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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
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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
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