Significance of Tumor Volume Related to Peritumoral Edema in Intracranial Meningioma Treated with Extreme Hypofractionated Stereotactic Radiation Therapy in Three to Five Fractions

Abstract

To investigate the treatment results of intracranial meningiomas treated with hypofractionated stereotactic radiation therapy in three to five fractions.
Thirty-one patients (32 lesions) with intracranial meningioma were treated with hypofractionated stereotactic radiation therapy in three to five fractions using CyberKnife. Fifteen lesions were diagnosed as Grade I (World Health Organization classification) by surgical resection and 17 lesions were diagnosed as meningioma based on radiological findings. The median follow-up time was 48 months. The median planning target volume was 6.3 cm(3) (range, 1.4-27.1), and the prescribed dose (D90≤) ranged from 21 to 36 Gy (median, 27.8) administrated in three to five fractions.
Five-year overall and progression-free survival rate of all 31 patients with intracranial meningioma was 86 and 83%, respectively. Five-year progression-free rate of all 32 lesions was 87%. Six of the 31 patients (19%) developed marked peritumoral edema, three of whom were asymptomatic and three symptomatic, the latter with late adverse effects of more than or equal to Grade 3. The mean planning target volume of the six lesions with marked peritumoral edema was 15.6 cm(3), and for the remaining 26 lesions without marked peritumoral edema was 7.1 cm(3) (P = 0.004). The threshold diameter of 2.56 cm for meningioma was calculated from the planning target volume (11 cm(3)) and was used as marker of developing peritumoral edema (P = 0.003).
Tumor volume is a significant indicative factor for peritumoral edema in intracranial meningioma treated with hypofractionated stereotactic radiation therapy in three to five factions.

Full text

Significance of Tumor Volume Related to Peritumoral Edema in
Intracranial Meningioma Treated with Extreme Hypofractionated
Stereotactic Radiation Therapy in Three to Five Fractions
Masahiro Morimoto1, *, Yasuo Yoshioka1, Hiroya Shiomi1, Fumiaki Isohashi1, Koji Konishi 1, Tadayuki Kotsuma1,
Shoichi Fukuda1, Naoki Kagawa2, Manabu Kinoshita2, Naoya Hashimoto2, Toshiki Yoshimine2and
Masahiko Koizumi3
1
Department of Radiation Oncology, Osaka University Graduate School of Medicine,
2
Department of Neurosurgery,
Osaka University Graduate School of Medicine and
3
Division of Medical Physics, Oncology Center, Osaka
University Hospital, Suita, Osaka, Japan
*For reprints and all correspondence: Masahiro Morimoto, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
E-mail: morimoto-knk@umin.ac.jp
Received December 23, 2010; accepted January 31, 2011
Background: To investigate the treatment results of intracranial meningiomas treated with
hypofractionated stereotactic radiation therapy in three to five fractions.
Methods: Thirty-one patients (32 lesions) with intracranial meningioma were treated with
hypofractionated stereotactic radiation therapy in three to five fractions using CyberKnife.
Fifteen lesions were diagnosed as Grade I (World Health Organization classification) by surgi-
cal resection and 17 lesions were diagnosed as meningioma based on radiological findings.
The median follow-up time was 48 months. The median planning target volume was 6.3 cm
3
(range, 1.4 – 27.1), and the prescribed dose (D90) ranged from 21 to 36 Gy (median, 27.8)
administrated in three to five fractions.
Results: Five-year overall and progression-free survival rate of all 31 patients with intracranial
meningioma was 86 and 83%, respectively. Five-year progression-free rate of all 32 lesions
was 87%. Six of the 31 patients (19%) developed marked peritumoral edema, three of whom
were asymptomatic and three symptomatic, the latter with late adverse effects of more than
or equal to Grade 3. The mean planning target volume of the six lesions with marked peritu-
moral edema was 15.6 cm
3
, and for the remaining 26 lesions without marked peritumoral
edema was 7.1 cm
3
(P¼0.004). The threshold diameter of 2.56 cm for meningioma was cal-
culated from the planning target volume (11 cm
3
) and was used as marker of developing peri-
tumoral edema (P¼0.003).
Conclusions: Tumor volume is a significant indicative factor for peritumoral edema in intra-
cranial meningioma treated with hypofractionated stereotactic radiation therapy in three to five
factions.
Key words: intracranial meningioma – stereotactic radiation therapy – CyberKnife – peritumoral
edema – tumor volume
INTRODUCTION
Surgical resection is the main treatment for intracranial
meningioma (1). However, radiation therapy may also be
considered for a tumor which is not suitable for resection, a
residual or recurrent tumor after surgical resection, and the
presence of factors, which contraindicate surgical resection
such as low performance status, advanced age or compli-
cations. For such cases, conventional radiation therapy
remains the preferred modality (2–5), but stereotactic radi-
ation therapy has recently come into worldwide use (6–12).
According to previous reports, results for stereotactic
†
Presented in part at the 69th annual meeting of the Japan Radiological
Society (2010) in Yokohama, Japan.
#The Author (2011). Published by Oxford University Press. All rights reserved.
Jpn J Clin Oncol 2011;41(5)609 – 616
doi:10.1093/jjco/hyr022
Advance Access Publication 16 March 2011
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radiation therapy for intracranial meningioma were compar-
able to those for conventional radiation therapy, but severe
adverse effects, such as peritumoral edema of intracranial
meningioma, have been also reported. The risk factors of the
peritumoral edema of intracranial meningioma are mainly
reported in radiosurgery (13 –28). However, there have been
few reports on the risk factors of the peritumoral edema of
intracranial meningioma treated with hypofractionated stereo-
tactic radiation therapy in three to five fractions.
The purpose of this study was to investigate the treatment
results for intracranial meningiomas treated with hypofractio-
nated stereotactic radiation therapy in three to five fractions
using CyberKnife and the risk factors for peritumoral edema
as an adverse effect.
PATIENTS AND METHODS
Between June 1999 and June 2008, 31 patients (32 lesions)
with intracranial meningioma were treated with extreme
hypofractionated stereotactic radiation therapy in three to
five fractions using CyberKnife at Osaka University
Hospital, Japan. Eligibility criteria for this treatment were:
(i) patients with tumors which were not suitable for
resection; (ii) patients with residual or recurrent tumors after
surgical resection; (iii) patients with factors contraindicative
of surgical resection such as low performance status, severe
complications or advanced age; (iv) patients with symptoms
caused by the tumor. In principle, the criterion for size was
a meningioma of ,3 cm. Patient characteristics and treat-
ment parameters are listed in Table 1. The median age was
68 years old (range, 18– 90), and there were 27 female and 4
male patients. One patient (two lesions) was diagnosed with
neurofibromatosis type II. Fifteen lesions were diagnosed as
Grade I (World Health Organization classification) by surgi-
cal resection or biopsy and the remaining 17 lesions as
meningioma based on radiological findings or clinical
course. The types and locations of the 32 meningiomas were
parasagittal meningiomas (8), falx (5), petroclival (4), caver-
nous sinus, convexity (3 each), sphenoidal ridge, tentorial,
cerebellopontine angle (2 each), and clival, middle cranial
fossa, anterior clinoidal (1 each). The median follow-up time
was 48 months (range, 10 – 127) and the median radiological
follow-up time was 40 months (range, 1 – 125).
The CyberKnife (Accuray, Sunnyvale, CA, USA) is a
stereotactic radiation therapy system with a 6-MV X-band
linac on a robot arm controlled along six axes. The guidance
system uses X-ray radiographic imaging to track the treat-
ment site and control the alignment of radiation beams from
the robot-mounted liniac. Shiomi et al. (29) reported that the
accuracy of this system as used at our hospital was 0.7 mm
(median). A thermoplastic plastic shell is used for fixation of
the patient. At our hospital, enhanced computed tomography
(CT) with a 1.25 mm slice thickness was performed with the
patient in the treatment position. The gross tumor volume
(GTV) was defined as the visible lesion detected by
enhanced CT with reference to magnetic resonance imaging
(MRI). The clinical target volume (CTV) was defined as
being of the same size as the GTV. The planning target
volume (PTV) was defined in principle as expansion of
0.1 cm of the CTV in all directions, with a median PTV of
6.3 cm
3
(range, 1.4–27.1). For 14 of 32 lesions, we chose
the treatment plan in which at least 90% of the PTV was
included within the prescribed isodose line (D90). The
remaining 18 were treated with a prescribed dose of D90,
which represents the dose with which 90% of the tumor
volume is irradiated. Our prescribed dose ranged from 21 to
36 Gy (median, 27.8) in three to five fractions. Twenty-one
gray in three fractions was used for 2 of the patients, 24 Gy
in three fractions for 12 patients (13 lesions), 25.5 Gy in
three fractions for 1 patient, 30 Gy in three fractions for 11
patients, 30 Gy in four fractions for 1 patient, 30 Gy in five
fractions for 3 patients and 36 Gy in three fractions for 1
patient. The total dose and fractionation for each patient
were decided at weekly meetings of the radiation oncologists
and the neuro-oncologists. However, the actual dose often
changed the dose according to the distance to the risk organs
or other patient factors, and it often depended on the judg-
ment of the primary doctor.
The dose was converted to the biologically equivalent
dose (BED) normalized to 2 Gy in 1 fraction (NTD of 2 Gy)
based on the following linear quadratic equation [BED ¼
Table 1. Patient characteristics and treatment parameters
Patients 31 (32 lesions)
Male 4
Female 27
Diagnosed pathologically 15
Diagnosed with radiological findings 17
The median age (range) 68 (18–90)
The median follow-up time (range) 48 months (10–127)
Tumor location
Parasagittal 8
Falx 5
Petroclival 4
Cavenous sinus 3
Convexity 3
Sphenoidal ridge 2
Tentorial 2
Cerebellopontine angle 2
Clival 1
Middle cranial fossa 1
Anterior clinoidal 1
The median total dose (90 D) (range) 27.8 Gy (21 –36)
The median fractionation (range) 3 (3–5)
The median planning target volume (range) 6.3 cm
3
(1.4–27.1)
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number of fractions dose per fraction (1 þdose per
fraction/(
a
/
b
)],
a
/
b
¼10 for early responding tissue,
a
/
b
¼
3 for late responding tissue). NTD 2 Gy,
a
/
b
¼10 of stereo-
tactic radiation therapy ranged from 29.8 to 66 Gy (median,
39.7), and its NTD 2 Gy,
a
/
b
¼3counterpartfrom42to
108 Gy (median, 54). Stereotactic radiation therapy was
delivered at one fraction a day which took about 1.5 to 1 h
to complete. All three to five fractions were administrated on
consecutive days except in case of holidays.
Our patients were routinely followed up every 0.5 – 12
months and follow-up MRI was performed routinely. The
tumor diameter in the X,Yand Zplanes on MRI was
determined for every case and the tumor size was classi-
fied as decreased, increased or unchanged. A decrease in
tumor size was defined as one of the three diameters of
the tumor as observed on MRI having decreased after
treatment to less than half of what it was before the treat-
ment. An increase in tumor size was defined as one of
the three diameters having increased after treatment to
more than 1.5 times of what it was before the treatment.
Unchanged tumor size was defined as not meeting for
either a decrease or an increase. This classification is a
modified version of the one by Selch et al. (30). The
patients with tumors unchanged or decreased in size were
defined as progression free.
Late adverse effects were defined as symptoms that
occurred more than 3 months after stereotactic radiation
therapy. Common terminology criteria for adverse events,
v4.0 were adopted for evaluation of such effects (31).
Edema was defined as marked peritumoral edema if it
developed .3 cm from the edge of the tumor as
observed on T2-weighted MRI after stereotactic radiation
therapy.
Retrospective treatment results were analyzed for evalu-
ation of the following clinical endpoints: overall survival
rate, progression-free survival rate, progression-free rate, the
appearance rate of marked peritumoral edema and the fre-
quency of adverse events more than or equal to Grade
3. Overall survival rate, progression-free survival rate and
progression-free rate were measured from the beginning of
stereotactic radiation therapy of the meningioma and were
estimated with the Kaplan–Meier method. Significant differ-
ences between groups were tested with t-test or Fishers exact
test. The findings of multivariate analysis were tested with
sequence regression analysis. The Pvalue was two-sided,
and a Pvalue of 0.05 or less was considered significant.
SPSS, version 12.0 (SPSS, Inc., Chicago, IL, USA) was
used for all statistical analyses.
RESULTS
OVERALL SURVIVAL,PROGRESSION-FREE SURVIVAL AND
PROGRESSION-FREE RATES
Five-year overall and progression-free survival rate of all 31
patients with intracranial meningioma were 86% (Fig. 1A)
and 83% (Fig. 1B), respectively. Five-year progression-free
rate for all 32 lesions was 87% (Fig. 1C). One patient
(2 lesions) who was diagnosed with neurofibromatosis type
II was alive with lesions unchanged at last the follow-up. Of
the 32 lesions, 3 were judged to have decreased, 25 to have
remained unchanged and 4 to have increased, with the latter
estimated to have increased at 25, 29, 37 and 105 months,
respectively, after stereotactic radiation therapy. The respect-
ive PTV and treatment doses were 3.3 cm
3
(24Gyinthree
fractions), 9.6 cm
3
(30 Gy in three fractions), 24.1 cm
3
(30 Gy in three fractions) and 27.1 cm
3
(30 Gy in three frac-
tions) and their locations were parasagittal (2), clival and
falx (1 each). Three patients underwent salvage treatment,
two patients surgical resection, one patient re-stereotactic
radiation therapy. Three patients with increased meningiomas
died of the disease at 30, 43 and 68 months after the initial
treatment. In addition to these three, three others died for a
total of 6 deaths. These other three patients whose menin-
gioma was controlled died of lung cancer, diabetes mellitus
and gastrointestinal bleeding, respectively.
MARKED PERITUMORAL EDEMA AND ADVERSE EVENTS
Six of the 31 patients (19%) developed marked peritumoral
edema, 3 asymptomatic and 3 symptomatic with late adverse
effects more than or equal to Grade 3. Three of the sympto-
matic patients developed seizure, gait disturbance and
central nervous system necrosis accompanied by loss due to
long-term heightened intracranial pressure. One of the three
patients whose PTV of convexity meningioma was 14.2 cm
3
developed seizure (Grade 3) 3 months after treatment with
24 Gy in three fractions and often required hospitalization to
control the seizure. One of the three patients whose PTV of
falx meningioma was 22.2 cm
3
developed gait disturbance
(Grade3)5monthsaftertreatmentwith30Gyinfivefrac-
tions. This patent was confined to a wheelchair and died of
gastrointestinal bleeding from unknown causes 8 months
after the initial stereotactic radiation therapy. The last of the
three patients whose PTV of cavernous sinus meningioma
was 13.1 cm
3
developed central nervous system necrosis
(Grade 4) 9 months after treatment with 36 Gy in three frac-
tions (Fig. 2A). She developed bilateral vision loss associ-
ated with bilateral papilledemas and marked peritumoral
edema (Fig. 2B,C) and underwent a craniotomy to reduce
the intracranial pressure. The necrotic tissue around the
tumor was confirmed pathologically. After 8 years, the
marked peritumoral edema seen in Fig. 2C was compara-
tively resolved (Fig. 2D). She was alive with bilateral vision
loss at the last follow-up. The respective PTV, treatment
dose and location of the marked peritumoral edema in the 3
asymptomatic patients were 5.9 cm
3
(24Gyinthree
fractions, falx), 11.4 cm
3
(30 Gy in four fractions, sphenoidal
ridge) and 27.1 cm
3
(30 Gy in three fractions, parasagittal).
A scatter chart of the PTVs with or without marked peri-
tumoral edema is shown in Fig. 3. We performed univariate
analysis. The mean PTV of the 6 lesions with peritumoral
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edema was 15.6 cm
3
, whereas that of the 26 lesions without
marked peritumoral edema was 7.1 cm
3
(P¼0.004). We
determined the threshold of the PTV with the strongest cor-
relation with marked peritumoral edema and found that PTV
of 11 cm
3
correlated most strongly (P¼0.003). We further
assumed that the tumor was a spherical and adopted the fol-
lowing formula for calculation: PTV (cm
3
)¼4/3 
p

(GTV diameter (cm)/2 þ0.1 cm)
3
. For a PTV of 11 cm
3
, the
diameter of the GTV was 2.56 cm. Of the 32 lesions, 9 GTV
diameters were .2.56 cm and 5 of the 9 diameters were
associated with marked peritumoral edema. Of the 32
lesions, 23 diameters of the GTV were 2.56 cm and 1 of
the 23 diameters were associated with marked peritumoral
edema. Intracranial meningiomas with a GTV diameter of
more than 2.56 cm developed significantly marked peritu-
moral edema.
The total dose and schedule with or without peritumoral
edema was converted to NTD of 2 Gy,
a
/
b
¼3, and the
respective average total doses were 68.1 and 62.0 Gy. The
difference in dosage between tumors with and without
peritumoral edema was not significant (P¼0.377). The
most frequent sites of the tumors with peritumoral edema
was falx, but this location turned out not to be significant
factor in peritumoral edema (P¼0.102). We also performed
multivariate analysis of PTVs dose and location. The
results showed that PTVs was a marginally significant factor
(P¼0.066), while the dose (P¼0.372) and the location
(P¼0.493) were not.
DISCUSSION
Clinical endpoints in this study were comparable to those of
other published study reports (2–12).
Reports on treatment of peritumoral edema with stereotac-
tic radiosurgery have appeared in the literature since the
1990s. Engenhart et al. (13) reported that 5 of 17 menin-
gioma patients (29%) developed a large area of brain edema
resulting from treatment with single high-dose radiation
therapy using a linac accelerator. Since then, the frequency
Figure 1. (A) Overall survival rate of meningioma patients (n¼31). (B) Progression-free survival rate of meningioma patients (n¼31). (C) Progression-free
rate of meningioma lesions (n¼32).
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and the risk factors of peritumoral edema have been widely
discussed. The frequency of mainly radiosurgery-induced
edema has been reported as 6–43% (13–28). The risk
factors of peritumoral edema resulting from treatment with
stereotactic radiation therapy are summarized in Table 2
(20–28).Patiletal.(20) reported that the risk factor was
parasagittal location, mainly for stereotactic radiosurgery
using CyberKnife. Chang et al. (21) reported that location or
dose was the risk factors of peritumoral edema with Gamma
Knife. Ganz et al. (22) reported that patients treated with
Gamma Knife developed edema preferentially in case of
non-basal tumors, especially those around the midline and
sagittal sinus. In all but one case where radiation-induced
edema was observed was the margin tumor dose 18 Gy or
more. Kalapurakal et al. (23) reported that the risk factors of
peritumoral edema were parasagittal location, presence of
pretreatment edema, sagittal sinus occulusion, use of .6Gy
per fraction for liniac stereotactic radiosurgery and radiation
therapy. Cai et al. (24) stated that the risk factors of peritu-
moral edema were tumor–brain contact interface area and
Figure 2. (A) Enhanced T1-weighted magnetic resonance image before stereotactic radiation therapy. The well-defined enhanced tumor which was compatible
with meningioma is indicated in the right cavenous sinus. (B) Bilateral eye-fundus images 9 months after stereotactic radiation therapy. Bilateral papilledemas
are indicated and were due to intracranial high pressure. (C) T2-weighted magnetic resonance image after stereotactic radiation therapy of 9 months. Marked
peritumoral edema was indicated. (D) T2-weighted magnetic resonance image 8 years after stereotactic radiation therapy. Marked peritumoral edema was
resolved compared with the image in (C).
Jpn J Clin Oncol 2011;41(5) 613
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tumor volume for meningioma treated with Gamma Knife.
Kollova et al. (25) found that the risk factors were age .60
years, no previous surgery, presence of pretreatment edema,
tumor volume .10 cm
3
, tumor location in anterior fossa and
marginal dose .16 Gy for treatment with Gamma Knife.
Novotny et al. (26) reported that no previous surgery, edema
present before stereotactic radiosurgery, tumor volume
.10 cm
3
, location in anterior fossa and maximum dose
.30 Gy were risk factors for peritumoral edema with
Gamma Knife. The importance of the tumor location was
thus most often reported in radiosurgery, whereas the impor-
tance of the tumor volume was reported only in Gamma
Knife. Kan et al. (27) reported that molecular factors for
peritumoral edema included vascular endothelial growth
factor of peritumoral edema after stereotactic radiosurgery
for intracranial meningiomas. Chen et al. (32) described the
causes of peritumoral edema as radiation necrosis, infiltration
of inflammatory cells and radiation injury to the vasculature
causing hyalinization of blood vessels. On the other hand,
Selch et al. reported no treatment-induced peritumoral
edema resulting from fractionated stereotactic radiation
therapy with 50.4 Gy in 28 fractions (30). Finally, Girvigian
et al. reported that fractionated stereotactic radiation therapy
(median, 50.4 Gy in 28 fractions) was associated with less
risk of post-treatment symptomatic peritumoral edema com-
pared with stereotactic radiosurgery treatment with a mar-
ginal dose of 14 Gy (28).
Most of the reports on the risk factors of peritumoral
edema in association with meningioma are concerned with
radiosurgery, while there have been hardly any reports of the
risk factors of tumor volume for peritumoral edema resulting
from hypofractionated stereotactic radiation therapy with
three to five fractions. In our study, marked peritumoral
edema was observed in 6 of 31 patients (19%), a rate which
was not high compared with other reports. As for the bio-
logical aspects, extreme hypofractionation was found to be
more harmful to normal cerebral tissue than conventional
radiation therapy because the
a
/
b
level of cerebral tissue is
supposed to be low. However, indication of meningioma
with the small volume (the PTV 11 cm
3
, diameter
2.56 cm) for hypofractionated stereotactic radiation therapy
has made it possible to reduce severe adverse effects. Our
study offers suggestions as to which meningiomas can be
indicated for stereotactic radiation therapy with three to five
fractions. We could not determine in our study whether
tumor location is a significant factor. The number of patients
might not be enough to reveal the difference in the incidence
Figure 3. Scatter chart of the planning target volume (PTV) with or
without marked peritumoral edema (n¼32). The difference in mean PTV
was significant (P¼0.004)
Table 2. The significant risk factors of the peritumoral edema in patients treated with stereotactic radiation therapy
Investigator Modality Case Total dose (Gy) Fractions Risk factors
Chang et al. (21) GK 140 15 1 Tumor location, dose
Ganz et al. (22) GK 35 12 1 Tumor location, dose
Kollova et al. (25) GK 331 12.5 1 Tumor location, tumor volume, age, no previous surgery,
presence of pretreatment edema
Novotny et al. (26) GK 331 12.5 1 Tumor location, tumor volume, dose, no previous surgery,
presence of pretreatment edema
Cai et al. (24) GK 182 13.6 1 Tumor– brain contact interface, tumor volume,
presence of pretreatment edema
Kalapurakal et al. (23) Linac 43 13.5– 54 1 Tumor location, dose, sagittal sinus occulusion,
presence of pretreatment edema
Kan et al. (27) Linac 18 13– 15 1 Molecular marker
Girvigian et al. (28) Linac 32 14 or 50.4 1 or 28 Single fraction
Patil et al. (20) CK 102 18 1 Tumor location
Present study CK 31 27.8 3 Tumor volume
GK, Gamma Knife; CK, CyberKnife.
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of peritumoral edema among the locations of the tumor. We
guessed another possibility that unlike treatment with a single
fraction, three to five fractions could overcome the problem of
the location compared with a single fraction. Hashiba et al.
(33) reported that the proliferative potential of meningioma
can be predicted from radiologic characteristics and 16 of 70
incidentally discovered meningiomas were found to have been
grown exponentially (34). The treatment timing of stereotactic
radiation therapy for such meningiomas with rapid growth
should therefore be considered carefully.
In conclusion, tumor volume was identified as a signifi-
cant factor for peritumoral edema in intracranial meningioma
treated with extreme hypofractionated stereotactic radiation
therapy in three to five factions using CyberKnife.
Specifically, careful attention should be paid when treating
meningiomas .2.56 cm in diameter. We have not been able
to establish a unified treatment or patient criteria in stereo-
tactic radiation therapy for meningioma at our institution.
We therefore had to establish our treatment strategy for
meningiomas based on the analyses performed in this study.
From now on, we will deliver 24 Gy in three fractions for
meningioma in principle and be more careful not to treat
large meningiomas with the PTVs .11 cm
3
or close to the
risk organs in the regimen. We will consider more fractiona-
tions for these cases according to need.
Acknowledgements
We deeply appreciated the following investigators who con-
tributed to this study: Iori Sumida, PhD, Yutaka Takahashi,
PhD and Toshiyuki Ogata, MS (Division of Medical
Physics, Oncology Center, Osaka University Hospital).
Conflict of interest statement
None declared.
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