Chapter 13

Cover Page
The handle http://hdl.handle.net/1887/25308 holds various files of this Leiden University
dissertation.
Author: Boetzelaer-van Hulsteijn, Leonie Theresia van
Title: Paragangliomas Pictured
Issue Date: 2014-04-17
CHAPTER 13
Regression and Local Control Rates after Radiotherapy for Jugulotympanic
Paragangliomas: Systematic Review and Meta-Analysis
L.T. van Hulsteijn1, E.P.M. Corssmit1, I.E.M. Coremans2, J.W.A. Smit1, J.C. Jansen3, O.M.
Dekkers1,4
Departments of 1Endocrinology and Metabolic Diseases, 2Radiotherapy,
3
Otorhinolaryngology and 4Epidemiology, Leiden University Medical Center, Leiden, the
Netherlands
Radiotherapy and Oncology 2013;106(2):161-168
193
Abstract
Background: The primary treatment goal of radiotherapy for paragangliomas of the head and
neck region (HNPGLs) is local control of the tumor, i.e. stabilization of tumor volume.
Interestingly, regression of tumor volume has also been reported. Up to the present, no metaanalysis has been performed giving an overview of regression rates after radiotherapy in
HNPGLs.
Therefore, the main objective of this study was to perform a systematic review and metaanalysis to assess regression of tumor volume in HNPGL-patients after radiotherapy. A
second outcome was local tumor control.
Methods: PubMed, EMBASE, Web of Science, COCHRANE and Academic Search Premier
and references of key articles were searched in March 2012 to identify potentially relevant
studies. Considering the indolent course of HNPGLs, only studies with ≥ 12 month follow-up
were eligible. Main outcomes were the pooled proportions of regression and local control
after radiotherapy as initial, combined (i.e. directly post-operatively or post-embolization) or
salvage treatment (i.e. after initial treatment has failed) for HNPGLs. A meta-analysis was
performed with an exact likelihood approach using a logistic regression with a random effect
at the study level. Pooled proportions with 95% confidence intervals (CI) were reported.
Results: Fifteen studies were included, concerning a total of 283 jugulotympanic HNPGLs in
276 patients. Pooled regression proportions for initial, combined and salvage treatment were
respectively 21%, 33% and 52% in radiosurgery studies and 4%, 0% and 64% in external
beam radiotherapy studies. Pooled local control proportions for radiotherapy as initial,
combined and salvage treatment ranged from 79 to 100%.
Conclusions: Radiotherapy for jugulotympanic paragangliomas results in excellent local
tumor control and therefore is a valuable treatment for these types of tumors. The effects of
radiotherapy on regression of tumor volume remain ambiguous, although the data suggest that
regression can be achieved at least in some patients. More research is needed to identify
predictors for treatment success.
194
Introduction
Background
Head and neck paragangliomas (HNPGLs) are rare tumors of paraganglia. They consist of
chromaffin tissue and are associated with the parasympathetic autonomic nervous system.
HNPGLs are named according to site of origin. The most common HNPGLs are the carotid
body tumor, vagal body tumor and jugulotympanic tumor (i.e. paraganglioma of the temporal
bone). 1-2 Due to their location in close proximity to important neurovascular structures, tumor
growth may lead to serious morbidity and cranial nerve impairment, however the majority of
HNPGLs are notoriously benign, indolent tumors and a “wait and scan” policy may be
advisable in appropriate cases.2-3 Therefore, if treatment is commenced, this should focus on
reducing morbidity rather than increasing survival.
With surgical treatment, it is possible to remove the tumor without recurrence. Surgery
however, leads to neurovascular complications in up to 60% of cases; especially cranial nerve
injury and, less frequently, carotid artery lesions.4-5 Radiotherapy is an alternative treatment in
HNPGL-patients. Irradiation produces fibrosis and vascular sclerosis rather than eradication
of the tumor cells.6-7 Its main objective is long-term local control, i.e. no progression of tumor
volume. Interestingly, it can also lead to tumor regression, which may result in reduction of
HNPGL associated symptoms.8-9
The effect of radiation is difficult to assess given the indolent natural course of HNPGLs.
Only long term follow-up might provide evidence that radiotherapy is a beneficial treatment
in these patients. Since HNPGLs almost never show spontaneous tumor volume reduction,
tumor regression is probably a better marker for radiotherapy effect than local tumor control.
Objective of the study
A few systematic reviews and meta-analyses of the effects of radiotherapy on HNPGLs have
been published.10-12 However, these reviews assessed the effect of radiotherapy by local
control rates rather than regression rates and up until now, a meta-analysis assessing
regression of tumor volume has not been performed. The main aim of the present study was to
perform a comprehensive systematic review and meta-analysis of tumor regression following
different types of radiotherapy in HNPGLs.
Materials and Methods
Eligibility criteria
Studies assessing the effect of radiotherapy on tumor volume of HNPGLs were eligible for
inclusion. The analysis aimed to assess the proportion of HNPGL-patients with tumor
regression after radiotherapy, with local control rates as second outcome. According to the
195
“Response evaluation in solid tumors (RECIST) criteria”, a partial treatment response is
defined as “at least a 30% decrease in the sum of diameters of target lesions, taking as
reference the baseline sum diameters”.13 However, the RECIST criteria have not (yet) been
widely accepted in the field of paragangliomas. More importantly, the primary intention of
treatment for HNPGLs is to reduce morbidity and relief of HNPGL-associated symptoms has
been observed after a regression of tumor volume of less than 30%.8,14 In view of this clinical
relevance, we broadened our definition and defined tumor regression as any tumor volume
less than the tumor volume before radiotherapy. Local control was defined as a tumor volume
equal to or less than the tumor volume at start of radiotherapy.
We aimed to stratify tumor regression and local control rates for radiotherapy as initial
treatment (i.e. without prior therapy), combined treatment (i.e. directly post-operatively or
post-embolization) or salvage treatment (i.e. after initial treatment has failed). Studies
regarding radiotherapy preoperatively were not included. In addition, we tried to stratify for
type of radiotherapy (i.e. radiosurgery/stereotactic radiotherapy (RS) or external beam
radiotherapy (EBRT)). In our analyses, we combined the results of the two types of high
precision radiotherapy: stereotactic radiotherapy and radiosurgery.
To accurately assess regression and local control rates, firstly, only studies determining
treatment response (tumor volume) by radiologic evaluation were eligible for inclusion.
Secondly, considering the indolent nature of HNPGLs,3 only studies with ≥ 12 month followup were eligible.
Studies concerning patients with malignant HNPGLs were excluded, unless data for patients
with benign HNPGLs could be extracted separately. We defined malignant HNPGL as the
presence of metastases, i.e. the presence of chromaffin tissue in nonchromaffin organs, distant
from the primary tumor.15-17
In case of multiple studies describing the same cohort, the study which comprised the highest
number of subjects and/or the longest duration of follow-up was included. Furthermore, only
studies reporting a population of more than 10 HNPGL-patients were included. Eligible
studies were restricted to languages familiar to the authors (English, French, German and
Dutch). When reported data were not sufficient for accurate data-extraction, we tried to
contact the authors for clarification.
Search strategy
In March 2012, PubMed, EMBASE, Web of Science, COCHRANE and Academic Search
Premier were searched to identify potentially relevant studies (Appendix 1). References of
key articles were assessed for additional relevant articles.
196
Data extraction
All studies obtained from the search strategy were entered into reference manager software
(Reference Manager version 12, Thomson Reuters, Philadelphia, PA) and were screened on
title and abstract. Potentially relevant studies were retrieved for detailed assessment. For
eligible studies, data were independently extracted by two reviewers (LvH and EC).
Disagreements between reviewers were resolved by consensus, but when doubt remained, a
third reviewer (OD) decided.
Risk of bias assessment
The present meta-analysis is based on observational studies. Risk of bias assessment was
based on study components that potentially bias an association between the intervention under
study (radiotherapy) and the outcomes (regression and local control). The following elements
were assessed for all studies:
1. Risk of selection bias. Inclusion of consecutive exposed patients or a random sample of the
inception cohort was considered a low risk of bias.
2. Adequacy of reporting of intervention (radiotherapy). When type and dose of radiotherapy
were reported, this was considered adequate.
3. Adequacy of measurements for regression and local control. The effect of radiotherapy on
tumor volume should have been measured by either sequential MRI or CT scanning.
4. Adequacy of result stratification per treatment modality (i.e. initial, combined or salvage
treatment).
5. Adequacy of follow-up. Loss to follow-up < 5% was considered to represent a low risk of
bias.
Statistical analysis
The main outcome of the present meta-analysis was the pooled proportion of HNPGLs with
regression after radiotherapy. The pooled proportion of HNPGLs with local control after
radiotherapy was the secondary outcome. For all studies, the proportion of HNPGLs with
tumor regression was calculated as the number of HNPGLs with tumor regression divided by
the total number of HNPGLs treated with radiotherapy. The same procedure was applied to
the proportion of HNPGLs with local control. For all proportions exact 95% confidence
intervals (95% CI) were calculated.
Meta-analysis was performed using an exact likelihood approach. The method used was a
logistic regression with a random effect at the study level. Given the expected clinical
heterogeneity a random effects model was performed by default and no fixed effects analyses
were performed. For meta-analysis of proportions the exact likelihood approach based on a
binomial distribution has advantages compared to a standard (DerSimonian and Laird)
random effects model that is based on normal distributions. Firstly, estimates from a binomial
197
model are less biased than estimates from models based on a normal approximation. This is
especially the case for proportions that are close to 0 or 1. Secondly, no assumptions are
needed for the exact approximation when dealing with zero-cells, whereas the standard
approach needs to add an arbitrary value (often 0.5) when dealing with zero-cells. Adding
values to zero-cells is known to contribute to the biased estimate of the model. All analyses
were performed with STATA 12.0 (Stata Corp, Texas, USA).
Results
Study selection
The initial search resulted in 1371 unique records; 137 were selected for detailed assessment
(Figure 1). After detailed assessment, 122 articles were excluded for following reasons: no
original data (n = 4), no radiologic evaluation (n = 51), inclusion of patients with < 12 months
follow-up (n = 14), inclusion of patients with malignant HNPGL (n = 4), outcome other than
local control or regression (n = 19), results reported for less than 10 patients (n = 26).
Furthermore, four studies comprised a cohort also described in another publication; the
studies with the smallest sample sizes were excluded.18-21 No new articles were found in
references of key articles. Finally, a total of 15 studies were included in the present analysis,
three written in French22-24 and 12 in English.8,14,25-34
Figure 1: Search strategy
198
Study characteristics
Study characteristics are displayed in Table 1. Included studies were published from 1986 to
2011. All included studies were classified as cohort studies.35
A total of 276 patients with 283 HNPGLs were included in this meta-analysis. The largest
study contained 41 subjects.30 Mean age ranged from 42 to 66 years. Mean duration of followup ranged from 39 to 137 months. All studies comprised patients with jugulotympanic tumors
only. One study also comprised one single patient with a thyroid paraganglioma.26
Radiotherapy was performed as initial therapy in 14 studies8,14,22-25,27-34 as combined therapy
in four22,24,27,33 and as salvage treatment in 12.8,14,22,25-29,31-34 In four studies HNPGL-patients
were treated with external beam radiotherapy (EBRT),22-24,30 in seven studies with
radiosurgery,8,14,25,27-28,31-32 and in two studies data of EBRT and radiosurgery were
described.26,33 In two studies patients were treated with stereotactic radiotherapy.29,34
Median pre-radiotherapy tumor volume ranged from 2.8 to 9.5 cc. The effects of radiotherapy
on tumor volume were assessed by magnetic resonance imaging (MRI) in 53% of included
studies,8,14,28-29,31-34 by computed tomography (CT) in 13%23-24 and by both in 13%.27,30 Three
studies (20%) did not specify type of imaging.22,25-26
199
JT (14)
JT (13)a
JT (18)
JT (13)
JT
(45
tumors in 41
patients)
JT (17)
Lee (2011)31
Chen
(2010)25
Genç
(2010)14
Hafez
(2010)28
Tran Ba Huy
(2009)30
200
(2007)29
Henzel
Tumor
localization
(n patients)
First author
(year
of
publication)
±
65 (range
30-82)
Median
59.5
43.6
49.6
14.6
Salvage (5)
Salvage (11)
Initial (6)
Initial (41)
Initial (11)
Salvage (2)
Initial (7)
Salvage (11)
Initial (9)
Salvage (4)
Initial (9)
42.3
(range
22.168.9)
61.8
14.5
Treatment
modality (n)
Median
±
Mean age
in years
Table 1: Characteristics of included studies
(17)
SR
EBRT
(41)
RS
(13)
RS
(18)
RS
(13)
(14)
RS
Type
of RT
(n)
dose-to-the-
cumulative
dose 57 Gy (range
52.5-65)
Median
Gy (range 13-20)
Dose-to-the-tumor
margin range 12-15
Gy
Mean total dose 45
Gy (range 44-50)
Mean
dose-to-thetumor margin 14.6 ±
1.5 Gy (range 12-16)
Mean
dose-to-thetumor margin 15.6
tumor margin 13.7
Gy (range 12.5-15.0)
Mean
Dose of RT
26.7)
7.4 (0.1-
n.r.
mean 8.4
5.5 (2.098.9)
5.9 (0.8817.95)
22.1)
9.5 (6.2-
Median
tumor
volume
in cc at
baseline
(range)
MRI
CT
MRI
MRI
MRI
n.s.
MRI
and/or
Follow-up
imaging
decrease
in
of
in
in
in tumor diameter,
50% reduction in
tumor dimension or
20% reduction in
preradiosurgical
volume
> 2 mm reduction
≥ 20% decrease in
tumor volume
Any decrease
tumor volume
Any decrease
tumor volume
15% decrease in
tumor volume
tumor volume
Any
Definition
regression
tumor volume
Stable or decreased
No progression in
tumor volume
Stable or decreased
tumor volume
< 15% progression
or a decrease in
tumor volume
No progression in
tumor volume
tumor volume
No progression in
Definition of local
control
12-84)
Median 40 (range
50
Range 12-48
52.5 ± 33.0
49.1 ± 42.9
13.2-143.7)
Median 40.3 (range
Mean duration of
follow-up
(months)
Median
56 (range
21-80)d
61.5
(EBRT)
63.5 (RS)
JT (11)
TPGL (1)
JT (18)
JT (33)e
Elshaikh
(2002)26
Eustacchio
(2002)27
Saringer
(2002)33
Median
58 (range
20-80)
n.r.
JT (22)
±
±
±
Zabel
(2004)34
14.8
65.9
(2005)
JT (14)c
Nguyen
23
55.8
11.6
JT (20)
Gerosa
(2006)8
55.4
19.7
JT
(20
tumors in 17
patients)b
Lim (2007)32
EBRT, 3 RS)
Salvage (6
RS)
Initial (3)
Combined
(6)
Salvage (9)
Initial
(9
EBRT, 6 RS)
Combined (9
Salvage (12)
Initial (10)
Salvage (12)
Initial (14)
Initial
(16
tumors in 13
patients)
Salvage (4)
Initial (3)
Salvage (17)
(15)
EBRT
(18)
RS
RS
(18)
EBRT
(5)
RS
(7)
SR
(22)
(14)
EBRT
RS
(20)
RS
(17)
RS: median maximal
dose 24 Gy (range
20-35)
EBRT: median total
dose 46.8 Gy (range
36-52)
tumor margin range
13-16 Gy
Median dose-to-thetumor margin 14 Gy
(range 12-20)
EBRT: dose-to-thetumor margin range
45-54 Gy
RS:
dose-to-the-
± 4.2 Gy (range 4560)
Median total dose
57.6 Gy
Mean
dose-to-thetumor margin 17.3
Gy (range 13-24)
Mean total dose 52.9
Mean
dose-to-thetumor margin 20.5 ±
3.7 Gy (range 14-27)
n.r.
5.2 (0.433.5)d
71.8
(10.5212.2)
n.r.
n.r.
mean 7.0
2.8 (1.26.2)
MRI
MRI, in some
cases CT in
addition*
n.s.
MRI
CT
MRI
MRI
in
Any decrease
tumor volume
Any decrease
tumor volume
n.a.
Any decrease
tumor volume
n.r.
in
in
in
≥ 20% decrease in
tumor volume
Any decrease
tumor volume
No progression in
tumor volume
Stable or decreased
tumor volume
Stable or decreased
tumor volume
Stable or decreased
tumor volume
tumor volume
Unchanged
or
decreased
tumor
volume
No progression in
Stable or decreased
tumor volume
201
3 patients)
62.4 (initial RS, 6
patients)
99.6
(combined
EBRT, 5 patients)
90
(combined
136.8
(initial
EBRT, 6 patients)
102 (initial EBRT,
Median 86.4 (range
18-120)
Median 39 (range
25-114)
Median 68.4 (19177)
66.4 ± 48.5
50.9
47.6 ± 43.4
JT (10)
Scherrer
(1986)24
Range 3070
59f
Salvage (5)
Initial (8)
Combined
(2)
Initial (6)
Combined
(3)
EBRT
(10)
EBRT
(14)
Mean total dose 50
Gy (range 45-60)
Mean total dose 50.6
± 6.2 Gy (range 4560)f
n.r.
n.r.
CT
and/or
tomography
n.s.
n.r.
Any decrease
tumor volume
in
n.r.
No progression in
tumor volume
104.4 ± 70.9
202
f
The authors included 53 patients in their study. Twenty patients were treated surgically and therefore excluded from our analyses.
Eighteen patients were included in this study. However, 4 patients received radiotherapy after total resection and could therefore not be analyzed for regression or local control. Therefore, we
excluded these four patients from our analyses, but were not able to exclude data from these patients for these variables.
e
* Data acquired after correspondence with the authors.
a
Originally, 15 patients were included in this study. However, we extracted data for 13 patients; 2 patients were excluded because of a follow-up duration of less than 12 months.
b
Originally, 18 patients were included in this study. However, we extracted data for 17 patients; 1 patient was excluded because of a follow-up duration of less than 12 months.
c
Originally, the authors described a cohort of 41 patients with JT paragangliomas. Twenty-three patients were treated surgically and excluded from our analyses. Two patients were treated with
combined therapy. Since it was unclear if local control was evaluated by radiological imaging, we also excluded data from these 2 patients from our analyses. In 14 patients treated with RT as
initial therapy, local control was evaluated by radiological imaging. For the purpose of this review, we extracted data from these patients only.
d
Originally, 19 patients were included in this study. However, 1 patient was followed up for less than 12 months. After correspondence with the authors, we were able to exclude data from this
patient from our analyses, except for these variables.
± = standard deviation, n.r. = not reported, n.s. = not specified, n.a. = not applicable
JT = jugulotympanic, TPGL = thyroid paraganglioma,
RT = radiotherapy, EBRT = external beam radiotherapy, RS = radiosurgery, SR = stereotactic radiotherapy
Gy = Gray, MRI = magnetic resonance imaging, CT = computed tomography
JT (14)
Baillet
(1990)22
EBRT, 4 patients)
73.2 (combined RS,
3 patients)
60 (salvage RS, 6
patients)
Range 24-132f
Risk of bias assessment
Summary characteristics of the risk of bias assessment are shown in Table 2. In 13 studies
(87%) included patients were explicitly described as consecutive exposed patients or as a
random sample of the inception cohort; in two studies this was unclear.30,32 The intervention
under study (i.e. radiotherapy) was adequately described in all studies. The effect of
radiotherapy on tumor volume was adequately measured in 11 studies.
In two studies, we were not able to stratify the effects of radiotherapy per treatment
indication.22,29 Actual loss to follow-up was reported in 10 of 15 studies (67%). In only one of
these 10 studies, loss to follow-up did not exceed 5%.27
Rate of tumor regression and local control: meta-analysis
Table 3 gives an overview of reported regression and local control proportions of included
studies. Reported treatment success after radiotherapy was consistently good for local control,
whereas for tumor regression reported proportions varied considerably. For radiosurgery (RS)
as initial treatment, regression proportions varied from 0.00 to 1.00. For RS as combined
therapy these proportions ranged from 0.00 to 0.50 and for RS as salvage therapy from 0.00 to
1.00. For external beam radiotherapy (EBRT) as initial treatment, regression proportions
ranged from 0.00 to 0.64.
Local control proportions reported in individual studies ranged from 0.67 to 1.00 for RS as
initial treatment modality. For RS as combined treatment only local control proportions of
1.00 were reported and for salvage treatment, proportions of 0.89 to 1.00. For EBRT as initial
treatment modality, local control proportions ranged from 0.86 to 1.00. When EBRT was used
in a combined or salvage treatment, these proportions ranged from 0.67 to 1.00 and 0.91 to
1.00, respectively.
Results of the random effects meta-analysis, stratified for type of radiotherapy and treatment
modality are displayed in Figure 2. Pooled regression proportions for radiosurgery as initial,
combined and salvage treatment were 21% (95% CI 9-69), 33% (95% CI 11-67) and 52%
(95% CI 28-74), respectively. For external beam radiotherapy, these proportions were 4%
(95% CI 0-59), 0% (95% CI 0-23), and 64% (95% CI 34-66).
Pooled local control proportions for radiosurgery as initial, combined and salvage treatment
were 99% (95% CI 74-100), 100% (95% CI 66-100) and 99% (95% CI 90-99), respectively.
For external beam radiotherapy, these proportions were 94% (95% CI 87-98), 79% (95% CI
51-93),
and
94%
(95%
CI
66-99).
203
Table 2: Risk of bias assessment of included studies
First author
Consecutive
Determinatio
Adequacy
Results
Number
(Year
of
publication)
patients
random
or
n
of
intervention
measurement
of regression
of
stratified per
treatment
patients lost
to follow-up
sample
of
modality
(%)
adequately
and/or
inception
cohort
reported
control
Lee
(2011)31
Yes
Yes
Yes
Yes
n.r.
Chen
Yes
Yes
Unclear
Yes
5 (33)a
(2010)
Genç
local
25
Yes
Yes
Yes
Yes
1 (6)
(2010)14
Hafez
Yes
Yes
Yes
Yes
n.r.
(2010)28
Tran Ba Huy
Unclear
Yes
Yes
n.a.
n.r.
Henzel
(2007)29
Yes
Yes
Yes
No
1 (6)
Lim
(2007)32
Unclear
Yes
Yes
Yesb
2 (11)c
Gerosa
(2006)8
Yes
Yes
Yes
Yes
n.r.
Nguyen
Yes
Yes
Yes
Yes
3 (7)d
(2009)30
(2005)
Zabel
23
Yes
Yes
Yes
Yes
2 (9)
(2004)34
Elshaikh
Yes
Yes
Unclear
n.a.
n.r.
(2002)26
Eustacchio
Yes
Yes
Yes
Yes
0 (0)
Saringer
(2002)33
Yes
Yes
Yes
Yes
5 (9)e
Baillet
(1990)22
Yes
Yes
Unclear
No
3 (17)f
Scherrer
(1986)24
Yes
Yes
No
Yes
1 (10)
(2002)
27
n.a. = not applicable, n.r. = not reported
a
Of 15 originally included patients.
b
Data acquired after correspondence with the authors.
c
Of 18 originally included patients.
d
Of 41 originally included patients.
e
Of 53 originally included patients.
f
Of 18 originally included patients.
204
of
0.33 (0.07-0.70)
1.00 (0.59-1.00)
(2011)31
Chen
(2010)25
Genç
1.00c (0.79-1.00)
0.31c (0.11-0.59)
0.00 (0.00-0.71)
0.40a 0.12-0.74)
Lim
(2007)32
Gerosa
(2006)8
Zabel
Saringer
(2002)33
(2002)
0.33 (0.04-0.78)
0.33a (0.01-0.91)
(2002)26
Eustacchio
27
n.a.
(2004)
Elshaikh
34
1.00b (0.79-1.00)
0.31b (0.11-0.59)
Henzel
(2007)29
1.00 (0.54-1.00)
1.00 (0.29-1.00)
n.a.
0.90 (0.56-1.00)
1.00 (0.29-1.00)
1.00 (0.72-1.00)
0.18a (0.02-0.52)
1.00 (0.59-1.00)
0.67 (0.30-0.93)
Hafez
(2010)28
(2010)14
1.00 (0.66-1.00)
Lee
1.00 (0.66-1.00)
(95% CI)
(95% CI)
0.00 (0.00-0.71)
0.50a (0.12-0.88)
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
(95% CI)
Regression
Regression
1.00 (0.29-1.00)
1.00 (0.54-1.00)
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
(95% CI)
Local control
Combined therapy (95% CI)
Local control
Initial therapy
Radiosurgery/Stereotactic radiotherapy
First author
(Year of publication)
Table 3: Regression and local control rates per treatment modality and type of radiotherapy
0.33 (0.04-0.78)
0.33a (0.07-0.70)
n.r.
0.25a (0.05-0.57)
0.53 (0.28-0.77)
0.25 (0.01-0.81)
0.31b (0.11-0.59)
0.00a (0.00-0.84)
0.91 (0.59-1.00)
1.00 (0.40-1.00)
1.00 (0.48-1.00)
(95% CI)
Regression
1.00 (0.54-1.00)
0.89 (0.52-1.00)
1.00 (0.59-1.00)
0.92 (0.62-1.00)
1.00 (0.80-1.00)
1.00 (0.40-1.00)
1.00b (0.79-1.00)
1.00 (0.16-1.00)
0.91 (0.59-1.00)
1.00 (0.40-1.00)
1.00 (0.48-1.00)
(95% CI)
Local control
Salvage therapy (95% CI)
205
0.00 (0.00-0.34)
0.00 (0.00-0.37)
Scherrer
(1986)24
1.00 (0.63-1.00)
0.91e (0.59-1.00)
1.00 (0.66-1.00)
n.a.
0.86 (0.57-0.98)
0.96d (0.85-0.99)
0.00 (0.00-0.84)
0.00 (0.00-0.71)
0.00 (0.00-0.34)
n.a.
n.a.
n.a.
1.00 (0.16-1.00)
1.00 (0.29-1.00)
0.67 (0.30-0.93)
n.a.
n.a.
n.a.
n.a.
0.64e (0.31-0.89)
n.a.
n.r.
n.a.
n.a.
n.a.
0.91e (0.59-1.00)
n.a.
1.00 (0.48-1.00)
n.a.
n.a.
206
n.a. = not applicable, n.r. = not reported
a
Data acquired after correspondence with the authors.
b
Results could not be stratified for radiotherapy as initial or salvage therapy: percentages relate to 16 patients for whom follow-up data were available.
c
Percentage relates to 16 tumors in 13 patients.
d
Percentage relates to 45 tumors in 41 patients.
e
Results could not be stratified for radiotherapy as initial or salvage therapy: percentages relate to 11 patients (6 receiving radiotherapy as initial treatment and 5 receiving radiotherapy as salvage treatment).
0.64e (0.31-0.89)
Baillet
(1990)22
(2002)
n.a.
(2002)26
Saringer
33
0.00 (0.00-0.23)
(2005)23
Elshaikh
0.27d (0.15-0.42)
(2009)
Nguyen
30
Tran Ba Huy
External beam radiotherapy
Figure 2: Meta-analysis
207
Discussion
The present systematic review and meta-analysis aimed to assess regression of tumor volume
and local control rates in HNPGLs treated with radiotherapy. Whereas regression rates
diverged considerably, both radiosurgery and external beam radiotherapy resulted in excellent
local control rates in jugulotympanic paragangliomas.
The high local control rates shown in this meta-analysis are not unexpected, taking into
account the fact that about half of the paragangliomas do not exhibit growth over time. 3 Our
results are in concordance with previously published reviews on local control rates after
radiotherapy for HNPGLs, albeit slightly lower.10-12 This is probably due to the fact that we
tried to abolish incorrectly positive local control rates by including only studies with a ≥ 12
month follow-up period. Nevertheless, a significant proportion of the local control will reflect
the natural course of the disease rather than treatment effect. Moreover, only one study
reported a loss to follow-up < 5%. This potential for selection bias may have overestimated
the effect of radiotherapy.
Included studies displayed heterogeneity in assessing the effects of radiotherapy. Although
most studies described which imaging techniques were used to determine treatment response,
precise volume measurement methods were often not reported. Since paragangliomas are
highly vascular tumors, blood flow or pressure may vary at different times when imaging
studies are performed.36 Therefore, small decreases in tumor size on imaging studies may not
actually represent true regression of tumor volume. Since most studies determined any
decrease of tumor volume as regression, this may have led to an overestimation of regression
rates in our meta-analysis. On the other hand, three included studies determined regression as
a ≥ 20% reduction of tumor volume.8,29-30 This variability in defining regression may
contribute to the variety in regression rates. Future research on the effects of radiotherapy on
HNPGLs should apply uniform criteria for changes in tumor size in order to objectively
assess treatment response.
In literature, an applied radiation dose of 45-50 Gy for EBRT and a marginal radiation dose of
at least 14 Gy for RS are recommended to achieve local control of HNPGLs. 37-39 The average
applied radiation doses of included articles are well within this range. The question arises
whether a higher dose is needed to achieve regression. Although no dose-effect correlation on
tumor shrinkage could be found by Gerosa et al.,8 none of the other included articles
addressed this issue and separate analyses would be unfeasible due to the small numbers of
included patients.
With the present systematic review we aimed to assess the effects of radiotherapy in all types
of HNPGLs. Yet, included studies only comprised jugulotympanic paragangliomas and one
thyroid paraganglioma. Therefore, our results are not generalizable to HNPGLs located
elsewhere than the jugulotympanic region. The fact that only few studies exist assessing the
208
effect of radiotherapy in carotid and vagal body tumors is probably due to the fact that most
authors consider surgery the treatment option of choice for cervical paragangliomas.40-42 Our
search resulted in only one study which accurately evaluated the effects of radiotherapy in
cervical paragangliomas, reporting local control rates of 0.96 for radiotherapy as initial
treatment and 0.88 for radiotherapy as salvage therapy.43 Unfortunately, this study included
patients with malignant HNPGLs and therefore was not eligible for inclusion in this review.
In our study, we were not able to take the indication for radiotherapy as initial treatment into
account. Since surgical treatment is generally considered the reference standard for HNPGLs
and initial treatment with radiotherapy is mostly used in HNPGL-patients who are either poor
surgical candidates due to old age or extensive co-morbidity, or due to the localization of the
tumor, e.g. the risk of sacrificing the vagal nerve in vagal body paragangliomas or intracranial
extension of jugulotympanic paragangliomas.23,30,44 In this latter group, regression of tumor
volume would be especially profitable. However, special attention must be paid when treating
large intracranial tumors adjacent to the brainstem with radiotherapy, since regression can be
preceded by temporary tumor volume progression due to development of edema.7,31
Complications reported after the use of fractionated (external beam) radiotherapy are
xerostomia, stenosis of the external auditory canal, alopecia, osteoradionecrosis of the
temporal bone and encephalopathy.45-47 Also, one must take into consideration the risk of
inducing secondary malignancies in young patients after treatment with radiotherapy,
although in HNPGL patients this risk is reported to be 0.3%.48 In EBRT studies included in
our review, mucositis and nausea were reported as acute side effects and xerostomia, serous
otitis media and vertigo as late side effects of radiotherapy.22-23,30 In studies concerning
stereotactic radiotherapy, transient low-grade xerostomia, nausea, taste irritation, middle ear
effusion, vertigo, headache and mucositis were reported as well as a maxillary bone
abscess.29,34
Studies in radiosurgery yielded higher regression and local control rates than EBRT studies,
indicating that radiosurgery is a more effective treatment than EBRT for jugulotympanic
paragangliomas. A benefit of radiosurgery over fractionated radiotherapy is that the patient is
treated in a single session with a reduced total radiation volume. In radiosurgery studies
included in our review, two patients sustained transient complications. One patient’s preexisting swallowing disorder worsened one month after irradiation and the second patient
developed ipsilateral incomplete facial nerve palsy 12 months after irradiation.33 None of the
included studies reported secondary malignancies.
209
Conclusions
According to the available evidence, radiotherapy seems to be a valuable treatment in
establishing local control in patients with jugulotympanic paragangliomas. The effects of
radiotherapy on regression of tumor volume remain ambiguous, although the data suggest that
regression is achieved at least in some patients. For a more precise determination of the
effects of radiotherapy in HNPGL-patients, prospective, long-term follow-up studies with
accurate radiologic evaluation and clear definitions of change in tumor volume are warranted.
210
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