in contrast tomost invasive treatments. Surgery, despite achieving

comparable LC rates, still yields a considerable risk forpersistent or newly developing cranial nerve palsies, thus,limiting the chances of symptom control.5,7 However, lessinvasive surgical methods seem to lower the rate of newlydeveloping postsurgical cranial nerve deficits.43,44

Today, variables indicating clinical outcomes are stilllacking. Various reports including this study investigatedprognostic factors for symptom control or clinicalprogression-free survival after treatment.11,15,16,20 Sal-labanda and colleagues found cranial nerve involvementto be significantly associated with a decreased chance ofsymptom improvement.11 However, the association wasapparent in univariate analysis, a multivariate analysiswas not conducted. Besides, Wakefield and colleaguesfound prior surgical resection to significantly correlatewith persistent neurological deficits compared with non-surgical cases.16 In contrast, our study found no prognos-tic factors for symptom improvement. Besides reportingsubjective symptom control, analyses of standardized Qolmeasurements before and after treatment could improveclinical decision making. However, only sparse standard-ized Qol data are available in the GJT literature.51-53

Galland-Girodet and colleagues found better scores forhearing and speech, trismus, and overall Qol for patientswith head and neck paragangliomas receiving radiother-apy alone vs those receiving radiotherapy and surgery.51

Patel and colleagues investigated Qol outcomes for pri-mary and secondary GJT patients after GK-based RS.52

Patients undergoing primary RS had better swallowingfunction than patients who underwent surgical re-section before.52 One study investigating fractionatedradiotherapy showed stable SF36 Qol measures forpatients undergoing primary radiotherapy.53 Finally, arecent single center study utilizing pretreatment andposttreatment SF12 data showed consistent Qol improve-ments after RRS.54 Overall, these findings suggest that RSand radiotherapy seem to be favorable in regard to post-treatment Qol in comparison with surgery. Despite thelack of data and sufficient studies, projected Qol out-comes after treatment should play an important rolewhen choosing the right treatment modality.

4.3 | Complications and toxicity

In addition, complications and treatment-related morbid-ity are linked to the clinical outcome of patients and havea significant impact on clinical decision making. In ourstudy cohort, only a few transient low-grade and persis-tent complications have been observed. This is also inagreement with the existing literature (Table 4). Compli-cation rates for RS range from 0% to 28%; most of thestudies (62%) had rates below 10%, with an overall rate of

EHRET ET AL. 9

8.8% throughout all studies. Our complication rate (7%) isin agreement with the reviewed literature. Most compli-cations were low grade, ranging from nausea, vertigo,headaches to transient cranial nerve deficits, and resolvedafter a short amount of time. However, we were not ableto find predictors of toxicity in regard to applied doses.Given the low rate of complications after RS, the majorityof other studies have not investigated the relationshipbetween dose and toxicity. However, most of the GJTshave been treated with doses around 16 Gy and low-grade complications occurred in less than 10% of patients(Table 4).

In contrast to surgery, RS has an advantageous com-plication profile with a lower risk, especially for post-treatment cranial nerve deficits.5,7 Fractionatedradiotherapy seems to have a slightly higher risk for com-plications, 10.4% and 6.5%, respectively.7 In contrast,complications after surgery are much more frequent andsevere. A review by Lieberson and colleagues reportedcomplication rates of ≥46% after surgery.5 Suárez and col-leagues reported major complications including CSF fis-tulas, aspirations, infections, meningitis, strokes, anddeath in 28% of surgical cases.7 These reviews underlinethe considerable complication risk for gross GJT resec-tions. Even though the risk for radiation-associated long-term complications like radiation-induced malignanciesis low, RS should be especially considered for olderpatients. Overall, candidates for GJT treatment should bewell-informed about the potential complications and tox-icity of RS, fractionated radiotherapy and surgery.

4.4 | Limitations

This study has various limitations. The retrospectivenature, due to selection and reporting biases, is an inher-iting limitation of the study and as most of the includedpatients underwent RS as their primary GJT treatment,histological confirmation was only performed in 39 out of101 patients. Nevertheless, the radiological diagnosis isconsidered reliable and accurate, often because of a char-acteristic contrast enhancement and especially in conjunc-tion with typical symptoms of GJTs and modern imagingmodalities (CT, MRI, and CE-MRA).55-58 In regard to theliterature and tumor biology of GJTs, the follow-up time ofour study is too short to detect late tumor recurrences reli-ably. These can occur even decades after treatment deliv-ery.5,8,38,39 While our initially reported LC is high, weexpect to see more and more local recurrences five or moreyears after treatment delivery. Moreover, our PFS mightbe too high given insufficient return of patient informationregarding deaths by any cause. This might be especiallythe case for outpatient only treatment facilities and

centers. Finally, we only reported the qualitative data forour posttreatment symptom analyses in this study and didnot provide audiograms or House-Brackmann scores. Thiscircumstance might limit the validity of our posttreatmentsymptom results. However, many of the published studieshave used this way of reporting to depict their findings.

4.5 | Current and future challenges

So far, only limited progress has been made in evaluatingmultimodal and interdisciplinary treatment optionsdespite the amount of retrospective reports. RS has shownat least equal to favorable results compared to fractionatedradiotherapy and surgical series in regard to LC, symptomcontrol and toxicity over the past decades.5,7 However,reporting heterogeneity, patient selection and technicaladvancements in all fields warrant a more detailed andcomprehensive analysis. It is essential to conduct morestudies on the primary and secondary treatment of GJTsand to evaluate multidisciplinary treatment options criti-cally. Comparative studies, ideally of prospective nature,could help to establish treatment guidelines and determinewhich patients could potentially benefit from surgical re-section or fractionated radiotherapy. Currently, there is alack of knowledge on how to maximize symptom controland posttreatment Qol. A prospective international multi-center study with standardized outcome evaluationsincluding audiograms, video-head impulse tests, caloricvestibular tests, extensive lower cranial nerve testing, andQol assessments could overcome the epidemiologic chal-lenges and improve clinical care for GJT patients. More-over, such a study should follow an interdisciplinaryapproach and include the expertise of neurosurgeons, neu-rologists, radiation, and otolaryngologist. Yet, it is impor-tant to note that the various treatment options available,the variety of patients in regard to neurological deficits,pretreatments, and tumor size as well as the low tumorincidence pose considerable challenges to conduct pro-spective trials. In addition, radiosurgical and multi-disciplinary treatment options for other paragangliomasshould be investigated as well and may be included in onelarge prospective trial. Considering our findings, similarlong-term experiences with GK, and the possibility to treatextracranial lesions, RRS may be suitable for the treatmentof other head and neck paragangliomas than GJTs.59

5 | CONCLUSION

This multicenter study is the largest series investigatingthe use of RRS for GJTs and, overall, the second-largestradiosurgical series for the treatment of GJTs. Results

10 EHRET ET AL.

show that RRS is a well-tolerated and effective treatmentmodality that achieves high LC rates and improvementin pretreatment deficits regardless of primary or second-ary treatment delivery. This is in agreement with theradiosurgical literature. RRS and RS in general may be asuitable treatment modality for the majority of GJTs.

ACKNOWLEDGMENTSThis work was supported by a grant for Felix Ehret issuedby the Ludwig-Maximilians-University of Munich.

CONFLICT OF INTERESTFelix Ehret reports grants from Ludwig-Maximilians-University Munich, during the conduct of the study;other from Accuray International, outside the submittedwork. Christoph Fürweger reports personal fees fromAccuray Inc. (Sunnyvale, California), outside the submit-ted work. Maximilian Ruge reports grants and personalfees from Accuray Inc. (Sunnyvale, California), outsidethe submitted work. Markus Kufeld has nothing to dis-close. Alfred Haidenberger has nothing to disclose. Chris-tian Schichor has nothing to disclose. Ralph Lehrke hasnothing to disclose. Susanne Fichte has nothing to dis-close. Carolin Senger has nothing to disclose. Martin Bleifhas nothing to disclose. Daniel Rueß has nothing to dis-close. Jörg-Christian Tonn has nothing to disclose. Alex-ander Muacevic has nothing to disclose. John-MartinHempel has nothing to disclose.

ORCIDFelix Ehret https://orcid.org/0000-0001-6177-1755

REFERENCES1. Moffat DA, Hardy DG. Surgical management of large glomus

jugulare tumours: infra- and trans-temporal approach.J Laryngol Otol. 1989;103(12):1167-1180.

2. Gulya AJ. The glomus tumor and its biology. Laryngoscope.1993;103(11 Pt 2 Suppl 60):7-15.

3. Lee JH, Barich F, Karnell LH, et al. National Cancer Data Basereport on malignant paragangliomas of the head and neck.Cancer. 2002;94(3):730-737.

4. Forbes JA, Brock AA, Ghiassi M, Thompson RC, Haynes DS,Tsai BS. Jugulotympanic paragangliomas: 75 years of evolutionin understanding. Neurosurg Focus. 2012;33(2):E13.

5. Lieberson RE, Adler JR, Soltys SG, Choi C, Gibbs IC,Chang SD. Stereotactic radiosurgery as the primary treatmentfor new and recurrent paragangliomas: is open surgical re-section still the treatment of choice? World Neurosurg. 2012;77(5–6):745-761.

6. Gottfried ON, Liu JK, Couldwell WT. Comparison of radiosur-gery and conventional surgery for the treatment of glomusjugulare tumors. Neurosurg Focus. 2004;17(2):E4.

7. Suarez C, Rodrigo JP, Bodeker CC, et al. Jugular and vagalparagangliomas: systematic study of management with surgeryand radiotherapy. Head Neck. 2013;35(8):1195-1204.

8. Guss ZD, Batra S, Limb CJ, et al. Radiosurgery of glomusjugulare tumors: a meta-analysis. Int J Radiat Oncol Biol Phys.2011;81(4):e497-e502.

9. Tripathi M, Rekhapalli R, Batish A, et al. Safety and efficacy ofprimary multisession dose fractionated gamma knife radiosur-gery for jugular Paragangliomas. World Neurosurg. 2019;131:e136-e148.

10. Gigliotti MJ, Hasan S, Liang Y, Chen D, Fuhrer R, Wegner RE.A 10-year experience of linear accelerator-based stereotacticradiosurgery/radiotherapy (SRS/SRT) for paraganglioma: a sin-gle institution experience and review of the literature.J Radiosurg SBRT. 2018;5(3):183-190.

11. Sallabanda K, Barrientos H, Isernia Romero DA, et al. Long-term outcomes after radiosurgery for glomus jugulare tumors.Tumori. 2018;104(4):300-306.

12. Hafez RFA, Morgan MS, Fahmy OM, Hassan HT. Long-termeffectiveness and safety of stereotactic gamma knife surgery asa primary sole treatment in the management of glomusjagulare tumor. Clin Neurol Neurosurg. 2018;168:34-37.

13. Sharma M, Meola A, Bellamkonda S, et al. Long-term outcomefollowing stereotactic radiosurgery for glomus Jugulare tumors:a single institution experience of 20 years. Neurosurgery. 2018;83(5):1007-1014.

14. Patel NS, Carlson ML, Pollock BE, et al. Long-term tumor con-trol following stereotactic radiosurgery for jugular para-ganglioma using 3D volumetric segmentation. J Neurosurg.2018;1-9. https://doi.org/10.3171/2017.10.JNS17764

15. Ibrahim R, Ammori MB, Yianni J, Grainger A, Rowe J,Radatz M. Gamma knife radiosurgery for glomus jugularetumors: a single-center series of 75 cases. J Neurosurg. 2017;126(5):1488-1497.

16. Wakefield DV, Venable GT, VanderWalde NA, et al. Compara-tive neurologic outcomes of salvage and definitive gamma kniferadiosurgery for glomus Jugulare: a 20-year experience.J Neurol Surg B Skull Base. 2017;78(3):251-255.

17. Winford TW, Dorton LH, Browne JD, Chan MD, Tatter SB,Oliver ER. Stereotactic radiosurgical treatment of glomusjugulare tumors. Otol Neurotol. 2017;38(4):555-562.

18. Dobberpuhl MR, Maxwell S, Feddock J, St Clair W, Bush ML.Treatment outcomes for single modality management of glo-mus jugulare tumors with stereotactic radiosurgery. Otol Neu-rotol. 2016;37(9):1406-1410.

19. El Majdoub F, Hunsche S, Igressa A, Kocher M, Sturm V,Maarouf M. Stereotactic LINAC-radiosurgery for glomusjugulare tumors: a long-term follow-up of 27 patients. PLoSOne. 2015;10(6):e0129057.

20. Gandia-Gonzalez ML, Kusak ME, Moreno NM, Sarraga JG,Rey G, Alvarez RM. Jugulotympanic paragangliomas treatedwith gamma knife radiosurgery: a single-center review of58 cases. J Neurosurg. 2014;121(5):1158-1165.

21. Sager O, Beyzadeoglu M, Dincoglan F, et al. Evaluation of lin-ear accelerator-based stereotactic radiosurgery in the manage-ment of glomus jugulare tumors. Tumori. 2014;100(2):184-188.

22. Hurmuz P, Cengiz M, Ozyigit G, et al. Robotic stereotacticradiosurgery in patients with unresectable glomus jugularetumors. Technol Cancer Res Treat. 2013;12(2):109-113.

23. de Andrade EM, Brito JR, Mario SD, de Melo SM, Benabou S.Stereotactic radiosurgery for the treatment of glomus Jugularetumors. Surg Neurol Int. 2013;4(Suppl 6):S429-S435.

EHRET ET AL. 11

24. Sheehan JP, Tanaka S, Link MJ, et al. Gamma knife surgery forthe management of glomus tumors: a multicenter study.J Neurosurg. 2012;117(2):246-254.

25. Chen PG, Nguyen JH, Payne SC, Sheehan JP, Hashisaki GT.Treatment of glomus jugulare tumors with gamma knife radio-surgery. Laryngoscope. 2010;120(9):1856-1862.

26. Genc A, Bicer A, Abacioglu U, Peker S, Pamir MN, Kilic T.Gamma knife radiosurgery for the treatment of glomusjugulare tumors. J Neurooncol. 2010;97(1):101-108.

27. Navarro Martin A, Maitz A, Grills IS, et al. Successful treat-ment of glomus jugulare tumours with gamma knife radiosur-gery: clinical and physical aspects of management and reviewof the literature. Clin Transl Oncol. 2010;12(1):55-62.

28. Ganz JC, Abdelkarim K. Glomus jugulare tumours: certainclinical and radiological aspects observed following gammaknife radiosurgery. Acta Neurochir. 2009;151(5):423-426.

29. Miller JP, Semaan M, Einstein D, Megerian CA, Maciunas RJ.Staged gamma knife radiosurgery after tailored surgical resec-tion: a novel treatment paradigm for glomus jugulare tumors.Stereotact Funct Neurosurg. 2009;87(1):31-36.

30. Sharma MS, Gupta A, Kale SS, Agrawal D, Mahapatra AK,Sharma BS. Gamma knife radiosurgery for glomus jugularetumors: therapeutic advantages of minimalism in the skullbase. Neurol India. 2008;56(1):57-61.

31. Lim M, Bower R, Nangiana JS, Adler JR, Chang SD. Radiosur-gery for glomus jugulare tumors. Technol Cancer Res Treat.2007;6(5):419-423.

32. Bitaraf MA, Alikhani M, Tahsili-Fahadan P, et al. Radiosurgeryfor glomus jugulare tumors: experience treating 16 patients inIran. J Neurosurg. 2006;105:168-174.

33. Feigl GC, Horstmann GA. Intracranial glomus jugularetumors: volume reduction with gamma knife surgery.J Neurosurg. 2006;105(Suppl):161-167.

34. Gerosa M, Visca A, Rizzo P, Foroni R, Nicolato A, Bricolo A.Glomus jugulare tumors: the option of gamma knife radiosur-gery. Neurosurgery. 2006;59(3):561-569.

35. Poznanovic SA, Cass SP, Kavanagh BD. Short-term tumor con-trol and acute toxicity after stereotactic radiosurgery for glomusjugulare tumors. Otolaryngol Head Neck Surg. 2006;134(3):437-442.

36. Eustacchio S, Trummer M, Unger F, Schrottner O, Sutter B,Pendl G. The role of gamma knife radiosurgery in the manage-ment of glomus jugular tumours. Acta Neurochir Suppl. 2002;84:91-97.

37. Saringer W, Khayal H, Ertl A, Schoeggl A, Kitz K. Efficiency ofgamma knife radiosurgery in the treatment of glomus jugularetumors. Minim Invasive Neurosurg. 2001;44(3):141-146.

38. Pollock BE, Foote RL. The evolving role of stereotactic radio-surgery for patients with skull base tumors. J Neurooncol. 2004;69(1–3):199-207.

39. Shapiro S, Kellermeyer B, Ramadan J, Jones G, Wiseman B,Cassis A. Outcomes of primary radiosurgery treatment of glo-mus jugulare tumors: systematic review with meta-analysis.Otol Neurotol. 2018;39(9):1079-1087.

40. Fayad JN, Keles B, Brackmann DE. Jugular foramen tumors:clinical characteristics and treatment outcomes. Otol Neurotol.2010;31(2):299-305.

41. Sanna M, De Donato G, Piazza P, Falcioni M. Revision glomustumor surgery. Otolaryngol Clin North Am. 2006;39(4):763-782.

42. Jackson CG, Kaylie DM, Coppit G, Gardner EK. Glomusjugulare tumors with intracranial extension. Neurosurg Focus.2004;17(2):E7.

43. Nonaka Y, Fukushima T, Watanabe K, et al. Less invasivetransjugular approach with fallopian bridge technique forfacial nerve protection and hearing preservation in surgeryof glomus jugulare tumors. Neurosurg Rev. 2013;36(4):579-586.

44. Borba LA, Araújo JC, de Oliveira JG, et al. Surgical manage-ment of glomus jugulare tumors: a proposal for approach selec-tion based on tumor relationships with the facial nerve.J Neurosurg. 2010;112(1):88-98.

45. Piras G, Mariani-Costantini R, Sanna M. Are Ouctomes ofradiosurgery for Tympanojugular Paraganglioma over-estimated? Otol Neurotol. 2019;40(5):688-689.

46. Prasad SC, Mimoune HA, D'Orazio F, et al. The role of wait-and-scan and the efficacy of radiotherapy in the treatment oftemporal bone paragangliomas. Otol Neurotol. 2014;35(5):922-931.

47. Cama A, Verginelli F, Lotti LV, et al. Integrative genetic, epige-netic and pathological analysis of paraganglioma reveals com-plex dysregulation of NOTCH signaling. Acta Neuropathol.2013;126(4):575-594.

48. Verginelli F, Perconti S, Vespa S, et al. Paragangliomas arisethrough an autonomous vasculo-angio-neurogenic programinhibited by imatinib. Acta Neuropathol. 2018;135(5):779-798.

49. Lin J, Liu C, Gao F, et al. miR-200c enhances radiosensitivityof human breast cancer cells. J Cell Biochem. 2013;114(3):606-615.

50. van Hulsteijn LT, Louisse A, Havekes B, et al. Quality of life isdecreased in patients with paragangliomas. Eur J Endocrinol.2013;168(5):689-697.

51. Galland-Girodet S, Maire JP, De-Mones E, et al. The role ofradiation therapy in the management of head and neckparagangliomas: impact of quality of life versus treatmentresponse. Radiother Oncol. 2014;111(3):463-467.

52. Patel NS, Link MJ, Tombers NM, Pollock BE, Carlson ML.Quality of life in jugular Paraganglioma following radiosurgery.Otol Neurotol. 2019;40(6):820-825.

53. Henzel M, Hamm K, Gross MW, et al. Fractionated stereotacticradiotherapy of glomus jugulare tumors. Local control, toxicity,symptomatology, and quality of life. Strahlenther Onkol. 2007;183(10):557-562.

54. Ehret F, Kufeld M, Fürweger C, et al. Single-session image-guided robotic radiosurgery and quality of life for glomusjugulare tumors. Head Neck. 2020;42:2421-2430.

55. Neves F, Huwart L, Jourdan G, et al. Head and neckparagangliomas: value of contrast-enhanced 3D MR angiogra-phy. AJNR Am J Neuroradiol. 2008;29(5):883-889.

56. van den Berg R, Schepers A, de Bruïne FT, et al. The value ofMR angiography techniques in the detection of head and neckparagangliomas. Eur J Radiol. 2004;52(3):240-245.

57. Larson TC 3rd, Reese DF, Baker HL Jr, McDonald TJ. Glomustympanicum chemodectomas: radiographic and clinical charac-teristics. Radiology. 1987;163(3):801-806.

58. Lo WW, Solti-Bohman LG, Lambert PR. High-resolution CT inthe evaluation of glomus tumors of the temporal bone. Radiol-ogy. 1984;150(3):737-742.

12 EHRET ET AL.

59. Spina A, Boari N, Gagliardi F, et al. Gamma knife radiosurgeryfor glomus tumors: long-term results in a series of 30 patients.Head Neck. 2018;40(12):2677-2684.

How to cite this article: Ehret F, Kufeld M,Fürweger C, et al. Image-guided roboticradiosurgery for glomus jugulare tumors—Multicenter experience and review of theliterature. Head & Neck. 2020;1–13. https://doi.org/10.1002/hed.26439

EHRET ET AL. 13