Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 1, pp.

113–118, 2010
Copyright Ó 2010 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/10/$–see front matter

doi:10.1016/j.ijrobp.2009.04.031

CLINICAL INVESTIGATION Brain

PROSPECTIVE EVALUATION OF RADIOTHERAPY WITH CONCURRENT AND

ADJUVANT TEMOZOLOMIDE IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE
INTRINSIC PONTINE GLIOMA

RAKESH JALALI, M.D.,* NIRMAL RAUT, M.D.,* BRIJESH ARORA, D.M.,y TEJPAL GUPTA, M.D.,*
DEBNARAYAN DUTTA, M.D.,* ANUSHEEL MUNSHI, M.D.,* RAJIV SARIN, F.R.C.R.,*
y
AND PURNA KURKURE, M.D.

* Department of Radiation Oncology; and y Medical Oncology, Division of Pediatric Oncology, Tata Memorial Centre, Mumbai, India

Purpose: To present outcome data in a prospective study of radiotherapy (RT) with concurrent and adjuvant
temozolomide (TMZ) in children with diffuse intrinsic pontine gliomas (DIPGs).
Methods and Materials: Pediatric patients with newly diagnosed DIPGs were prospectively treated with focal RT
to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m2, Days 1–42). Four weeks after com-
pleting the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m2, Days 1–5) was given every 28 days to a maximum
of 12 cycles. Response was evaluated clinically and radiologically with magnetic resonance imaging and positron
emission tomography scans.
Results: Between March 2005 and November 2006, 20 children (mean age, 8.3 years) were accrued. Eighteen pa-
tients have died from disease progression, one patient is alive with progressive disease, and one patient is alive with
stable disease. Median overall survival and progression-free survival were 9.15 months and 6.9 months, respec-
tively. Grade III/IV toxicity during the concurrent RT-TMZ phase included thrombocytopenia in 3 patients, leu-
copenia in 2, and vomiting in 7. Transient Grade II skin toxicity developed in the irradiated fields in 18 patients.
During the adjuvant TMZ phase, Grade III/IV leucopenia developed in 2 patients and Grade IV thrombocytopenia
in 1 patient. Patients with magnetic resonance imaging diagnosis of a high-grade tumor had worse survival than
those with a low-grade tumor (p = 0.001). Patients with neurologic improvement after RT-TMZ had significantly
better survival than those who did not (p = 0.048).
Conclusions: TMZ with RT has not yielded any improvement in the outcome of DIPG compared with RT alone.
Further clinical trials should explore novel treatment modalities. Ó 2010 Elsevier Inc.

Brainstem glioma, Diffuse intrinsic pontine glioma, Temozolomide, Radiotherapy, MRI.

INTRODUCTION up to 78 Gy with altered fractionation with or without chemo-

Brainstem gliomas constitute approximately 10% of all cen-
tral nervous system tumors in children and constitute the ma-
jor cause of death among children with brain tumors (1).
Brainstem tumors are recognized as a heterogeneous group
with management options ranging from observation in tectal
gliomas with an extremely good prognosis to palliative radio-
therapy (RT) in the universal aggressive diffuse intrinsic pon-
tine gliomas (DIPGs). DIPGs, because of their location, may
impart a poor prognosis independent of histology (2).
Improvement in outcome has been elusive despite decades
of intensive clinical and laboratory research, with local tumor
progression being the main cause of death. Although
significant effort has been directed at escalating doses almost
therapy, the final conclusions regarding altered fractionation
schedules have been disappointing (3).
The last few years have crystallized our use of temozolo-
mide (TMZ) in glioblastoma in the adult patient population,
with encouraging results (4, 5). The patient populations in
these series have excluded those with pontine tumors. We
sought to explore the results of using TMZ in pediatric
DIPGs for many reasons. The favorable features for using
TMZ were its proven efficacy in gliomas, radiosensitization
potential, low toxicity profile, and suitable kinetic properties.
A Phase II feasibility study was therefore planned and initi-
ated at our center to test the hypothesis that this option is at

Reprint requests to: Rakesh Jalali, M.D., Department of Radiation
Oncology, 125, Tata Memorial Hospital, Parel, Mumbai, India 400
012. Tel: (+91) 22 24177153; Fax: (+91) 22 24146937; E-mail:
rjalali@tmc.gov.in
Presented at the Eighth Congress of the European Association for
Neuro-Oncology, Barcelona, Spain, September 12–14, 2008.
The study was partly funded by an intramural grant from Tata
113
Memorial Centre.
Conflict of interest: none.
Acknowledgments—We are grateful to NATCO Pharma Ltd. (Hy-
derabad, India) for supplying temozolomide and the Brain Tumour
Foundation of India for supporting this work.
Received March 4, 2009, and in revised form April 22, 2009.
Accepted for publication April 22, 2009.
114 I. J. Radiation Oncology d Biology d Physics
least as effective as in adult glioblastoma. The study was ap-
proved by our institutional scientific and ethics committees.
METHODS AND MATERIALS
Between March 2005 and November 2006, 20 patients were en-
rolled in this Phase II study per the study protocol approved by our
institutional scientific and ethics committees. Eligibility criteria in-
cluded patients aged between 3 and 21 years, Karnofsky perfor-
mance score of at least 50, and a clinicoradiologic diagnosis of
DIPG. Required clinical criteria were the presence of at least 2 of
the following symptoms: pyramidal tract involvement, cerebellar
signs and symptoms, and/or cranial nerve deficits attributable to tu-
mor. Radiologic inclusion criteria were based on a computed tomog-
raphy (CT) or magnetic resonance imaging (MRI) study showing
diffuse involvement of the brainstem ($50% involvement of a brain-
stem segment or involvement of >2 of these segments with or with-
out enhancement on injection of intravenous contrast material). A
surgical intervention to obtain histologic proof was attempted in
suitable cases where the tumors had exophytic components and
surgical biopsy was deemed reasonable. Patients with localized
and focal brainstem lesions were excluded. A repeat MRI study
along with biological imaging studies including magnetic resonance
spectroscopy (MRS) and magnetic resonance perfusion studies was
also performed. A final diagnosis of a DIPG was established after
evaluation by oncologists, neurosurgeons, radiologists, and pathol-
ogists at joint neuro-oncology meetings. Eligible patients had ade-
quate hematologic, renal, and hepatic function (hemoglobin level
$11 g%; total leukocyte count $4,000/mm with absolute neutro-
phil count $1,500/mm3 and platelet count $100,000/mm3; liver en-
zyme level <2.5 upper limit of normal; and serum creatinine level
<1.5 upper limit of normal). All children who had prior treatment
with any chemotherapy/RT or who had any medical condition
interfering with chemotherapy were not considered for the study.
A positron emission tomography (PET)–CT scan was preferable,
though not mandatory, before initiating treatment. Before accrual,
informed consent was obtained from all patients and/or their parents
or legal guardians.
Radiotherapy
Patients were immobilized with a customized thermoplastic
mask. The target volume included all areas of hypodensity seen
on a CT scan or abnormality seen on T2-weighted/fluid-attenuated
inversion recovery sequences of an MRI scan with a 2-cm margin,
which was reconstructed on the topogram of the diagnostic MRI
scan. Bilateral parallel opposing fields were used, and field sizes
were verified on the conventional simulation. A dose of 54 Gy in
30 daily fractions over a period of 6 weeks was prescribed at the
center of the target volume. Radiation was delivered by megavoltage
beam on a 6-MV linear accelerator or a telecobalt machine. Partic-
ular attention was given to encompassing the tumor if going inferi-
orly along the spinal cord.
Concurrent chemotherapy
From the first day of RT, patients were given oral TMZ at a dose
of 75 mg/m2 for 7 days per week, including on weekends or public
holidays when RT was not given. TMZ was given on an empty
stomach ($4 hours after last meal) 30 to 60 minutes before RT
and in the morning on days without RT. Prophylactic antiemetics
were used during the concurrent chemoradiotherapy phase. Prophy-
lactic anti–Pneumocystis carinii medication was administered in the
form of oral co-trimoxazole. Blood counts were repeated every
Volume 77, Number 1, 2010
week. TMZ was suspended for an absolute neutrophil count lower
than 1.5  109/L, platelet count lower than 100,000/mL, and
CTCAE v3.0 (Common Terminology Criteria for Adverse Events
version 3.0) nonhematologic Grade III toxicity or greater.
Adjuvant chemotherapy
Adjuvant TMZ was started 28 days after the completion of RT. A
physical, neurologic, hematologic, and biochemical examination;
MRI scan; and PET-CT scan were performed. The TMZ dosage
phase was 200 mg/m2 on Days 1 through 5, and cycles were
repeated every 28 days. Adjuvant chemotherapy was planned for
a maximum of 12 cycles unless there was clear evidence of progres-
sion or unacceptable toxicity. Patients underwent a detailed clinical
examination and recording of any toxicity profile at each visit during
the adjuvant chemotherapy phase. Radiologic scans were done at the
time of the initiation of adjuvant treatment and at any time when
clinical progression was suspected.
Statistical analysis
Actuarial survival (overall and progression free) was generated
for patients by the Kaplan-Meier method. Toxicity data were re-
corded prospectively according to the CTCAE v3.0 criteria. The
log-rank test was used to assess survival by prognostic factors
such as age, performance status, type of tumor, grade, completion
of treatment, and so on.
RESULTS
Patient demographic profile
The mean age of the 20 patients (15 boys and 5 girls) was
8.3 years (Table 1). Of the patients, 12 (60%) had a symptom
duration of less than 1 month, and 7 patients had all three car-
dinal clinical signs of DIPG.
Imaging
Baseline pretreatment MRI scan evaluation showed typical
diffuse expansile lesions in the pons with frequent extension
to the medulla, midbrain, and cerebellum. On intravenous
contrast administration, tumors in 6 patients showed no en-
hancement, 11 had a patchy enhancement, and 3 had diffuse
enhancement. The mean tumor volume was 12.4 mL (range,
2.4–24 mL). MRI perfusion scans showed hyperperfusion in
13 patients and hypoperfusion in 7. We considered postcon-
trast enhancement, magnetic resonance spectroscopy find-
ings, and hyperperfusion on magnetic resonance perfusion
as markers for arbitrarily dividing the tumors into high grade
or low grade on MRI. An MRI-based diagnosis of a high-
grade tumor and a low-grade tumor was seen in 12 patients
and 8 patients, respectively. Eleven patients underwent
a baseline pre-RT PET-CT scan with 5-fluorodeoxyglucose
(FDG) as the radiotracer, which showed increased uptake
in 6 patients and no uptake in 5. Eight patients with an exo-
phytic component were considered suitable for a surgical bi-
opsy and had histologic proof of a glioma. Six patients had
a pathologic diagnosis of a low-grade glioma, and two had
an anaplastic astrocytoma. All patients with low-grade gli-
oma on histology had diffuse involvement of the brainstem
consistent with a DIPG. In other 12 patients, surgical
 RT and temozolomide in diffuse pontine gliomas d R. JALALI et al. 115

Table 1. Demographic profile of 20 children with diffuse more than six cycles, and 3 completed all 12 cycles of adju-
intrinsic pontine glioma treated with radiotherapy along with vant TMZ.
concurrent and adjuvant temozolomide
Age
Mean (range) 8.3 y (3–18 y) Survival
Median 8y Median overall survival (OS) of the entire cohort was 9.15
Sex months (range, 1.7–47 months), and median progression-free
Male 15 (75%) survival (PFS) was 6.9 months (Fig. 1). Of the patients, 16
Female 5 (25%) lived for more than 6 months, 7 lived for more than 1 year,
Body surface 0.875/m2 (0.56–1.23/m2)
area [mean (range)] and only 3 lived for more than 18 months. At present, 18 pa-
Duration of symptoms tients have died from disease progression, 1 patient is alive
<1 mo 12 (60%) with progressive disease, and 1 patient is alive with stable
>1 mo 8 (40%) disease. Three patients had spinal metastatic disease at the
Clinical presentation
time of disease progression.
Three signs 7 (35%)
(cranial nerve palsy,
long tract signs, and
ataxia)
Response
Cranial nerve 6 (30%) Neurologic recovery was evident in the majority of cases,
palsy and long with reversal of cranial nerve deficits and improvement of
tract signs cerebellar signs. During the initial concurrent RT-TMZ
Cranial nerve 5 (25%) phase, 2 patients did not show any neurologic improvement,
palsy and ataxia
Ataxia and long 2 (10%) 7 patients had only partial improvement, and 11 patients had
tract signs significant neurologic improvement. MRI scan was consid-
KPS ered for all patients who completed at least 4 weeks of
50 5 (25%) post-RT follow-up. One patient died immediately after com-
60 4 (20%) pletion of RT-TMZ, and thus follow-up MRI was not done.
70 5 (25%)
80 6 (30%) Median survival in patients showing a complete response
NPS and no/partial response evaluated on the PET scan after ther-
0, 1 10 (50%) apy was 13.1 months and 14.5 months, respectively
2, 3 10 (50%) (p = 0.966). Response of treatment on FDG-PET therefore
Biopsy
did not seem to correlate with outcome in these patients.
Not done 12 (60%)
Low-grade glioma 6 (75%)
High-grade glioma 2 (25%)
Toxicity profile
Abbreviations: KPS = Karnofsky performance score; NPS = neu- In the concurrent phase Grade I/II leucopenia was seen in 3
rologic performance score. patients and Grade III/IV was seen in 2 (Table 2). One of
these patients with severe leucopenia was diagnosed with
intervention was considered too hazardous and diagnosis was malaria and also had Grade III thrombocytopenia. Grade III
established per typical imaging characteristics. thrombocytopenia was observed in 2 patients (1 patient
also had leucopenia). Therefore 3 patients had Grade III/IV
hematologic toxicity (2 patients with both thrombocytopenia
and leucopenia and 1 patient with only thrombocytopenia).
Treatment-related parameters
All patients accrued in the trial completed the planned con-
current RT and TMZ phase. The mean body surface area of
the entire cohort of patients at the initiation of the treatment
was 0.875/m2 (range, 0.56–1.23/m2). The mean dose of
TMZ in the concurrent and adjuvant settings was 65 mg
(range, 40–90 mg) and 174.6 mg (range, 100–260 mg), re-
spectively. None of the patients required discontinuation of
RT except in 1 patient where RT had to be temporarily with-
held for 3 days because of a heightened skin reaction in the
RT portals with superadded infection. Four patients required
admission during treatment with concurrent RT and TMZ
(three because of Grade III vomiting and one with Grade
III thrombocytopenia). The median duration of radiation
treatment was 41 days (range, 39–49 days). Of the patients,
2 received no adjuvant TMZ (1 died before starting the adju-
vant phase and Grade IV toxicity developed in 1), 8 received Fig. 1. Overall survival (in months). Cum = cumulative
116 I. J. Radiation Oncology d Biology d Physics Volume 77, Number 1, 2010

Table 2. Toxicity profile of 20 children with a diffuse icantly better survival (p = 0.048). Histologic diagnosis of the
intrinsic pontine glioma treated with radiotherapy along with tumor did not show any significant impact on OS (p = 0.112).
concurrent and adjuvant temozolomide
Patients with features of high-grade tumor on radiologic im-
Concurrent RT and TMZ aging, however, had a poorer outcome than those with low-
Hemoglobin grade tumors (p = 0.001). Age, performance status, symptom
Grade I 1 (5%) duration, and severity of hydrocephalus did not show any im-
Grade II 1 (5%)
Leukocyte count pact on survival function.
Grade III 1 (5%)
Grade IV 1 (5%) DISCUSSION
Platelet count
Grade I 1 (5%) With TMZ emerging as an integral component of manage-
Grade III 2 (10%) ment in adult malignant brain tumor in recent years, we
Grade IV 1 (5%) sought to examine its role in the equally challenging scenario
Vomiting of pediatric diffuse pontine gliomas. The protocol design was
Grade I 1 (5%) similar to the one used for adult glioblastomas except that the
Grade II 11 (55%)
Grade III 6 (30%) number of adjuvant TMZ cycles was increased to 12 (instead
Grade IV 1 (5%)
Skin toxicity
Table 3. Correlation of various prognostic factors with
Grade I 1 (5%)
overall survival
Grade II 18 (90%)
Grade III 1 (5%) Mean overall
Adjuvant TMZ Factors Parameters survival (mo) p Value
Hemoglobin
Grade I 1 (5%) Age <8 y 10.97 0.917
Grade II 2 (10%) >8 y 10.33
Leukocyte count Sex Male 11.76 0.317
Grade I 1 (5%) Female 8.76
Grade II 1 (5%) KPS at presentation <70 9.17 0.134
Grade III 1 (5%) >70 12.48
Grade IV 1 (5%) NPS at presentation 0, 1 11.29 0.648
Platelet count 2, 3 10.57
Grade IV 1 (5%) Symptom duration <1 mo 10.85 0.913
Vomiting >1 mo 11.3
Grade II/III 7 (35%) Clinical Three signs 8.26 0.158
Hospitalization during concurrent RT-TMZ 6 (30%) presentation
Grade III/IV thrombocytopenia 3 (50%) Two signs 12.50
Grade III Vomiting 3 (50%) MRI tumor volume <12 cm2 9.04 0.249
Febrile neutropenia during adjuvant TMZ 2 (10%) >12 cm2 13.96
Varicella-zoster infection 2 (10%) MRI contrast Non-enhancing 13.98 0.166
enhancement
Abbreviations: RT = radiotherapy; TMZ = temozolomide. Enhancing 9.63
During the concurrent phase, the most common nonhema- MRI grade High grade 8.87 0.043
Low grade 15.10
tologic toxicity was vomiting. Grade III/IV vomiting was seen MRS grade High grade 8.79 0.258
in 7 patients (35%). Skin toxicity was common but not severe. Low grade 12.99
Fever was seen in 2 patients; this was proven to be of malarial Magnetic resonance Hyperperfusion 8.87 0.043
etiology in 1. Among the 19 patients eligible for adjuvant perfusion
Hypoperfusion 15.10
TMZ, adjuvant treatment was started in 18 whereas 1 patient
PET scan No uptake 14.28 0.911
did not receive any adjuvant TMZ because of the develop- Uptake present 13.78
ment of Grade IV thrombocytopenia during the concurrent MRI + MRS + High grade 6.8 0.001
phase. During the adjuvant phase, Grade III/IV leucopenia perfusion
was observed in 2 patients and Grade IV thrombocytopenia diagnosis
Low grade 15.14
in 1. No further adjuvant TMZ was given in these patients. Histopathologic High-grade glioma 7.05 0.112
Varicella-zoster infection developed in 2 patients during the diagnosis
adjuvant phase, and they were treated conservatively. In 1 pa- Low-grade glioma 14.19
tient with lower cranial nerve palsy, aspiration pneumonia de- Clinical response Partial/no response 8.23 0.048
veloped after the second cycle of adjuvant therapy, which Significant response 13.31
PET response No/partial response 14.59 0.966
subsided with conservative management, and adjuvant Complete response 13.1
TMZ was restarted 2 weeks after the scheduled time.
Abbreviations: KPS = Karnofsky performance score; NPS = neu-
Prognostic factors rologic performance score; MRI = magnetic resonance imaging;
Patient-related factors were analyzed with respect to OS MRS = magnetic resonance spectroscopy; PET = positron emission
(Table 3). Patients with neurologic improvement had signif- tomography.
 RT and temozolomide in diffuse pontine gliomas d R. JALALI et al.
of 6 in adults). Treatment was generally fairly well tolerated.
In the concurrent phase Grade I/II leucopenia and Grade III/
IV leucopenia were seen in 25% and 10% of cases, respec-
tively. Grade III thrombocytopenia was observed in 10% pa-
tients. In this phase of treatment the most common severe
nonhematologic toxicity was vomiting. The toxicity profile
was well within the acceptable range in the adjuvant phase.
Our prospective series of patients with DIPGs treated
aggressively by use of concurrent RT and TMZ followed
by adjuvant TMZ, however, showed a median OS and PFS
of 9.15 months and 6.93 months, respectively. These findings
were not better than the results generally known historically
or results in a previous study (2). With standard conventional
RT, median PFS and OS range from 5 to 8.8 months and 7 to
16 months, respectively (2). There was no difference in the
survival function and response rate in our study population
treated with RT and TMZ compared with historical data.
Therefore the addition of TMZ to RT was disappointing
and did not show any benefit in this group of patients, in
contrast to what has been found in adult glioblastomas.
A majority of our cases showed some neurologic recovery
at the time of evaluation after the conclusion of the initial
concurrent RT-TMZ phase. It is known that RT leads to neu-
rologic improvement in many of these patients and may allow
a reduction of steroid dose (6). It was seen that patients with
significant neurologic improvement could expect a better
outcome, because they had a mean OS of 13.31 months
whereas patients with little neurologic recovery had a mean
OS of only 8.23 months. Although a majority of our patients
showed significant neurologic improvement after the initial
concurrent RT-TMZ phase, even a partial radiologic re-
sponse was observed only in 50% of cases assessed by
MRI scan at 4 weeks’ post-RT follow-up. Patients with fea-
tures of high-grade tumor on imaging showed poorer sur-
vival. Other factors such as age, initial performance status,
symptom duration, and presence or absence of hydrocepha-
lus did not show any impact on survival. Although histologic
diagnosis of high-grade glioma did not affect the survival
outcome on comparison with low-grade glioma statistically,
this finding may be because of the smaller number of patients
in our study cohort.
Despite a number of clinical trials having been conducted
over the last several decades to improve results in patients
with DIPGs, the outcome in these patients has been frustrat-
ing and has remained largely unchanged. Numerous Phase I
/II trials were conducted with altered RT fractionation sched-
ules, concurrent chemoradiotherapy, radiation sensitizers,
and systemic CT (7–10). In a series of radiation dose–escala-
tion studies, doses from 64.8 to 78 Gy with hyperfractionated
radiotherapy had shown increased toxicity without any sur-
vival benefit (11). A trial of concurrent carboplatin and etopo-
side at a dose of 70.2 Gy with hyperfractionated radiotherapy
did not improve outcome over RT alone (2-year survival rate,
11%) (12). There was no benefit with the addition of a regi-
men of lomustine, vincristine, and prednisone (13). Other
chemotherapeutic schedules, interferon, bradykinin, RMP-
7, cyclosporine, and tamoxifen with or without RT also did
117
not show any survival advantage (14, 15). A randomized trial
with concurrent chemotherapy and dose escalation also
showed no significant benefit over conventional treatment
(Pediatric Oncology Group 9239) (16). Broniscer et al.
(17) reported the results of a multi-institutional study exam-
ining the role of neoadjuvant irinotecan followed by RT and
then TMZ. Median survival was only 12 months (1-year OS
rate, 48%) with a high incidence of hematologic toxicities.
Cohen et al. (18) have presented a summary of prospective
data of 61 DIPG patients treated with concurrent TMZ and
RT, followed by adjuvant TMZ. The 1-year OS rate was
only 39%, and 61% of patients died within 12 months of di-
agnosis and 89% within 18 months. This trial also concluded
that TMZ does not improve the outcome in children with
DIPGs. Another small study using a combination of TMZ
and cis–retinoic acid with RT has also failed to show any
meaningful impact (19). Biological agents such as the anti-
epidermal growth factor receptor agent Nimotuzumab have
shown some promise in a preliminary phase II study, and
the efficacy of Nimotuzumab requires further evaluation (20).
Because we have reached a relatively difficult situation for
any chemoradiotherapy schedule, as in other sites, a major
breakthrough regarding survival improvement could be
expected to come from molecular studies (21). However,
a major limitation in conducting any molecular/biological
studies in DIPG is the lack of tissue diagnosis. The location
of DIPG does not allow any attempt at surgical excision.
High-grade gliomas in DIPG may have different molecular
genetics and may require different treatment strategies, but
this requires confirmation by molecular studies. However,
because biopsy is usually not done in most patients and there-
fore molecular biology of the disease is largely unknown,
DIPG is usually diagnosed by clinicoradiologic means (22).
Imaging is therefore likely to play an important role in char-
acterizing these tumors and may well provide some insights
into the molecular profile and perhaps even therapies ad-
dressing the affected pathways. Biological imaging methods
such as PET scan have been used recently. FDG-PET scan is
nonspecific, and amino acid–based PET studies are usually
recommended for central nervous system neoplasms. In our
study the FDG-based PET scan findings did not show any
correlation with survival. Among the newer MRI modalities,
perfusion scan findings had a significant survival function
correlation. The perfusion scan correlation may be because
of angiogenesis mechanisms, and thus future trials with anti-
angiogenic target molecules could be attempted as well.
There are numerous theories as to why TMZ has failed to
have an impact in patients with a DIPG. Apart from different
molecular biology and response to TMZ, other reasons could
be the compromised dose of TMZ delivered in pediatric
brainstem glioma patients. It would be interesting to perform
methylguanine methyltransferase analysis to determine its
correlation with TMZ response. Methylguanine methyltrans-
ferase analysis was not performed in our patients. The lack of
histologic material in a large majority of these patients with
DIPGs is likely to be a major hindrance in carrying out
such analyses.
118 I. J. Radiation Oncology d Biology d Physics
In summary, TMZ with RT has not yielded any improve-
ment in the outcome of DIPG compared with RT alone.
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