Pediatr Blood Cancer 2008;50:1163–1168
Brain-Sparing Radiotherapy for Neuroblastoma Skull Metastases
Suzanne L. Wolden, MD,1* Christopher A. Barker, MD,1 Brian H. Kushner, MD,2 Haritha Bodduluri, MD,1
Cesar Della-Biancia, PhD,1 Kim Kramer, MD,2 Shakeel Modak, MD,2 and Nai-Kong V. Cheung, MD, PhD2
Background. Neuroblastoma (NB) frequently metastasizes to the
skull, often diffusely involving the calvarium and skull base.
Radiotherapy may enhance local control; however, irradiating the
brain is undesirable in young patients. The purpose of this study was
to describe the technique, outcome and toxicities in patients with
high risk NB metastatic to the skull treated with brain-sparing skull
radiotherapy (BSRT). Procedure. Between 1999 and 2007, 31
patients with INSS stage four high risk NB, aged 2–32 years (median
6 years), underwent multimodality therapy, including radiotherapy
to the whole skull using a brain-sparing technique never previously
described in this population. Dosimetric analyses were performed to
compare the BSRT technique to a whole brain radiotherapy (WBRT)
technique. Patients were either treated to consolidate upfront
induction therapy (n ¼ 22) or to palliate relapsed disease (n ¼ 9).
Key words: brain-sparing; skull; local control; neuroblastoma; radiation oncology; radiation therapy
INTRODUCTION
A century ago, Hutchinson first described the propensity for
neuroblastoma (NB) to metastasize to the skull [1]. In fact, some
series have reported skull metastases in 40% of patients with NB [2].
It is unclear whether this is simply due to the fact that the skull
accounts for 20–25% of the body’s bone volume and active marrow
in small children [3] or whether there are other pathologic factors
that foster spread to the skull.
As a tumor known to be very radiosensitive [4,5], limited areas of
skull involvement are easily treated with local radiotherapy to a dose
of 21 Gy, alongside intensive systemic therapy [6,7]. However, in
some cases skull metastases can be extensive with diffuse involve-
ment of the entire calvarium and skull base. Such cases present a
difficult challenge because large field photon radiotherapy would
require full dose irradiation of the entire brain. Whole brain
radiotherapy is an especially unappealing option in high risk NB
patients whose median age is 3 [8]. Whole brain radiotherapy doses
as low as 18 Gy are known to cause significant problems with
neurocognitive development and hypothalamic/pituitary function in
young children [9], via numerous neuropathogenetic mechanisms
that are not entirely clear [10].
As a potential solution to this problem, we have employed a
technique of combined photon/electron skull radiotherapy that
allows delivery of full dose radiotherapy to the bones of the skull
with relative sparing of the brain parenchyma. Herein, the details of
the Memorial Sloan-Kettering Cancer Center experience with the
technique are described.
METHODS
Patients
Thirty-one consecutive patients with diffuse skull metastases
(
3 major skull bones or regions involved) from NB were treated
with BSRT (described below) between September 1999 and March
2007. Assent and informed consent for treatment was obtained
from minor patients and adult patients or parents, respectively. The
ß 2007 Wiley-Liss, Inc.
DOI 10.1002/pbc.21384
Results. Thirty of 31 patients (97%) completed the full course of
BSRT. Median follow-up was 19 months (range 1–83 months).
Radiographic response to therapy was noted in 89% of patients. The
actuarial rate of disease control in the skull was 89% and 60% 1 year
after starting BSRT in patients treated in consolidation and for
palliation, respectively. BSRT delivered half of the mean radiation
dose to the brain when dosimetrically compared to whole brain
radiotherapy. Few patients experienced significant toxicity.
Conclusions. BSRT in NB patients with diffuse skull metastases
offers dosimetric advantages over WBRT and results in good local
control when used in the consolidative setting. The technique is well
tolerated and while toxicity appears acceptable, longer follow-up is
necessary. Pediatr Blood Cancer 2008;50:1163–1168.
ß 2007 Wiley-Liss, Inc.
medical records of patients were retrospectively reviewed with
approval from the institutional review board.
The median age at the time of radiation therapy was 6 years with
a range of 2–32 years. Eighteen patients were male and 13 were
female. All patients had high risk stage 4 NB according to the
Children’s Oncology Group risk grouping and the revised Inter-
national Neuroblastoma Staging System [11,12]. Each patient
received intensive systemic therapy according to a series of
institutional protocols, as well as cooperative group protocols,
(N6, N7, N8, POG 9640, COG ANBL00P1, COG A3973,
CCG 3891) (http://www.cancer.gov/clinicaltrials/POG-9640;
http://www.cancer.gov/clinicaltrials/COG-ANBL00P1; http://www.
cancer.gov/clinicaltrials/COG-A3973; http://www.cancer.gov/
clinicaltrials/CCG-3891) [13–18]. Twenty-two patients were treat-
ed with consolidative skull radiotherapy at the conclusion of initial
systemic therapy, as part of definitive treatment with curative intent.
The other nine were treated for skull involvement at the time of
relapse for local disease control and palliation. Performance status
was assessed before and after radiotherapy, according to the method
of Lansky or Karnofsky [19–21]. The extent of disease and pattern
of relapse in the skull, and elsewhere, was ascertained from CT and/
or MRI, 123I-metaiodobenzylguanidine and/or PET scans. Bones of
the skull base (sphenoid, petrous temporal, anterior occipital) that
are difficult to identify individually with imaging were collectively
described as ‘‘skull base.’’ Patients were followed for complications
of therapy by the primary oncologist and in the long-term follow-up
clinic; screening for complications was performed as warranted by
clinical risk factors.
— —————
1
Department of Radiation Oncology, Memorial Sloan-Kettering
Cancer Center, New York, New York; 2Department of Pediatrics,
Memorial Sloan-Kettering Cancer Center, New York, New York
*Correspondence to: Suzanne L. Wolden, Department of Radiation
Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York
Avenue, New York, NY 10021. E-mail: woldens@mskcc.org
Received 13 July 2007; Accepted 30 August 2007
1164 Wolden et al.
BSRT Technique
All patients were simulated for radiotherapy using an Aquaplast
face mask for immobilization. Younger children who could not
cooperate with immobilization received Propofol anesthesia for
simulation and twice daily for treatment. Plain or digitally
reconstructed radiographs were obtained of the head and upper
neck. As shown in Figure 1, right and left lateral 6 MeV electron
fields (included in the region marked ‘‘e-’’ in Fig. 1) were used
to minimize the depth of the radiation dose. The outer perimeter of
the calvarium and skull base were included in right and left lateral 6
MV photon fields. The globes, face and the middle of the cranium
were blocked (as indicated in Fig. 1 by strikethrough). The electron
fields were designed to directly match the area of the lateral skull
block for the photon fields. The photon energy was 6 MV and the
electron energy was 6 MeV in all cases.
There was no gap and no overlap between fields, and match lines
were not shifted during treatment because of the relatively low
prescription dose. Twenty-five (81%) patients received BSRT twice
daily with 1.5 Gy to a total dose of 21 Gy. Of the remaining patients
treated with an alternative dose and fractionation scheme because of
aggressive, chemotherapy refractory disease: 3 (10%) received BSRT
once daily with 2 Gy to a total dose 30 Gy, 1 (3%) received BSRTonce
daily with 3 Gy to a total dose 30 Gy, and 1 (3%) received 1.5 Gy of
BSRT twice in 1 day, and thereafter was treated with 1.8 Gy once daily
to a total dose 30 Gy. Patients treated with an alternative dose and
fractionation scheme were all receiving treatment with palliative
intent (three were adults older than 18 years). All but one of the
children in the study were treated using hyperfractionation.
Fig. 1. Lateral simulation x-ray of the brain-sparing skull radio-
therapy technique, with energy fields, and blocks indicated. [Color
figure can be viewed in the online issue, which is available at www.
interscience.wiley.com.]
Pediatr Blood Cancer DOI 10.1002/pbc
Dosimetric Analysis
The photon/electron technique for whole skull radiotherapy was
dosimetrically compared to whole brain radiotherapy with photons.
A three-dimensional virtual simulation was performed using each
technique on the same patient. Dose-volume histograms were
obtained for the bones of the skull and the whole brain in order to
perform a comparison of doses using the two techniques.
Statistics
Performance status before and after radiotherapy was compared
using a two-tailed Student’s paired t-test (a ¼ 0.05). The Kaplan–
Meier method was used to calculate actuarial rates of disease control
in the skull as well as overall survival. Disease-free survival was
defined as being alive with no relapse of NB.
RESULTS
Outcome
Thirty of 31 patients (97%) completed the full course of BSRT.
One patient experienced a brief treatment delay not related to BSRT.
Median follow-up was 19 months (range 1–83 months).
Symptoms due to skull metastases were infrequent. Headache
was the most common complaint associated with skull metastases.
In all patients (n ¼ 4) who presented with headache, pain relief was
noted after completing radiotherapy. Three patients presented with a
discrete mass on the skull. A decrease in the size of the mass after
radiotherapy was noted in all three patients. Two patients presented
with unilateral proptosis, and two others presented with unilateral
ptosis of the eye. These ocular problems resolved after BSRT. One
patient presented with unilateral esotropia, which did not respond to
BSRT. In addition, one patient presented with monocular blindness
which did not resolve after radiotherapy.
Performance status was very good in all patients before and after
radiotherapy. The mean performance status score prior to radio-
therapy was 90%. The mean performance status score after
radiotherapy was 97% (P < 0.05). No patient experienced a decline
in performance status after radiotherapy. Sixteen patients (53%)
experienced an improvement in their performance status score after
radiotherapy.
Patients had an average of 6 (range 3–10) skull bony regions
involved with NB prior to beginning radiotherapy. As indicated in
Table I, most lesions were located in the parietal or frontal bones.
Radiographic follow up after radiotherapy was available in
27 patients. Twenty-three (89%) of these patients exhibited a
treatment response to therapy on imaging.
TABLE I. Hemiskull Involvement With Metastatic
Neuroblastoma
Skull region Number of hemiskulls involved
Parietal 43
Frontal 40
Base 37
Occipital 21
Orbital 19
Temporal 17
Maxilla 10
Mandible 3

Fig. 2. Local control in patients with high risk stage 4 neuroblastoma treated with brain-sparing radiotherapy in consolidation.
The actuarial rate of disease control in the skull was 89% and
60% 1 year after starting BSRT in patients treated as consolidation
and palliation, respectively (Fig. 2). Analysis of the patients with
skull failures revealed that relapses were focal rather than diffuse.
They did not appear to be located in the region of the photon/electron
match line. Because the relatively low dose of whole skull
radiotherapy, failures could be safely re-treated with a second
course of focal radiotherapy.
Dosimetric Analysis
Isodose displays for whole brain radiotherapy and the photon/
electron brain-sparing technique are shown in Figure 3. Dose
volume histograms comparing radiation dose to the whole brain is
shown in Figure 4. The brain-sparing photon/electron technique
delivers a higher dose to the skull bones (the intended target) at
104% of the prescribed dose, versus 102% with whole brain
radiotherapy. Conversely, the mean dose to the whole brain with the
photon/electron technique is half that of whole brain radiation, 52%
and 104% of the prescribed dose, respectively.
Toxicity
Acute toxicity was limited to grade 1 nausea and/or vomiting in
nine patients. One patient experienced grade 1 mucositis. Endocrine
evaluation in 25 patients revealed grade 1 and grade 2 primary
hypothyroidism in 3 and 1 patients, respectively. One patient
developed grade 2 secondary hypothyroidism. Three children have
mild generalized thinning of their hair and another reported small
patches of permanent epilation near his forehead; all received 21 Gy.
The remaining patients have had no identifiable problems with hair
growth. Sensorineural hearing loss in speech frequencies (500–
2,000 Hz) was noted in 4 of 12 patients assessed. Two patients had
moderate (41–55 dB) loss, and 2 patients had severe (71–90 dB)
loss. In the high frequencies (4,000–8,000 Hz), 10 of 12 patients
experienced hearing loss. Eight patients had mild to moderate loss
(26–55 dB), and 2 patients had severe (71–90 dB) loss. Neuro-
cognitive dysfunction was noted in two patients; one of these
Pediatr Blood Cancer DOI 10.1002/pbc
Brain-Sparing RT for NB Skull Mets 1165
children still demonstrated neuropsychological capacity within
normal limits. One child was noted to develop dysmorphic cranial
features. Dental problems were not noted. No problems with vision
(including cataracts) were noted.
DISCUSSION
Radiotherapy is an important component of multimodality
treatment of high risk NB [6,7]. Patients frequently have metastases
to the skull and the involvement is often extensive. In the past, such
patients have either been under-treated using no radiotherapy, or
inadequate fields of radiotherapy that do not cover all skull disease.
Alternatively, patients may have been over-treated with whole brain
radiotherapy, potentially leading to significant neurocognitive
consequences in survivors of this childhood cancer [9]. Since the
survival rate for high risk NB has been steadily increasing due to
improvements in systemic therapy, it is imperative that consol-
idative radiotherapy be optimized to control involved sites of
disease and to minimize the potential for late effects of therapy. For
relapsed patients, control of disease in the skull is important from a
palliative and quality of life standpoint [22,23]. Skull disease
frequently causes severe pain and can lead to cranial nerve palsies
and even visual disturbances [24,25].
Sangthawan et al. recently published a report of 20 high risk NB
patients treated with chemotherapy, surgery, primary and metastatic
site radiation, myeloablative chemotherapy, peripheral blood
stem cell rescue, and 13-cis-retinoic acid [2]. Eight patients (40%)
presented with skull metastases. Two of these eight patients were
treated with chemotherapy alone, because MIBG imaging was
negative after induction chemotherapy. Six of eight underwent
involved field radiation therapy to 21 Gy, using a spot radiation
technique. After a median follow up of 7 months, both of the patients
treated with chemotherapy alone (i.e., not with radiation therapy)
for skull metastasis experienced relapse in the skull. Of the six
patients treated with involved field radiation therapy, 3 (50%)
experienced skull relapse, although the authors do not comment if
the recurrence occurred at the original site of disease. In total, 6 of 20
(30%) patients experienced failure in the skull, making it the most
1166 Wolden et al.

Fig. 3. Isodose displays for (A) whole brain radiotherapy and (B) the brain-sparing radiotherapy technique. [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.]

Fig. 4. Dose volume histogram demonstrating the radiation dose by brain volume with (red) whole brain radiotherapy versus (green) brain-sparing
skull radiotherapy. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Pediatr Blood Cancer DOI 10.1002/pbc

common site of relapse. The authors recommended more aggressive
evaluation and treatment of skull metastases. Given the high rate of
skull failure in patients treated with chemotherapy alone, when
compared to patients treated with involved field radiation therapy,
consideration must be given to treating the skull with radiotherapy
during consolidation. Our report describes an alternative technique
of radiotherapy which involves treating the entire skull, with the
intent of preventing recurrence of skull disease. Further studies will
be necessary to determine if skull radiation therapy improves the
outcome of patients with high risk NB.
The brain-sparing technique used for patients in this series has
also been used to treat adult patients with angiosarcoma of the scalp,
a very rare tumor that often involves the entire scalp [26]. The dose
used for angiosarcoma patients is 60 Gy, thereby requiring shifting
the match line between the photon and electron fields. This was not
felt to be necessary in NB patients because of the lower doses and
because shifting would cause more radiation exposure to the brain.
The hot spots at the match line were 20% higher than the hot spots in
a whole brain field but these represent small volumes and are well
within tolerance doses for the brain. The fact that relapses did not
specifically occur in the region of the match line argues that under-
dosing at the junction is not a problem.
All patients in the present study completed radiotherapy without
significant delay or acute toxicity. Late complications of therapy
reported in this series are consistent with those reported in other
series from our institution of children treated for advanced NB [27].
Primary hypothyroidism was experienced by several patients in the
present study but this is unlikely due to skull radiotherapy since the
thyroid gland was not in the field. More likely, this was a result of
radioimmunotherapy [27]. One patient experienced secondary
hypothyroidism, which could be attributed to radiotherapy, although
calculated doses to the pituitary were significantly less than
published tolerable doses to the CNS (45 Gy) [28]. Similarly,
sensorineural hearing loss was encountered with several patients. In
prior studies from our institution, 97% of NB patients treated with
cisplatin experienced hearing loss [27,29]. With doses less than 40–
50 Gy, skull radiotherapy is not expected to contribute to
sensorineural hearing loss in the setting of multimodality therapy
[30]. Because formal neurocognitive testing was not performed
prior to beginning therapy, no formal follow-up testing was
performed. However, all but two children have advanced in school
as expected. Of the two patients with documented neurocognitive
dysfunction, one still performs within the normal range. The other
patient with neurocognitive dysfunction may have had neuro-
developmental delays prior to diagnosis and the initiation of therapy.
Future studies using formal tools to assess neurocognitive status
before and after radiotherapy would be helpful to fully assess this
point.
The rate of disease control in the skull was good for patients who
received 21 Gy as consolidative treatment at the conclusion of their
initial systemic therapy with curative intent. The rate of control was
worse for patients who were irradiated at the time of relapse in the
skull. This is likely due to several factors including a larger extent of
disease in the skull at the time of radiotherapy and the fact that
relapsed disease is much more likely to be chemotherapy and
radiation resistant. Five of the nine patients with relapsed disease
were identified as having a particularly worrisome clinical picture
and were thus treated with 30 Gy. Unfortunately, these patients did
not seem to fare better as a result of the higher dose. It is unclear
whether an even higher dose should be considered for relapsed
Pediatr Blood Cancer DOI 10.1002/pbc
Brain-Sparing RT for NB Skull Mets 1167
patients, as suggested by other studies [31] or if other modalities,
such as concurrent chemotherapy, should be explored.
ACKNOWLEDGMENT
The authors thank Amy Budnick, Heather Chan, Michael
Sullivan for their assistance gathering data.
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