Received: 5 December 2016
Revised: 29 March 2017
Accepted: 30 March 2017
DOI: 10.1111/ajco.12695
ORIGINAL ARTICLE
Robotic radiosurgery of head and neck paragangliomas: a single institution experience ˙Ilker Tosun1
Banu Atalar2
Gökhan Aydin2
Bülent Yapici2
1 Radiation Oncology Division, Acıbadem
2 Bilgehan Sahin ¸
Görkem Güngör2
Enis Özyar2
Abstract
˘ Turkey Bodrum Hospital, Mugla, 2 Department of Radiation Oncology, Acibadem
R Aim: CyberKnife is a robotic stereotactic radiotherapy system. The aim of this study is to evalR uate the effectiveness and the safety of CyberKnife on treating head and neck paragangliomas
University, Istanbul, Turkey Correspondence ˙Ilker Tosun, Ortakent Mah Gölba¸sı Sok No:11 ˘ Turkey. 48420, Bodrum – Mugla, Email:
[email protected]
and to report our results.
The study has not been previously presented.
body paragangliomas and three cases had tympanic paragangliomas. One patient had bilateral
Methods: Between March 2009 and June 2014, 12 patients with head and neck paragangliomas have been referred to our clinic: in three cases had jugular paragangliomas, five cases had carotid neck paragangliomas (right neck; carotid body paraganglioma, left neck; jugular pargangliomas). R up to a total All of them received fractionated stereotactic radiotherapy with CyberKnife
median dose of 24 Gy (reference isodose 67–90%). The median tumor volume was 35.5 cc (range, 5.3—113.8 cc). The median follow up was 30 months (range, 0–66 months). Local tumor control was assessed according to RECIST criteria on follow-up imaging studies. Results: There were no acute or late toxicity related with stereotactic radiotherapy after treatment. No local tumor progression was observed on magnetic resonance imaging and none of our patients showed progressive clinical status. Seven tumors shrinked in size (54%). Five tumors (46%) had stable size during follow up. Local control rate was 100%. Conclusion: Stereotactic radiotherapy is a good alternative to surgery for the treatment of head and neck paragangliomas coming up with a clear benefit of acute and late side effects. R CyberKnife seems to be a safe and efficient system treating head and neck paragangliomas.
KEYWORDS
CyberKnife radiosurgery, glomus jugulare tumor, paraganglioma, radiosurgery, radiotherapy
1
INTRODUCTION
older than abdominal PGLs at the time of diagnosis (43 years vs. 36 years of age).5 The male-to-female ratio of PGLs are usually
Paragangliomas (PGLs) are rare neuroendocrine tumors, which are
equal.6
paraganglia.1
Most of PGLs have benign nature and have manageable size (the
Parasympathetic ganglia-derived PGLs are mostly located at the neck
average volume was 17.1 cm3 for HNPGLs and 94.1 cm3 for other
and skull base region.2 Head and neck PGLs (HNPGLs), formerly
tumors).2 A wait and scan approach is often advised as the majority
known as glomus tumors mostly occurs in the bifurcation of carotid
of HNGPLs have slow growing character.7 Although HNPGLs are gen-
arteries (carotid body PGL), tympanic area (tympanic PGL), the dome
erally benign tumors, tumor bulk may result neurovascular structure
of internal jugular vein (jugular PGL) and along the vagal nerve (vagal
damage by cranial nerve deficits and cause serious morbidity. The main
PGL).3
treatment options for HNPGLs are surgical resection and radiation
derived from either parasympathetic or sympathetic
The specific incidence of PGLs are unknown as they are usually reported together with other pheochromocytomas. The annual incidence of pheochromocytoma/PGLs has been estimated to be year.4
therapy (RT). Although tumors can be surgically resected it may lead to neurovascular injury approximately in 60% of patients.8 RT is an alternative treatment strategy for HNPGL patients.
PGLs are mostly discovered in
HNPGLs can be treated by both conventionally fractionated RT
the fourth and fifth decades of life.3 HNPGL patients tend to be
(CFRT) and stereotactic radiotherapy (SRT) approaches. Local
0.8 per 100.000 person /
Asia-Pac J Clin Oncol. 2017;1–5.
wileyonlinelibrary.com/journal/ajco
c 2017 John Wiley & Sons Australia, Ltd
1
2
CyberKnife
CyberKnife
CyberKnife
CyberKnife
CyberKnife
CyberKnife
and have a better dose distribution which spares healthy struc-
CyberKnife
of HNPGLs.16 Compared to CFRT, SRT provides better precision
CyberKnife
been widely used as a promising treatment modality for treatment
CyberKnife
effects for critical structures.12 Within the past 15 years, SRT has
CyberKnife
However, administering CFRT to wide fields may cause serious side
CyberKnife
Treatment machine
control rate with CFRT is reported to be between 79% and 100%.11
CyberKnife
TOSUN ET AL .
no follow-up
66 months
49 months
52 months
57 months
no follow-up
28 months
36 months
33 months
found to be safe and efficacious for the treatment of HNPGLs.13–15
22 months
USA) and linac-based stereotactic radiotherapy systems have been
2 months
Follow-up
R (CK; Accuray Incorporated, Sunnyvale, CA, Sweden), CyberKnife
17 months
R (GK; Elekta AB, Stockholm, tures around the target. Gamma Knife
7 Gy
7 Gy
7 Gy
10 Gy
8 Gy
8 Gy
5 Gy
5 Gy
We retrospectively reviewed 12 HNPGL patients treated with CK in
5 Gy
(SRS).16
8 Gy
to be 97% and 95% respectively after stereotactic radiosurgery
8 Gy
Dose/fraction
patients, tumor control and clinical control rates were reported
8 Gy
In a meta-analysis, which included a total of 335 glomus jugulare
21 Gy Yes
21 Gy
21 Gy Yes
Yes
24 Gy
30 Gy No
No
25 Gy
24 Gy No
No
25 Gy
24 Gy
24 Gy
25 Gy Yes
between March 2009 and June 2014. From our patient database,
Yes
Total of 12 patients with HNPGLs were treated with SRT at our clinic
No
METHODS AND MATERIALS
Yes
Total dose Prior surgery
2
Yes
as describing our results.
24 Gy
our clinic. This report evaluates effectiveness and safety of CK as well
C1
D2
D2
D2
C2
C2, C2
C3
staging (Table 2).
D2
eters are summarized in Table 1. Fisch classification is used for tumor
D2
and tumor response. Patient characteristics and radiotherapy param-
C
rence status, radiotherapy parameters, acute and late complications
C
Fisch classification
der, tumor size and location, pretreatment symptoms and signs, recur-
D2
we identified patient and tumor characteristics including age, gen-
created by defining a 2 to 5 mm margin to GTV (median 3 mm). The
Glomus caroticum 49 12
Female
Glomus jugulare/nasopharyngeal componant
Glomus timpanicum Female
Male
40
61
10
11
Left carotis bulbus, glomus caroticum
Glomus caroticum Female
Right: glomus caroticum Left: glomus jugulare Male
Glomus timpanicum
Glomus timpanicum Female
Male
Glomus caroticum
Tumor localization
Glomus jugulare
Glomus jugulare Female
Male
Female
41
29
8
9
able. GTV was defined according to the radiological findings. PTV was
27
were fused with contrast-enhanced T1- and T2-weighted MRI if avail-
44
each patient underwent a thin (1 mm) slice CT scan and those images
4
sion: 3.5.4) was used for treatment planning. For target delineation,
5
R (verand received fractionated SRT with curative intent. MultiPlan
65
All patients were treated with CK G4 system using 6-MV photons
34
diagnosis.
2
Five patients had no prior treatment therewith no histopathological
3
tary PGLs. Seven patients had prior surgery and recurrent tumor.
Gender
tation and family history, this patient was regarded as a heredi-
Male
succinate dehydrogenase D gene. Because bilateral disease presen-
Age
had PGLs as well and genetic studies have revealed a mutation in
43
left neck; jugular PGL). It was learned that his father and sister
1
One patient had bilateral neck PGLs (right neck; carotid body PGL,
Patient number
patients), vertigo (one patient) and hypoglossal paralysis (one patient).
TA B L E 1
ing loss (three patients), neck mass (two patients), hoarseness (two
Patient characteristics and radiotherapy modality
other symptoms presented were pulsatile mass (three patients), hear-
Male
toms were pulsatile tinnitus (five patients) and pain (five patients),
36
Type C (50%) or D (50%) disease. The most common presenting symp-
57
three patients had tympanic PGLs. All patients presented either with
6
patients had jugular PGLs, five patients had carotid body PGLs and
7
this report. The median age was 42 years (range, 27–65 years). Three
Glomus caroticum
Six male (50%) and six female (50%) patients were analyzed in
3
TOSUN ET AL .
TA B L E 2
Fisch classification of glomus tumors
3
RESULTS
A
Limited to middle ear cleft
B
Limited to the tympanomastoid area
3.1
C
Involving the infralabyrinthine compartment and petrous apex of the temporal bone
All patients tolerated radiotherapy well. No acute or late toxicity
D1
Intracranial extension 2 cm in greatest dimension
Clinical response
related with SBRT was seen after treatment. None of the patients developed new cranial nerve deficits. All of our patients’ clinical status was stable and one patient had symptomatic relief.
3.2
Tumor control
median number of fractions was 3 (range, 3–5) and the median fraction
MRI was performed for all patients after treatment. No local tumor
per dose was 7 Gy (range, 5–10 Gy). Total dose was ranged between 21
progression was observed. Seven of 13 tumors (54%) had partial
and 30 Gy (median 24 Gy) and prescription isodose lines were selected
response and five tumors (46%) were considered as stable disease dur-
between 67% and 90% (median 75%; Figure 1). The median overall
ing follow-up. Decreases in tumor volume did not correlate with symp-
treatment time was 3 days (range, 2–5 days). The median maximum
tomatic improvement. Overall local control rate of 100% was obtained.
tumor diameter was 56 mm (range, 26–92 mm) and the median tumor volume was 35.5 cc (range, 5.3–113.8 cc). In case with bilateral disease
3.3
Toxicity
both lesions at the neck were treated with fractionated SRT using CK system one month apart. The median follow up was 30 months (range, 0–66 months). Follow up time was calculated from the last day of SRT procedure. Two
Following SBRT none of our patients experienced acute or late toxicities including carotid blowout syndrome, vertigo, hearing loss, otorrhoe, pulsatile tinnitus and pulsatile mass.
patients have no follow up. The responses to treatment were evaluated by serial physical and imaging examinations performed after completion of SRT by an experienced radiologist and radiation oncologist.
4
DISCUSSION
Stabilization or absence of symptoms were considered as clinical control. Local tumor control was assessed according to RECIST criteria17
HNPGLs treatment strategy is based upon retrospective data; the
on follow-up imaging studies.
optimal management relies on clinical and radiological assessment.18
F I G U R E 1 Definitive RT planning with CK. A total dose of 24 Gy (8 Gy/fraction, prescribed isodose: 82%) to a Fisch C class left glomus jugulare tumor (tumor size; 26 × 22 × 22 mm, volume; 5340 cc) [Colour figure can be viewed at wileyonlinelibrary.com]
4
TOSUN ET AL .
Complication risks have to be minimized while deciding on curative
alternative to surgery particularly where operation would be highly
approach. Three main roads up to management exist; observation,
dangerous for vascular and/or neural structures around. External RT
resection and primary RT.
history of HNPGLs starts with conventional fractionation. Daily doses
Although these tumors reflect a broad spectrum of clinical behav-
of 1.8 to 2 Gy RT, five days/week, delivered between 45 and 50.4
ior, fortunately most of them are in benign behavior.2 In a retrospec-
Gy to the PTV. Lower doses than 40 Gy showed higher risk for local
tive study7 including 48 HNPGL patients, patients were followed with-
recurrence.10 Hinerman et al.23 presented their 35 years results of
out any treatment. The median tumor growth rate was 1 mm annu-
HNPGL treatment with external RT. A total of 104 patients with 121
ally and the median tumor doubling time was reported as four years.
PGLs received RT. A total of 104 tumors had no prior treatment. A
In another study, 43 patients were followed with serial imaging (CT
total of 89 PGLs received CFRT, 11 PGLs received intensity modulated
or MRI) and 70% of patients were asymptomatic. Forty-two percent
radiotherapy (IMRT), 15 PGLs received fractionated SRT and 6 PGLs
of tumors were stable during five years follow-up time. Twenty per-
underwent SRS. The overall crude local control rate for all 121 lesions
cent of tumors’ size was reduced. Thirty-eight percent of tumors grew
was 95%, with an ultimate local control rate of 96%. They reported
but the mean growth rate was 0.2 cm annually.19 From this point of
20 mild or moderate complications in 104 patients (19%) following
view, initial observation might be the choice of decision for small and
RT. There were no severe complications. They concluded that exter-
asymptomatic nonsecreting HNPGLs while close monitoring is war-
nal RT provides high tumor control therewith minimal complications.
ranted. Seven of our patients had prior surgical intervention and all of
Despite the scarcity of literature evidence, RT may not be as effective
our patients received curative SBRT. All treatment options including
as surgery for catecholamine secreting HNPGLs. RT seems to be impo-
observation were discussed with patients as well.
tent in reducing catecholamine secretion.26 Surgery must be taken into
Historically, surgical removal of HNPGLs was the first treatment choice.20
consideration for these specific subgroup.
The major complication associated with surgery is cra-
After SRS was introduced for HNPGLs, CFRT usage shifted towards
nial nerve damage.16,18,20,21 Less common complications are vascular
SRS in many clinics. SRS enables clinician to spare healthy structures
problems (stroke and bleeding).18,21 In a systemic review of retrospec-
while prescribing ablative radiation doses for the tumor.
tive series which includes 1084 juguler PGL patients, local control was
Theoretically, SRS has lower complication rates than CFRT depend-
85% and 965 new cranial nerve deficits were reported after surgery.21
ing on smaller radiation fields and it provides shorter treatment
During vagal PGL resection, vagal nerve deficit is unavoidable and
times.24 Guss et al.16 published a meta-analysis including 19 studies
nerve-preserving try-outs usually bring out postoperative failure of
with a total of 335 glomus jugulare patients who are treated with SRS.
complete resection as well as nerve palsies.20,21 Green et al.22 reported
They reported 97% tumor control (unchanged or reduced tumor vol-
high rate of cranial nerve deficits after surgery up to 46% of patients,
ume) and 95% clinical control (unchanged or improved clinical sta-
in addition, they found out a 15% decrease in quality of life. As a result
tus). In another meta-analysis,25 46 publications describing outcomes
of experience, surgical removal of HNPGLs potentially cause morbidity
for 869 jugular PGL patients, SBRT success was shown compared to
and mortality especially for tumors surrounded by critical structures.
surgery. Tumor control rates for gross total resection alone (GTR; 351
Moreover, some surgeons use preoperative arterial embolization for
patients) was 86%, subtotal resection alone (STR; 82 patients) was
HNPGLs. This procedure adds some additional risks for severe mor-
69%, STR plus SBRT (97 patients) was 71%, and SBRT alone (339
bidity such as blindness, cranial nerve deficits, stroke and death. For-
patients) was 95%. Furthermore, SBRT alone group was more challeng-
tunately, the risk is reported to be in low range (0–13%).14,20 Six of our
ing in terms of treatment success. Fisch class D tumor rates were the
patients had prior surgery and two of them had arterial embolization
highest in SBRT alone group (57%); GTR (19%), STR (29%) and STR plus
before surgery. One patient had right vision loss, left hemiplesia, right
SBRT (9%). Cranial nerve (CN) neuropathy rates for patients follow-
facial paralysis, hypoglossus paralysis after embolization. Despite small
ing GTR was worse than SRS (CN IX [38% vs 9.7%], X (26% vs 9.7%),
patient size, our results support the risk related with embolization.
and XI (40% vs 12%), although the rates of CN XII deficits were compa-
In this study, we retrospectively evaluated 10 HNPGL patients
rable (18% vs 8.7%). Current study is well matched with similar stud-
treated with fractionated SRT in our clinic. After a median 30 months
ies published in literature. All of our patients had stable or improved
follow-up, our findings indicated either stable disease or partial
clinical status. Lim et al. also revealed parallel results with us.15 How-
response. Local tumor control was 100%. Our follow-up time is not
ever, treatment success with SBRT doesn’t seem to be correlated with
covering long time range but our primary goal here is evaluating effi-
tumor shrinkage.18 This may create radiological assessment problems.
cacy and safety of CK for HNPGL tumors. Although this retrospec-
We achieved tumor regression in seven patients (1 patient had >50%)
tive analysis involves limited patient size, our results support the of
and remaining five patients had stable tumor. We believe that radiolog-
CK for HNPGL treatment. There is lack of data in literature regard-
ical and clinical status must be considered together while evaluating
ing HNPGLs, which are primarily treated with CK.15 To date, published
HNPGLs during follow-up.
meta-analyses showed that GK experience is
overwhelming.16,25
Because of lack of previously published CK data, we chose fractionated SBRT, perhaps much safer than single fraction SBRT, and none of our
5
CONCLUSION
patients came up with post-SBRT complications. Local control rates of RT ranged between 79% and 100% in
HNPGLs are usually non catecholamine-secreting benign tumors. Sur-
the literature9 and it seems to be a reasonable approach as an
gical removal provides good local control rates but comes up with
5
TOSUN ET AL .
increased risk of complications. RT is a good alternative for surgery. FCRT and SBRT local control rates are comparable and also they are higher than surgery with far less complication risk. Besides this, SBRT must be planned and administered meticulously since an inaccuracy may cause marginal miss and tumor recurrence. In our clinic, we have treated HNPGL patients with CK (fractionated SBRT) and achieved 100% local control. No patient had post-SBRT complications and none of them presented with disease progression during follow-up. Our results are well matched with published literature data. CK seems to be a safe and efficient system treating HNPGLs. Current study is valuable supporting literature data; however, our results must be confirmed by studies with larger patient size and longer follow-up. CONFLICT OF INTEREST No conflict of interest was declared by the authors. FINANCIAL DISCLOSURE The authors declared that this study has received no financial support.
REFERENCES 1. Welander J, Söderkvist P, Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2011;18:253–76. 2. Lee JA, Duh QY. Sporadic paraganglioma. World J Surg. 2008;32:683–7. 3. Corssmit EP, Romijn JA. Clinical management of paragangliomas. Eur J Endocrinol. 2014;171:231–43. 4. Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58:802–4. 5. Al-Harthy M, Al-Harthy S, Al-Otieschan A, Velagapudi S, Alzahrani AS. Comparison of pheochromocytomas and abdominal and pelvic paragangliomas with head and neck paragangliomas. Endocr Pract. 2009;15:194–202. 6. Mannelli M, Castellano M, Schiavi F, et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochro- mocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009;94:1541–7.
11. de Jong AL, Coker NJ, Jenkins HA, Goepfert H, Alford BR. Radiation therapy in the management of paragangliomas of the temporal bone. Am J Otol. 1995;16:283–9. 12. Thabet MH, Kotob H. Cervical paragangliomas: diagnosis, management and complications. J Laryngol Otol. 2001;115:467–74. 13. Eustacchio S, Leber K, Trummer M, Unger F, Pendl G. Gamma knife radiosurgery for glomus jugulare tumours. Acta Neurochir (Wien). 1999;141:811–8. 14. Maarouf M, Voges J, Landwehr P, et al. Stereotactic linear acceleratorbased radiosurgery for the treatment of patients with glomus jugulare tumors. Cancer. 2003;97:1093–8. 15. Lim M, Gibbs IC, Adler JR Jr, Chang SD. Efficacy and safety of stereotactic radiosurgery for glomus jugulare tumors. Neurosurg Focus. 2004;17:E11. 16. Guss ZD, Batra S, Limb CJ, et al. Radiosurgery of glomus jugulare tumors: a meta-analysis. Int J Radiat Oncol Biol Phys. 2011;81:497– 502. 17. Eisenhauera EA, Therasseb P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of cancer. 2009;45:228–47. 18. Papaspyrou K, Mann WJ, Amedee RG. Management of head and neck paragangliomas: review of 120 patients. Head Neck. 2009;31:381–7. 19. Langerman A, Athavale SM, Rangarajan SV, Sinard RJ, Netterville JL. Natural history of cervical paragangliomas: outcomes of observation of 43 patients. Arch Otolaryngol Head Neck Surg. 2012;138:341–5. 20. Persky MS, Setton A, Niimi Y, Hartman J, Frank D, Berenstein A. Combined endovascular and surgical treatment of head and neck paragangliomas–a team approach. Head Neck. 2002;24:423–31. 21. Suárez C, Rodrigo JP, Bödeker CC, et al. Jugular and vagal paragangliomas: Systematic study of management with surgery and radiotherapy. Head Neck. 2013;35:1195–204. 22. Green JD Jr, Brackmann DE, Nguyen CD, Arriaga MA, Telischi FF, De la Cruz A. Surgical management of previously untreated glomus jugulare tumors. Laryngoscope. 1994;104:917–21. 23. Hinerman RW, Amdur RJ, Morris CG, Kirwan J, Mendenhall WM. Definitive radiotherapy in the management of paragangliomas arising in the head and neck: a 35-year experience. Head Neck. 2008;30:1431– 8. 24. Li G, Chang SD, Adler JR, Lim M. Irradiation of glomus jugulare tumors: a historical perspective. Neurosurg Focus. 2007;23:E13.
7. Jansen JC, vanden Berg R, Kuiper A, vander Mey AG, Zwinderman AH, Cornelisse CJ. Estimation of growth rate in patients with head and neck paragangliomas influences the treatment proposal. Cancer. 2000;88:2811–6.
25. Ivan ME, Sughrue ME, Clark AJ, et al. A meta-analysis of tumor control rates and treatment-related morbidity for patients with glomus jugulare tumors. J Neurosurg. 2011;114:1299–305.
8. Bradshaw JW, Jansen JC. Management of vagal paraganglioma: is operative resection really the best option? Surgery. 2005;137: 225–8.
26. Hall FT, Perez-Ordonez B, MacKenzie RG, Gilbert RW. Does catecholamine secretion from head and neck paragangliomas respond to radiotherapy? Case report and review of the literature. Skull Base. 2003;13:229–34.
9. van Hulsteijn LT, Corssmit EP, Coremans IE, Smit JW, Jansen JC, Dekkers OM. Regression and local control rates after radiotherapy for jugulotympanic paragangliomas: systematic review and meta-analysis. Radiother Oncol. 2013;106:161–8. 10. Kim JA, Elkon D, Lim ML, Constable WC. Optimum dose of radiotherapy for chemodectomas of the middle ear. Int J Radiat Oncol Biol Phys. 1980;6:815–9.
How to cite this article: Tosun ˙I, Atalar B, Sahin ¸ B, et al. Robotic radiosurgery of head and neck paragangliomas: a single institution experience. Asia-Pac J Clin Oncol. 2017;00:1-5. https://doi.org/10.1111/ajco.12695
