Chapter 45
Chemotherapy of Brainstem Gliomas
Viviana Benitez and Matthias A. Karajannis
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
INTRODUCTION
Brainstem gliomas account for 10%–20% of pediatric brain
tumors [1]. The median age at diagnosis ranges from 5 to
9 years of age. Notably, brainstem gliomas represent a
range of diseases rather than a single entity, ranging from
low-grade tumors which may require only limited treatment
and carry a favorable prognosis to high-grade tumors that
are rapidly progressive despite aggressive therapy.
About 80% of brainstem gliomas are located in the pons,
whereas the remaining 20% can be found in the medulla,
midbrain, or cervicomedullary junction. Historically, pedi-
atric brainstem gliomas have been divided into three main
categories with distinct imaging and clinical features:
diffuse intrinsic pontine gliomas (DIPG), focal tectal
gliomas, and posterior exophytic/cervicomedullary gliomas
[2]. DIPG account for 80% of brainstem gliomas. The
typical duration of symptoms in DIPG patients is short
(<2 months), and they classically present with ataxia, long
tract signs, and/or cranial nerve deficits. DIPG are recog-
nized by characteristic imaging findings of a diffuse pontine
lesion, encasing the basilar artery. At the time of diagnosis,
contrast enhancement on magnetic resonance imaging
(MRI) may or may not be present, and is not predictive
of outcome [3]. The diagnosis can be made based on clinical
and imaging features alone, and when biopsied the histo-
logic appearance may range from diffuse astrocytoma or
anaplastic astrocytoma to glioblastoma. Regardless of
initial histological grade, however, progression-free sur-
vival (PFS) in DIPG patients is generally 5–6 months and
overall survival (OS) <1 year [1,2].
Posterior exophytic/cervicomedullary gliomas account
for 10%–15% of brainstem gliomas. These patients usually
have a longer duration of symptoms at diagnosis
(>2 months) and often present with headache and emesis,
as well as dysphagia and weakness. The tumors usually
arise from the floor of the fourth ventricle or from the cer-
vicomedullary junction. On imaging, they tend to be focal
with a posterior exophytic component, and typically show
Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy. https://doi.org/10.1016/B978-0-12-812100-9.00046-2
Copyright © 2018 Elsevier Inc. All rights reserved.
enhancement on postcontrast MRI. When biopsied, these
tumors have pilocytic astrocytoma histology [2]. The third
type of brainstem glioma is composed of focal tectal
gliomas, and these account for about 5% of brainstem
gliomas. These tumors often have >2 months of symptoms
at diagnosis and usually have signs of elevated intracranial
pressure such as headaches and emesis. They are located in
the region of the tectal plate and commonly have hydro-
cephalus on imaging. Histology is usually that of low-grade
glioma [2]. Of note, brainstem gliomas associated with NF1
are considered as a separate entity. Patients with NF1 more
commonly have optic pathway gliomas, but a small per-
centage can develop gliomas in the brainstem. These
tumors tend to behave less aggressively, can sometimes
be asymptomatic, and regress on occasion.
Alternative diagnoses should be considered when eval-
uating focal brainstem gliomas, namely primitive neuroec-
todermal tumors (PNET) of the brainstem. These are often
characterized by younger age of onset, a focal none-
nhancing tumor, and aggressive tumor behavior and
growth [4]. Of note, recent advances in molecular classifi-
cation have allowed the demonstration that a significant
proportion of tumors previously diagnosed as PNETs, in
fact display molecular profiles indistinguishable from
other CNS entities, namely ATRTS, ETMRs, and HGG
[5]. Other possibilities to consider in the differential diag-
nosis include histiocytic lesions, tuberculoma, or abscess.
In these cases, pathological diagnosis with a biopsy is
indicated.
Factors that seem to affect prognosis of brainstem
gliomas include presentation with cranial nerve palsies, evi-
dence of hypodense tumor involving the entire brainstem,
and malignant tumor histology such as mitoses. These are
typically associated with shorter survival [6]. Favorable
prognostic factors include the diagnosis of NF1, symptom
duration >12 months at diagnosis, calcification noted on
the tumor, exophytic location of the glioma, and low-grade
pathology including the presence of Rosenthal fibers [7].
585
586 SECTION V Chemotherapy for Specific Tumors—Pediatrics

DIAGNOSTIC APPROACH

Clinical presentation

Signs of elevated ICP: lethargy, Brainstem findings: cranial neuropathies,

headache, emesis focal weakness, ataxia

Duration of symptoms

<2 months duration >2 months duration

Diagnostic Imaging:

MRI brain with and without contrast

preferred modality

+/– MR spectroscopy

Pontine, diffuse, variably Floor of fourth ventricle,

enhancing, encasing basilar dorsally exophytic,
artery enhancing

DIPG Cervicomedullary glioma

Atypical clinical history,

Focal, tectal plate, evidence
radiographic appearance, or
hydrocephalus
research trial

Tectal glioma Consider tissue biopsy

OVERVIEW OF INITIAL TREATMENT

The treatment paradigm for brainstem gliomas varies is paramount, given their management will differ signifi-
depending on their location and histology. Recognition of cantly from that of the more common DIPG. Biopsy of
the more favorable low-grade histology brainstem gliomas DIPG is safe using modern techniques and should be

considered in the context of clinical trials [8]. Specifically,
biopsy can confirm diagnosis and may identify actionable
molecular targets and help risk stratification in both
treatment and prognosis.
Focal Brainstem Gliomas
In the 15%–20% of brainstem gliomas that are low-grade
astrocytomas, management can include observation, sur-
gical resection, and if not resectable or progressive, then
RT and/or chemotherapy [9]. Focal brainstem gliomas
account for 20% of brainstem gliomas, usually occurring
outside the pons. Histologically, these are either pilocytic
astrocytomas or, less commonly, diffuse astrocytomas.
Similar to pilocytic astrocytomas located in other regions
of the brain, genetic alterations leading to MAPK sig-
naling pathway activation, most commonly involving
BRAF, have been identified in the majority of focal
brainstem gliomas [10]. For instance, BRAF-KIAA1549
fusions have been found in 66%–80% of all juvenile
pilocytic astrocytomas, including 62% of those in the
brainstem, whereas BRAF V600E mutations are more
common in the grade II diffuse astrocytomas as well as
in pleomorphic xanthoastrocytomas and slightly less
common in gangliogliomas [11–13]. In contrast to DIPG
and other diffusely infiltrating tumors, focal brainstem
gliomas are often amenable to surgical resection, particu-
larly those that are exophytic or cervicomedullary in
location [14]. If resection is not feasible, stereotactic
biopsy can be helpful in establishing a diagnosis, which
is greatly aided by currently available molecular testing.
In tectal gliomas, due to typical presentation of obstructive
hydrocephalus, third ventriculostomy or VP shunt
placement are often effective [15].
In the case of progression or inoperable disease, chemo-
therapy is the preferred treatment. The combination of vin-
cristine and carboplatin has been shown to achieve stable
disease in 68%–75% of patients [16]. Another regimen com-
monly used is the combination of thioguanine, procarbazine,
lomustine (CCNU), and vincristine (TPCV). A randomized
controlled trial comparing the use of these two regimens in
patients under age 10 with low-grade gliomas showed
improved 5-year PFS of 52% for TPCV versus 39% for
vincristine-carboplatin [17]. However, due the increased
toxicity of TPCV, including prolonged marrow suppression
and the risk of secondary myelodysplastic syndrome/acute
leukemia associated with procarbazine and lomustine, vin-
cristine and carboplatin remains the preferred upfront
regimen at many institutions [18,19]. Recently, the Canadian
Pediatric Brain Tumor Consortium evaluated the use of
weekly vinblastine (6 m/m2) over 70 weeks in therapy-naı̈ve
pediatric patients with progressive low-grade gliomas. Out
of 54 patients studied, 25.9% had a complete, partial, or
minor response. The 5-year OS and PFS rates were 94%
Chemotherapy of Brainstem Gliomas Chapter 45 587
and 53%, respectively. Notably, this treatment was well tol-
erated without significant effect in quality of life [20].
Recurrent Treatment for Focal Brainstem
Gliomas
A variety of regimens have shown to be active in the setting
of recurrent LGG, including vinblastine, bevacizumab with
or without irinotecan, everolimus, and a metronomic oral
antiangiogenic regimen (celecoxib, thalidomide, fenofi-
brate, cyclophosphamide, and etoposide) [21–24]. Clinical
trials are presently evaluating the use of BRAF or MEK
inhibitors for the treatment of recurrent LGG, including
focal brainstem gliomas [25]. In the case of focal brainstem
gliomas, RT has been found to be effective in inducing pro-
longed remission; however, given severe associated toxic-
ities in young children in particular, it should be reserved
for patients who have failed other treatment options. This
is especially so given the excellent prognosis for these
tumors [26].
Brainstem gliomas in patient with Neurofibromatosis
Type 1 behave biologically different from lesions with a
similar appearance in patients without this disorder.
Although these lesions may sometimes clinically and radio-
graphically progress, most do not require specific inter-
vention, and rather, can be observed. A retrospective
review of 21 patients with NF1 and brainstem lesions
showed that most were biologically indolent with only
10 having radiographic progression or clinical progression
at 3.75 years. Seven of those patients had tumors stabilize in
size or regress without intervention. Only four patients
required treatment, and these were the focally enhancing
tumors. Therapy consisted of biopsy, excision, or radio-
therapy. All lesions were low grade and stabilized after
therapy. The authors concluded that intervention of these
tumors can be limited to lesions that rapidly grow on serial
imaging or produce significant clinical symptoms [27].
Diffuse Intrinsic Pontine Gliomas
DIPG account for approximately 80% of pediatric
brainstem gliomas. They range from WHO grade II–IV
on pathological evaluation, but grade does not seem to
affect prognosis. H3K27M mutations in two histone genes
have been found in about 80% of DIPG [28]. H3K27M
mutant DIPG invariably harbor additional oncogenic driver
mutations, most commonly including TP53, PDGFRA, and
ACVR1, and is recognized as a clinicopathological entity
with other H3K27M mutant midline gliomas including tha-
lamic and spinal cord tumors, all of which show similar
molecular features, as well as equally aggressive behavior
and resistance to conventional therapies. Another much less
commonly found mutation in those without the histone
mutation is MYCN amplification [29].
588 SECTION V Chemotherapy for Specific Tumors—Pediatrics
RT remains the only therapy proven to improve the sur-
vival in patients with DIPG despite numerous clinical trials
and ongoing research. Conventional RT leads to clinical
improvement in the majority of these patients (65%) but
PFS is short (<6 months in most) and survival is poor
(<1 year median survival) [1]. Evaluation of hyperfractio-
nated RT (HRT) compared with conventional RT has failed
to show a benefit, and higher doses of 75.6 and 78 Gy can
lead to significant morbidity including steroid dependency,
vascular events, white matter changes, hormone defi-
ciencies, seizure disorders, and hearing loss [30,31]. Fur-
thermore, studies looking at chemotherapy plus RT have
shown poor response to both single and multiagent reg-
imens, both prior to RT and as adjuvant chemotherapy
[9,32]. The remainder of this chapter will focus in more
detail on the treatment of DIPG.
RADIATION THERAPY IN DIPG
The current standard treatment for newly diagnosed DIPG
is fractionated focal intensity-modulated radiation therapy
(IMRT) to the tumor bed to a total dose of 54–60 Gy (given
as 1.8–2 Gy fractions once daily for 5 days per week over
6 weeks). About 70%–80% of patients with DIPG respond
to RT with some transient neurological improvement. One
study evaluating timing of RT showed no significant impact
on the outcome with duration of time from diagnosis to start
of RT [33].
Hyperfractionated Irradiation in DIPG
Higher doses of RT using HRT (66–78 Gy) do not appear to
provide a survival advantage when compared with standard
dose and fractionated protocols. For instance, the Pediatric
Oncology Group (POG) conducted a phase I/II study to
assess the efficacy and toxicity of sequentially escalated
doses of HRT in children with malignant brainstem
gliomas. In their study, they compared a dose of 75.6 Gy
with results from doses of 66 and 70.2 Gy. Treatment with
the higher dose of 75.6 Gy resulted in neurological
improvement in 77% of patients, with a PFS of 7 months
and a median survival time (MST) of 10 months. Toxicities
or morbidity noted in their study included skin reactions and
steroid use >3 months. Their conclusion was that there was
no evidence of improved outcome with higher doses of
HRT [30]. Another trial conducted by the Children’s
Oncology Group (COG) was a phase I/II trial with the goal
to determine the outcome of treatment with HRT to a total
dose of 78 Gy in children with DIPG. They noted clinical
improvement in 34% of patients, with 14% of patients
showing a >50% reduction in their tumor size radiograph-
ically. The OS in this trial was 35% at 1 year and 11% at
3 years. Of note, 33/66 patients required steroid treatment
for prolonged periods, and radiation-induced necrotic
damage was noted in 6/14 autopsied patients. They con-
cluded that there was no evidence of improved survival with
higher dose HRT and there was evidence of prolonged use
steroid dependency in their cohort of patients [31].
Another phase I/II trial evaluated a group of children
and adults with brainstem glioma treated with HRT at a
total dose of 72 Gy. Median time to tumor progression
(TTP) was 59 weeks (66 weeks in adults, 44 weeks in
children) and MST was 74 weeks (92 weeks in adults and
64 weeks in children). Notably, there was no increased radi-
ation toxicity noted with the fractionation schedule and
dose studied [34]. HRT at a dose of 72 Gy was again looked
at in a phase I/II trial by the Children’s Cancer Group
(CCG) in 53 children with diffuse intrinsic or malignant
brainstem glioma. Overall 53% of patients had an objective
response, with a partial response in 13%. The OS rate was
38% at 1 year and 14% at 2 years. Children with symptoms
lasting >2 months prior to diagnosis had a better prognosis.
The authors concluded that while imaging response rates
were increased using HRT, no improvement in overall
outcome was observed compared with conventional
RT [35].
Hypofractionated Irradiation in DIPG
Other studies have compared the use of hypofractionated
RT versus conventional RT in the treatment of pediatric
DIPG. One such randomized controlled trial evaluated
72 children with newly diagnosed DIPG and randomized
them for treatment with hypofractionated RT, where they
received 39 Gy in 13 fractions 5 days weekly, versus a
regimen of conventional RT, where they received 54 Gy
in 30 fractions over 6 weeks. Their results showed that
OS and PFS were slightly shorter (not a statistically signif-
icant difference) for the hypofractionated group than the
standard group. However, the authors noted that this
method may put fewer burdens on the patients and near
comparable results [36]. Another study looked at
27 children with DIPG and treated them with either
44.8 Gy given in 16 fractions or 39 Gy given in 13 fractions.
They compared these regimens to a matched cohort of
patient receiving conventional RT. They found no signif-
icant difference in OS and PFS between these regimens,
and the hypofractionated schedule allowed patients to
spend significantly less time receiving RT. Another point
made by the authors was that in most patients (78%), this
allowed for steroids to be weaned off earlier [37].
Reirradiation at Time of Progression
A study looking at a small series of patients who received
re-irradiation at the time of progression with 18–20 Gy
focal RT over 2 weeks showed that this therapy was gen-
erally well tolerated with most showing both clinical and

radiographic improvement, with MST of 5 months to sub-
sequent progression [38]. This benefit of PFS at the time of
re-irradiation was also demonstrated in another single-
institution clinical trial [39]. The SIOP-E-HGG/DIPG
working group also noted a survival benefit with
re-irradiation at the time of progression in patients with
DIPG. They noted that median OS was 13.7 months for
patients undergoing re-irradiation (versus 10.3 months with
upfront radiation). They also noted clinical improvement in
77% of patients, with no grade 3–4 toxicity noted [40].
CHEMOTHERAPY OF DIPG
Different strategies using chemotherapy to treat DIPG, such
as high-dose chemotherapy followed by stem cell rescue,
neoadjuvant chemotherapy (single or multiagent), con-
current chemotherapy with RT, and adjuvant chemo-
therapy, have not demonstrated any survival benefit when
compared with conventional RT alone. Notably, the current
standard of therapy in the treatment of adult GBM, RT with
concurrent and adjuvant temozolomide (TMZ), has not
shown any improved outcome in pediatric patients with
DIPG. Below is a summary of some of the chemotherapy
regimens studied in DIPG and their outcomes.
Concomitant Chemotherapy and Irradiation
Approaches
Some studies have focused on evaluating the use of chemo-
therapy concurrent with RT. One randomized phase III
study evaluated chemotherapy with vincristine, CCNU,
and prednisone together with RT total dose of 50–60 Gy
compared with RT alone in newly diagnosed patients. In
this study, PFS was similar in both arms, MST was
9 months in both arms, and OS was 17% for RT alone
versus 23% for the RT plus chemotherapy group. Therefore,
no significant difference in the outcome was observed. Of
note, an increased risk of infection was associated with
the adjuvant therapy. Limitations of this study, conducted
in the late 1970s, include limited imaging modalities (pri-
marily CT was used) which could confound the cohort
of patients, with perhaps some lower grade histologies
included [41].
More recently, chemotherapy has been used concur-
rently with RT as a radiosensitizer. In the majority of these
studies, while there is no excess toxicity with the addition of
chemotherapy to RT, there is also no added benefit noted.
A Pediatric Oncology Group (POG) study compared
outcome in patients with brainstem gliomas treated with
HRT at a dose of 70.2 Gy versus similar RT plus cispla-
tinum (as a radiosensitizer) by continuous infusion on
weeks 1, 3, and 5 of RT and showed worse survival in
patients receiving HRT plus cisplatinum versus HRT alone.
Note that in the phase I study, three dose levels were studied
Chemotherapy of Brainstem Gliomas Chapter 45 589
(1: 50 mg/m2/120 h, 2: 75 mg/m2/120 h, 3: 100 mg/m2/
120 h) and grade 2–4 myelosuppression was seen in 3/5
patients treated at dose level 3. One child died of massive
hemorrhage at the tumor site after 2 days of treatment [32,42].
A phase I/II study evaluating carboplatin combined with
HRT (total dose 72 Gy) showed that the cumulative
maximum tolerated dose for carboplatin was 1540 mg/
m2. The dose-limiting toxicity was hematologic. In this
study, the median PFS was 8 months and OS was 12 months
[43]. Another study by the Brainstem Glioma Cooperative
Group (BGCG) evaluated the efficacy of RT plus tamoxifen
in patients with DIPG. They used a treatment dose of
200 mg/m2 daily of tamoxifen along with RT and then
for 52 additional weeks. In their study, 50% of the patients
showed a radiographic response, with an MST of
10.3 months. While overall well tolerated, the study showed
no significant change in overall prognosis [44].
More recently, in the German cooperative group HIT-
GBM studies using RT combined with intensive chemo-
therapy, survival was improved compared with historical con-
trols only in pediatric patients with high-grade glioma whose
tumors were gross totally resected, but not in other patients,
including DIPG patients. In the HIT-GBM-C protocol,
patients with newly diagnosed HGG including DIPG were
treated with conventional RT and concurrent chemotherapy
(one cycle of cisplatin + etoposide + vincristine (PEV), fol-
lowed by weekly vincristine, and then one cycle of
cisplatin + etoposide + ifosfamide (PEI) in the last week of
RT). They were subsequently treated with maintenance che-
motherapy consisting of additional cycles of PEI followed by
valproic acid. Of 97 patients, 21 had gross total resection and
29 had partial resection. OS was 91% at 6 months, 56% at
12 months, and 19% at 60 months. The 5-year OS for patients
with gross total resection treated on this protocol was 63%
compared with 17% for the historical control group (HIT-
GBM-A and HIT-GBM-B). No difference in survival was
observed in patients with incompletely resectable disease,
including DIPG patients [45].
TMZ has been studied in many clinical trials for DIPG,
given its proven benefit in prolonging survival in adult
patients with GBM [46]. However, pediatric studies evalu-
ating its use along with RT have not shown any benefit over
historical controls using RT alone. For instance, an open-
label phase II study (ACNS0126) by the COG evaluated
the outcome of TMZ concurrent with RT followed by
adjuvant TMZ. They studied 63 children with newly diag-
nosed DIPG, with a TMZ dose of 90 mg/m2/day  42 days
along with RT at a dose of 59.4 Gy, followed by mainte-
nance treatment with TMZ at a dose of 200 mg/m2/
day  5 days every 28 days for 10 cycles, beginning 4 weeks
after completion of RT. The mean EFS was 14% and mean
OS was 40%, with median time to death of 9.6 months. This
study showed chemoradiotherapy with TMZ followed by
adjuvant TMZ was not more effective than RT alone
590 SECTION V Chemotherapy for Specific Tumors—Pediatrics
[47]. A UK phase II trial studied RT plus concomitant TMZ
(75 mg/m2) followed by up to 12 courses of 21 days of
adjuvant TMZ (100 mg/m2) every 4 weeks. The OS was
56% at 9 months and 35% at 1 year. Median survival was
9.5 months. Overall, this trial showed no survival benefit
with the addition of TMZ in patients treated with standard
RT [48]. The German HIT-HGG 2007 study reported six
children (2 with DIPG, 4 with high-grade gliomas) treated
with CSI and concurrent metronomic TMZ (75 mg/m2/
day). Median PFS was 4 months and median OS was
7.6 months. Major toxicities included myelosuppression,
with treatment interrupted or discontinued in 4/6 patients
due to >grade 3 hematotoxicity [49].
Of note, one large series studied the prognostic signifi-
cance of genomic and epigenetic alterations through
molecular analysis of >200 pediatric glioblastomas. In their
study, MGMT promoter hypermethylation was found in
about 25% of pediatric glioblastomas, with marked vari-
ability among molecular subgroups. MGMT promoter
methylation status has been established as a robust pro-
spective and predictive (for treatment benefit with TMZ)
biomarker in adult glioblastoma [50]. Interestingly, K27
tumors (more commonly those found in midline structures
such as thalamus and brainstem) very rarely showed
MGMT methylation (3%). In fact, midline tumor location,
K27M mutation, and presence of oncogene amplifications
each were associated with a poor outcome. This study
may explain some of the reasoning for the poor outcome
and lack of efficacy of TMZ-based therapy for DIPG,
given the lack of MGMT promoter methylation in these
tumors [51].
Neoadjuvant Chemotherapy Approaches
Some studies have looked at chemotherapy given prior to
RT. This method of treatment is more often used in younger
children with the intent to delay radiation until more than
3 years old. Limitations of these studies include the fact that
despite initiation of chemotherapy prior to RT, in many
cases the patient went on to receive RT as planned. This
was often due to the early progression seen with chemo-
therapy, leading to discontinuation of chemotherapy and
initiation of RT.
A phase II study from the Pediatric Oncology group
(POG) evaluated the response of treating children with
brainstem tumors with chemotherapy followed by HRT
(total dose of 66 Gy). The chemotherapy regimen consisted
of four cycles of cisplatin (100 mg/m2) and cyclophos-
phamide (3 g/m2). They studied 32 patients, of whom
65% improved clinically after two to three cycles. Radio-
graphically, three patients had partial responses (defined
as >50% shrinkage) and 23 patients had stable disease.
Six patients were noted to have progressive disease. MST
was 9 months. Toxicities included marrow suppression,
electrolyte abnormalities, and ototoxicity. The authors con-
cluded that while chemotherapy can be added prior to HRT
in these patients with both clinical and objective responses
seen, other agents would need to be identified for overall
improved outcome and survival [52].
The Children’s Cancer Group (CCG) evaluated the
efficacy of two chemotherapy regimens prior to hyperfrac-
tionated external beam radiation therapy (HFEBRT) (total
dose of 72 Gy) in children with primary high-risk brainstem
tumors. Regimen A consisted of three courses of carbo-
platin, etoposide, and vincristine, whereas Regimen
B consisted of cisplatin, etoposide, cyclophosphamide,
and vincristine. Radiographic response was evaluated with
MRI after induction chemotherapy and HFEBRT. Overall
10% of the patients treated with Regimen A responded
objectively to chemotherapy; 27% improved with com-
bined chemotherapy and RT. For those treated with
Regimen B, 19% responded to chemotherapy alone and
23% to both chemotherapy and RT. In both groups, EFS
was 17% at 1 year and 6% at 2 years. Notably, grade 3–4
leukopenia were observed in 60% of patients treated with
Regimen A and 90% of those treated with Regimen B. In
conclusion, neither the chemotherapy regimen improved
the percentage of patients who responded nor the PFS or
OS compared with prior series of patients treated with
RT alone [53].
Overall outcome in the above studies that looked at
older children was poor, with MST less than a year, and
no improved outcome when compared with RT alone.
Results were better when evaluating postoperative chemo-
therapy and delayed radiation in a younger subset of
patients. The “Baby POG” study evaluated children less
than 36 months old with biopsy proven malignant brain
tumors. These children were treated with two cycles of
cyclophosphamide plus vincristine, and two cycles of cis-
platin plus etoposide. This sequence of chemotherapy
was continued until either the disease progressed or the
children were >48 months of age. Complete or partial
response was seen in 39% of patients after two cycles of
chemotherapy. PFS was 41% at 1 year and 39% at 2 years.
Notably, this study included multiple types of malignant
brain tumors, and patients with brainstem gliomas or
embryonal tumors had little or no response [54]. Also
important to note is that infant GBM patients have long
been known to have a better prognosis than GBM in older
children. Recent studies indicate that this improved
outcome is likely due to distinct oncogenic drivers seen
in infant GBM patients. Specifically, infant high-grade
gliomas often lack K27M mutations or TP53 mutations,
and are more likely to have NTRK gene fusions as a
potential driver [55].
Frappaz and colleagues studied frontline chemotherapy
with tamoxifen/BCNU/cisplatin alternating with high-dose
methotrexate, aimed at delaying radiation therapy until the

time of progression. They found a significantly improved
median survival of 17 months compared with 9 months in
historical controls. However, they also noted prolonged
hospitalization and increased infections in the chemo-
therapy group [55]. The German HIT-GBM protocols eval-
uated a variety of chemotherapy regimens in the treatment
of DIPG. One study (HIT-GBM-D protocol) evaluated
frontline therapy with high-dose methotrexate as a single
agent for pediatric high-grade glioma and DIPG. Patients
received 24-h infusions of methotrexate (5 g/m2) on days
1 and 15, followed by 54 Gy of RT with concurrent cis-
platin, etoposide, vincristine, and ifosfamide. Overall, after
treatment with methotrexate, 18/19 had stable disease and
1/19 had a partial response. Event-free survival was noted
to be 43% at 1 year. This was comparable to other regimens
studied by this group; however, not shown to be superior to
outcome with RT alone [56].
Studies evaluating treatment of newly diagnosed
brainstem gliomas with high-dose chemotherapy and autol-
ogous stem cell rescue have also been disappointing. For
instance, one study evaluated nine children with newly
diagnosed high-risk brain tumors treated with high-dose
thiotepa/cyclophosphamide chemotherapy followed by
autologous bone marrow infusion and involved field
HRT. Six of these patients were suffering from brainstem
gliomas. Two patients had partial responses, one had a
minor response, three had stable disease, and one patient
had progressive disease. Two patients, one with brainstem
glioma, achieved a complete remission following radiation.
This OS was not felt to be better than standard therapy [57].
Another phase II study evaluated the use of high-dose
BCNU (800 mg/m2) followed by autologous stem cell
transplant in children with high-grade gliomas. Seven of
these patients had DIPGs. Only one objective response
was noted 1 month after treatment; five patients had stable
disease and seven progressed [58].
Adjuvant Chemotherapy Approaches
Other studies have focused on the use of chemotherapy
agents following RT in the treatment of DIPG. The majority
of these have been demonstrated to be either ineffective or
unable to show prolonged survival or time to progression.
For instance, one pilot study looking at the feasibility and
benefit of high-dose chemotherapy after RT in patients with
DIPG showed three deaths related to high-dose chemo-
therapy complications but no survival benefit (MST of
10 months) [59].
The use of TMZ has also been evaluated as a treatment
modality after radiotherapy for newly diagnosed DIPG in
children. A multiinstitutional study allowed for treatment
with intravenous irinotecan for two cycles prior to conven-
tional RT. They then evaluated the use of TMZ (200 mg/
m2) for 5 days for a total of six cycles, starting 4 weeks after
Chemotherapy of Brainstem Gliomas Chapter 45 591
RT completion. In terms of the irinotecan, 16/33 patients
were treated with this regimen, but 6 stopped it due to
clinical progression and 1 due to toxicity. In terms of the
treatment with TMZ, grade 3–4 neutropenia and thrombo-
cytopenia were noted in 33% and 29% respectively, of TMZ
cycles. Median survival was 12 months with a 1-year sur-
vival of 48%. Again, this study did not show improved
prognosis with the use of TMZ after RT [60].
Chemotherapy for Recurrent DIPGs
Treatment with single-agent chemotherapy, multiagent reg-
imens, and high-dose chemotherapy with autologous stem
cell rescue have been studied extensively in patients with
recurrent brainstem gliomas. The overall response seen in
these studies is very poor and short lived [9].
In studies looking at single-agent chemotherapy in
recurrent disease, the overall response rates were poor, with
very short lasting effect seen, if any effect at all. For
instance, in a phase I trial of high-dose cyclophosphamide
(80 mg/kg or greater) in children with recurrent brain
tumors the overall response rate was 89% and the mean
duration of response was 7 months. In the seven patients
with recurrent gliomas, there was one complete response
and four partial responses. The main toxicity seen was
hematologic [61]. Another phase II trial looked at carbo-
platin (560 mg/m2 every 4 weeks) in 95 patients with
recurrent brain tumors. Complete or partial responses were
seen in 1/19 children with brainstem glioma [62]. In a study
that looked at 12 children with recurrent brainstem gliomas
treated with VP-16 (50 mg/m2 every 21 days), six patients
demonstrated a radiographic response (one complete, three
partial, two stable disease) with a median duration of
response of 8 months [63].
Study of multiagent chemotherapy in patients with
recurrent disease has shown some response, but this has
appeared short lived. For instance, in a study looking at
the treatment of recurrent brainstem gliomas with a regimen
consisting of 5-FU, CCNU, hydroxyurea, and 6-MP, 76%
responded with stabilization or disease improvement, but
progression occurred in 25 weeks. This is less than the
median survival from recurrence of brainstem gliomas
which is 27 weeks [64].
Studies have also looked at high-dose chemotherapy
with autologous stem cell rescue in recurrent disease. These
studies have not shown improved outcome. For instance, in
a phase II study that evaluated high-dose busulfan (150 mg/
m2  4 days) and thiotepa (350 mg/m2  3 days) with autol-
ogous bone marrow transplant in childhood malignant
tumors, five partial responses were observed (all in patients
with diagnoses other than brainstem gliomas), and one
objective response was seen in a patient with brainstem
glioma. In this study, toxicity was high with bone marrow
aplasia and complications affecting skin, liver, and
592 SECTION V Chemotherapy for Specific Tumors—Pediatrics
neurological status [65]. Dunkel and colleagues have inves-
tigated the effectiveness of high-dose thiotepa (300 mg/m2)
and etoposide (250–500 mg/m2) regimens with autologous
stem cell rescue in patients with pontine tumors, 10 of
whom had recurrent disease. Their study had two toxic
deaths in the setting of septicemia and multiorgan failure.
The MST was 4.7 months from transplant in those with
recurrent disease. Therefore, survival was not prolonged
and adverse effects could be serious [66].
NEWER THERAPIES
Newer strategies for the treatment of DIPG are needed. One
of the major limitations of treatment for DIPG is efficient
delivery of effective therapies to the tumor, with penetration
of the blood–brain barrier a major obstacle. New strategies
for drug delivery currently being studied include intra-
arterial/intra-thecal chemotherapy, intranasal drug deli-
very, and convection-enhanced catheter directed therapy.
However, each has met with limited success.
One preclinical study looking at intranasal delivery
studied the use of the telomerase inhibitor GRN163 in rats
with human tumor xenografts. It was noted that this agent
was found to be present in the tumor cells with peak accu-
mulation 4 h after delivery. It also was found to prolong sur-
vival in rats from 35 days in the control group to 75.5 days
in the GRN163 treated group [67]. The use of convection-
enhanced delivery (CED) has also been recently looked at
with a number of drugs. For instance, one pilot study eval-
uated two children with DIPG who were treated with CED
of topotecan, a topoisomerase inhibitor, via infusion
through bilateral catheters placed in the brainstem. The first
patient was treated 210 days after diagnosis, after RT was
completed and at the time of tumor recurrence. Post-
treatment MRIs showed reduction in tumor size and edema,
but the patient died 49 days after treatment. The second
patient was treated 24 days after diagnosis, prior to RT.
Posttreatment MRIs again showed a modest reduction in
tumor size. This patient was subsequently treated with
RT but died 120 days after treatment. The authors con-
cluded that while survival was not prolonged, a moderate
treatment effect was noted, and that more studies were
needed to determine the optimal flow rate for CED [68].
Souwedaine and colleagues have noted that brainstem
CED for the treatment of DIPG is appealing due to the
compact nature and poor treatment options for this tumor.
The safety of brainstem CED has been well established in
preclinical trials [69,70], and more recently, in early stage
clinical trials. A few clinical trials are currently underway
which are evaluating the use of CED in treating DIPG
with targeted macromolecules such as antibodies and
immunotoxins [71]. In a recent phase I trial CED is
used to deliver 8H9 conjugated to a therapeutic radio-
isotope directly into the brainstem tumor via a surgically
placed infusion catheter (ClinicalTrials.gov identifier
NCT01502917); results for this trial are pending.
With increased efforts in recent years to perform tumor
biopsies in DIPG patients, combined with advances in
molecular diagnostics, several therapeutically targetable,
recurrent genomic alterations, and other molecular targets
have been identified in DIPG. These targets include muta-
tions or amplifications of the PDGFRA and ACVR1 onco-
genes, and overexpression of EGFR, many of which are
being studied currently in clinical trials. One phase
I study evaluated the use of EGFR inhibitor erlotinib
(125 mg/m2) in the treatment of malignant brain tumors
in children, either as monotherapy or with RT. Group 1
included refractory or relapsed brain tumors treated with
erlotinib alone and Group 2 included newly diagnosed
brainstem gliomas treated with erlotinib plus RT. In Group
2, OS was 12 months with only 6 grade 4–5 adverse events
noted in both groups [72]. Another phase 2 study looked at
the use of the anti-EGFR antibody, nimotuzumab (150 mg/
m2), in the treatment of progressive DIPG in pediatric
patients. This drug was administered IV weekly from weeks
1 to 7 and once every 2 weeks from weeks 8 to 18. Overall
18 of 44 patients experienced serious adverse effects, the
majority associated with disease progression. Median PFS
was 1.7 months and median survival was 3.2 months. The
authors concluded that nimotuzumab has modest activity
in DIPG and that a small subset of patients appeared to
benefit from this treatment [73].
A phase I trial of imatinib, a TKI of PDGF-R, in children
with newly diagnosed brainstem gliomas from the PBTC
established the maximum tolerated dose in those not
receiving enzyme-inducing anticonvulsant drugs as
465 mg/m2 with a PFS at 6 months of 70%. However, there
was evidence of possible increased risk of intratumoral
hemorrhage, which needs to be further studied [74].
Another biologic agent that has been the focus of several
studies in recurrent pediatric HGG given its clinical utility
in recurrent adult glioblastoma, is bevacizumab, a mono-
clonal antibody against VEGF-A. Narayana and colleagues
have reported on their single-institution experience with
bevacizumab in pediatric patients with recurrent or pro-
gressive HGG. They have reported that 12 patients were
treated with bevacizumab 10 mg/kg every 2 weeks along
with irinotecan 125 mg/m2. Ten patients tolerated therapy
without serious toxicity, two patients had partial responses
while four had stable disease. The median PFS was
2.25 months and median OS was 6.25 months. They have
noted that outcome in pediatric patients was inferior com-
pared with adult patients, likely due to biological differ-
ences between adult and pediatric tumors [75]. More
recently, the Pediatric Brain Tumor Consortium evaluated
the use of bevacizumab and irinotecan in children with
recurrent malignant gliomas and brainstem gliomas in a
phase II study. They noted no sustained responses and a
6-month PFS of 41.8% in malignant gliomas and 9.7% in

brainstem gliomas. The combination was well tolerated, but
unfortunately had minimal efficacy [76].
Histone deacetylase inhibitors have been more recently
of interest, especially in light of the molecular findings in
DIPG, where many of these tumors harbor K27M muta-
tions. One institution evaluated the use of valproic acid in
the outcomes of children with DIPG. Their standard of
therapy included RT and weekly carboplatin and vin-
cristine. They have evaluated patients treated with this
regimen without valproic acid versus with valproic acid,
and found statistically significant improved median EFS
(6.5 vs 9.5 months in treated patients) and OS (7.8 vs
13.4 months in treated patients) [77]. Another histone dea-
cetylase inhibitor which is currently being studied in
clinical trial is panobinostat. A preclinical study of panobi-
nostat using a genetically engineered mouse model showed
that this drug was an effective targeted agent against DIPG
human and mouse tumor cells in vitro. It potentially
inhibited cell proliferation and viability, and induced apo-
ptosis. In vivo studies in a panel of xenografts and geneti-
cally engineered mouse models showed that the drug
reached the brainstem tumor tissue and reduced prolifer-
ation of cells. However, it did not significantly impact
the survival in these mice, which the authors concluded
was due to toxicity with higher doses [78].
Immunotherapeutic approaches for DIPG are being
pursued in a variety of ongoing clinical trials. A pilot study
investigated the use of a peptide vaccine against glioma-
associated antigens (GAA) in 26 children with DIPG and
HGGs. In this study, only 2 children had progressive
disease, 5 had symptomatic pseudoprogression that
responded to dexamethasone, 19 had stable disease, 2 had
partial responses, and 1 had a minor response. The vaccine
was well tolerated overall, and had an OS that was between
6.3 and >38 months and a positive immune response in
eight patients [79]. Currently there is an intense interest
in developing therapies using immune checkpoint inhib-
itors, including an ongoing study by the PBTC using pem-
brolizumab, an anti-PD-1 antibody, in children with
recurrent HGG, including DIPG (ClinicalTrials.gov Iden-
tifier: NCT02359565). Cell-based immunotherapeutic
strategies, such as dendritic cell-based tumor vaccines,
are also being developed for children with malignant brain
tumors, including HGG [80]. Lastly, chimeric antigen
receptor (CAR) T-cell therapy is emerging for the treatment
of adult glioblastoma patients, and is likely to be explored in
future pediatric trials as well [81].
CONCLUSIONS
Brainstem gliomas comprise a range of disease entities that
can range from low-grade tumors which require little or no
treatment and have an excellent prognosis, to high-grade
tumors that are resistant to available therapies and
Chemotherapy of Brainstem Gliomas Chapter 45 593
associated with a dismal outcome. For DIPG, PFS is typi-
cally 5–6 months and OS <1 year. RT remains the only
therapy proven to improve survival in patients with DIPG
despite numerous clinical trials and ongoing research.
Higher doses of RT using HRT (66–78 Gy) do not appear
to provide a survival advantage when compared with
standard dose and fractionated protocols. Different strat-
egies using chemotherapy to treat DIPG, including high-
dose chemotherapy followed by stem cell rescue, neoad-
juvant chemotherapy (single or multiagent), concurrent che-
motherapy with RT, and adjuvant chemotherapy, have not
demonstrated any survival benefit when compared with
conventional RT alone. The blood-brain barrier and a lack
of penetration of many therapeutic agents into brain tumor
tissue have been recognized as major obstacles to therapy.
Recent advances in treatment delivery include CED, which
is currently studying the use of targeted macromolecules
such as antibodies and immunotoxins in treating DIPG. In
addition, promising novel immunotherapy approaches are
rapidly emerging for the treatment of gliomas, and are
hoped to mature over the next years, providing a much-
needed effective treatment option for children with DIPG.
REFERENCES
[1] Freeman CR, Farmer JP. Pediatric brain stem gliomas: a review. Int
J Radiat Oncol Biol Phys 1998;40(2):265–71.
[2] Guillamo JS, Doz F, Delattre JY. Brain stem gliomas. Curr Opin
Neurol 2001;14(6):711–5.
[3] Hargrave D, Chuang N, Bouffet E. Conventional MRI cannot predict
survival in childhood diffuse intrinsic pontine glioma. J Neurooncol
2008;86(3):313–9.
[4] Zagzag D, Miller DC, Knopp E, Farmer JP, Lee M, Biria S, et al.
Primitive neuroectodermal tumors of the brainstem: investigation
of seven cases. Pediatrics 2000;106(5):1045–53.
[5] Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D,
et al. New brain tumor entities emerge from molecular classification
of CNS-PNETs. Cell 2016;164(5):1060–72.
[6] Albright AL, Guthkelch AN, Packer RJ, Price RA, Rourke LB. Prog-
nostic factors in pediatric brain-stem gliomas. J Neurosurg 1986;
65(6):751–5.
[7] Cohen MEM. Prognostic factors in brainstem gliomas. Neurology
1986;36(5):602.
[8] Cage TA, Samagh SP, Mueller S, Nicolaides T, Haas-Kogan D,
Prados M, et al. Feasibility, safety, and indications for surgical biopsy
of intrinsic brainstem tumors in children. Childs Nerv Syst 2013;
29(8):1313–9.
[9] Freeman CR, Perilongo G. Chemotherapy for brain stem gliomas.
Childs Nerv Syst 1999;15(10):545–53.
[10] Jones DTW, Hutter B, J€ager N, Korshunov A, Kool M, Warnatz H-J,
et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilo-
cytic astrocytoma. Nat Genet 2013;45(8):927–32.
[11] Jeuken JWM, Wesseling P. MAPK pathway activation through
BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic
fusion gene with diagnostic, prognostic, and therapeutic potential.
J Pathol 2010;222(4):324–8.
594 SECTION V Chemotherapy for Specific Tumors—Pediatrics
[12] Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF. Association of
molecular alterations, including BRAF, with biology and outcome in
pilocytic astrocytomas. Acta Neuropathol (Berl) 2010;119(5):641–9.
[13] Horbinski C. To BRAF or not to BRAF: is that even a question
anymore? J Neuropathol Exp Neurol 2013;72(1):2–7.
[14] Teo C, Siu TL. Radical resection of focal brainstem gliomas: is it
worth doing? Childs Nerv Syst 2008;24(11):1307–14.
[15] Li KW, Roonprapunt C, Lawson HC, Abbott IR, Wisoff J, Epstein F,
et al. Endoscopic third ventriculostomy for hydrocephalus associated
with tectal gliomas. Neurosurg Focus 2005;18(6A):E2.
[16] Packer RJ, Ater J, Allen J, Phillips P, Geyer R, Nicholson HS, et al.
Carboplatin and vincristine chemotherapy for children with newly
diagnosed progressive low-grade gliomas. J Neurosurg 1997;
86(5):747–54.
[17] Ater JL, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR,
et al. Randomized study of two chemotherapy regimens for treatment
of low-grade glioma in young children: a report from the Children’s
Oncology Group. J Clin Oncol 2012;30(21):2641–7.
[18] Perry JR, Brown MT, Gockerman JP. Acute leukemia following
treatment of malignant glioma. J Neurooncol 1998;40(1):39–46.
[19] Karajannis MA, Lyden DC, Khakoo Y, Dunkel IJ. Treatment-related
myelodysplastic syndrome after chemotherapy for childhood low-
grade astrocytoma. J Pediatr Hematol Oncol 2006;28(10):700.
[20] Lassaletta A, Scheinemann K, Zelcer SM, Hukin J, Wilson BA,
Jabado N, et al. Phase II weekly vinblastine for chemotherapy-naı̈ve
children with progressive low-grade Glioma: a Canadian Pediatric
Brain Tumor Consortium Study. J Clin Oncol 2017;34(29):3537–43.
[21] Bouffet E, Jakacki R, Goldman S, Hargrave D, Hawkins C, Shroff M,
et al. Phase II study of weekly vinblastine in recurrent or refractory
pediatric low-grade glioma. J Clin Oncol 2012;30(12):1358–63.
[22] Gururangan S, Fangusaro J, Poussaint TY, McLendon RE, Onar-
Thomas A, Wu S, et al. Efficacy of bevacizumab plus irinotecan in
children with recurrent low-grade gliomas—a Pediatric Brain Tumor
Consortium study. Neuro Oncol 2014;16(2):310–7.
[23] Kieran MW, Yao X, Macy M, Leary S, Cohen K, MacDonald T, et al.
Final results of a prospective multi-institutional phase II study of
everolimus (RAD001), an mtor inhibitor, in pediatric patients with
recurrent or progressive low-grade glioma. A poetic consortium trial.
Neuro Oncol 2014;16(Suppl 3):iii27.
[24] Robison NJ, Campigotto F, Chi SN, Manley PE, Turner CD,
Zimmerman MA, et al. A phase II trial of a multi-agent oral antian-
giogenic (metronomic) regimen in children with recurrent or pro-
gressive cancer. Pediatr Blood Cancer 2014;61(4):636–42.
[25] Banerjee A, Jakacki RI, Onar-Thomas A, Wu S, Nicolaides T, Young
Poussaint T, et al. A phase I trial of the MEK inhibitor selumetinib
(AZD6244) in pediatric patients with recurrent or refractory low-
grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study.
Neuro Oncol 2017;19(8):1135–44.
[26] Green AL, Kieran MW. Pediatric brainstem gliomas: new under-
standing leads to potential new treatments for two very different
tumors. Curr Oncol Rep 2015;17(3):436.
[27] Pollack IF, Shultz B, Mulvihill JJ. The management of brainstem
gliomas in patients with neurofibromatosis 1. Neurology 1996;
46(6):1652–60.
[28] Khuong-Quang D-A, Buczkowicz P, Rakopoulos P, Liu X-Y,
Fontebasso AM, Bouffet E, et al. K27M mutation in histone H3.3
defines clinically and biologically distinct subgroups of pediatric
diffuse intrinsic pontine gliomas. Acta Neuropathol (Berl)
2012;124(3):439–47.
[29] Barrow J, Adamowicz-Brice M, Cartmill M, MacArthur D, Lowe J,
Robson K, et al. Homozygous loss of ADAM3A revealed by genome-
wide analysis of pediatric high-grade glioma and diffuse intrinsic
pontine gliomas. Neuro Oncol 2011;13(2):212–22.
[30] Freeman CR, Krischer JP, Sanford RA, Cohen ME, Burger PC, del
Carpio R, et al. Final results of a study of escalating doses of hyper-
fractionated radiotherapy in brain stem tumors in children: a Pediatric
Oncology Group study. Int J Radiat Oncol Biol Phys 1993;
27(2):197–206.
[31] Packer RJ, Boyett JM, Zimmerman RA, Albright AL, Kaplan AM,
Rorke LB, et al. Outcome of children with brain stem gliomas after
treatment with 7800 cGy of hyperfractionated radiotherapy.
A Childrens Cancer Group Phase I/II Trial. Cancer 1994;74
(6):1827–34.
[32] Freeman CR, Kepner J, Kun LE, Sanford RA, Kadota R, Mandell L,
et al. A detrimental effect of a combined chemotherapy-radiotherapy
approach in children with diffuse intrinsic brain stem gliomas? Int
J Radiat Oncol Biol Phys 2000;47(3):561–4.
[33] Pai Panandiker AS, Wong JK, Nedelka MA, Wu S, Gajjar A,
Broniscer A. Effect of time from diagnosis to start of radiotherapy
on children with diffuse intrinsic pontine glioma. Pediatr Blood
Cancer 2014;61(7):1180–3.
[34] Edwards MS, Wara WM, Urtasun RC, Prados M, Levin VA,
Fulton D, et al. Hyperfractionated radiation therapy for brain-stem
glioma: a phase I-II trial. J Neurosurg 1989;70(5):691–700.
[35] Packer RJ, Boyett JM, Zimmerman RA, Rorke LB, Kaplan AM,
Albright AL, et al. Hyperfractionated radiation therapy (72 Gy) for
children with brain stem gliomas. A Childrens Cancer Group Phase
I/II Trial. Cancer 1993;72(4):1414–21.
[36] Zaghloul MS, Eldebawy E, Ahmed S, Mousa AG, Amin A, Refaat A,
et al. Hypofractionated conformal radiotherapy for pediatric diffuse
intrinsic pontine glioma (DIPG): a randomized controlled trial.
Radiother Oncol 2014;111(1):35–40.
[37] Janssens GORJ, Gidding CEM, Van Lindert EJ, Oldenburger FR,
Erasmus CE, Schouten-Meeteren AYN, et al. The role of hypofrac-
tionation radiotherapy for diffuse intrinsic brainstem glioma
in children: a pilot study. Int J Radiat Oncol Biol Phys
2009;73(3):722–6.
[38] Fontanilla HP, Pinnix CC, Ketonen LM, Woo SY, Vats TS,
Rytting ME, et al. Palliative reirradiation for progressive diffuse
intrinsic pontine glioma. Am J Clin Oncol 2012;35(1):51–7.
[39] Wolff JE, Rytting ME, Vats TS, Zage PE, Ater JL, Woo S, et al.
Treatment of recurrent diffuse intrinsic pontine glioma: the MD
Anderson Cancer Center experience. J Neurooncol 2012;
106(2):391–7.
[40] Janssens GO, Gandola L, Bolle S, Mandeville H, Ramos-Albiac M,
van Beek K, et al. Survival benefit for patients with diffuse intrinsic
pontine glioma (DIPG) undergoing re-irradiation at first progression:
A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG
working group. Eur J Cancer 2017;73:38–47.
[41] Jenkin RD, Boesel C, Ertel I, Evans A, Hittle R, Ortega J, et al. Brain-
stem tumors in childhood: a prospective randomized trial of irradi-
ation with and without adjuvant CCNU, VCR, and prednisone.
A report of the Childrens Cancer Study Group. J Neurosurg 1987;
66(2):227–33.
[42] Kadota RP, Mandell LR, Fontanesi J, Kovnar EH, Krischer J,
Kun LE, et al. Hyperfractionated irradiation and concurrent cisplatin
in brain stem tumors: a Pediatric Oncology Group pilot study (9139).
Pediatr Neurosurg 1994;20(4):221–5.

[43] Allen J, Siffert J, Donahue B, Nirenberg A, Jakacki R, Robertson P,
et al. A phase I/II study of carboplatin combined with hyperfractio-
nated radiotherapy for brainstem gliomas. Cancer 1999;86
(6):1064–9.
[44] Broniscer A, Leite CC, Lanchote VL, Machado TM, Cristófani LM.
Radiation therapy and high-dose tamoxifen in the treatment of
patients with diffuse brainstem gliomas: results of a Brazilian coop-
erative study. Brainstem Glioma Cooperative Group. J Clin Oncol
2000;18(6):1246–53.
[45] Wolff JEA, Driever PH, Erdlenbruch B, Kortmann RD, Rutkowski S,
Pietsch T, et al. Intensive chemotherapy improves survival in pedi-
atric high-grade glioma after gross total resection: results of the
HIT-GBM-C protocol. Cancer 2010;116(3):705–12.
[46] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B,
Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant
temozolomide for glioblastoma. N Engl J Med 2005;352(10):987–96.
[47] Cohen KJ, Heideman RL, Zhou T, Holmes EJ, Lavey RS, Bouffet E,
et al. Temozolomide in the treatment of children with newly diag-
nosed diffuse intrinsic pontine gliomas: a report from the Children’s
Oncology Group. Neuro Oncol 2011;13(4):410–6.
[48] Bailey S, Howman A, Wheatley K, Wherton D, Boota N, Pizer B,
et al. Diffuse intrinsic pontine glioma treated with prolonged temozo-
lomide and radiotherapy—results of a United Kingdom phase II trial
(CNS 2007 04). Eur J Cancer 2013;49(18):3856–62.
[49] M€ uller K, Schlamann A, Guckenberger M, Warmuth-Metz M,
Gl€uck A, Pietschmann S, et al. Craniospinal irradiation with con-
current temozolomide for primary metastatic pediatric high-grade
or diffuse intrinsic pontine gliomas. A first report from the GPOH-
HIT-HGG Study Group. Strahlenther Onkol 2014;190(4):377–81.
[50] Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, de Tribolet N,
Weller M, et al. MGMT gene silencing and benefit from temozo-
lomide in glioblastoma. N Engl J Med 2005;352(10):997–1003.
[51] Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D,
Capper D, et al. Integrated analysis of pediatric glioblastoma reveals
a subset of biologically favorable tumors with associated molecular
prognostic markers. Acta Neuropathol (Berl) 2015;129(5):669–78.
[52] Kretschmar CS, Tarbell NJ, Barnes PD, Krischer JP, Burger PC,
Kun L. Pre-irradiation chemotherapy and hyperfractionated radiation
therapy 66 Gy for children with brain stem tumors. A phase II study of
the Pediatric Oncology Group, Protocol 8833. Cancer 1993;
72(4):1404–13.
[53] Jennings MT, Sposto R, Boyett JM, Vezina LG, Holmes E,
Berger MS, et al. Preradiation chemotherapy in primary high-risk
brainstem tumors: phase II study CCG-9941 of the Children’s Cancer
Group. J Clin Oncol 2002;20(16):3431–7.
[54] Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC,
Cohen ME, et al. Postoperative chemotherapy and delayed radiation
in children less than three years of age with malignant brain tumors.
N Engl J Med 1993;328(24):1725–31.
[55] Frappaz D, Schell M, Thiesse P, Marec-Berard P, Mottolese C,
Perol D, et al. Preradiation chemotherapy may improve survival in
pediatric diffuse intrinsic brainstem gliomas: final results of BSG
98 prospective trial. Neuro Oncol 2008;10(4):599–607.
[56] Wolff JE, Kortmann R-D, Wolff B, Pietsch T, Peters O, Schmid H-J,
et al. High dose methotrexate for pediatric high grade glioma:
results of the HIT-GBM-D pilot study. J Neurooncol 2011;102
(3):433–42.
[57] Kedar A, Maria BL, Graham-Pole J, Ringdahl DM, Quisling RG,
Mickle JP, et al. High-dose chemotherapy with marrow reinfusion
Chemotherapy of Brainstem Gliomas Chapter 45 595
and hyperfractionated irradiation for children with high-risk brain
tumors. Med Pediatr Oncol 1994;23(5):428–36.
[58] Bouffet E, Khelfaoui F, Philip I, Biron P, Brunat-Mentigny M,
Philip T. High-dose carmustine for high-grade gliomas in childhood.
Cancer Chemother Pharmacol 1997;39(4):376–9.
[59] Bouffet E, Raquin M, Doz F, Gentet JC, Rodary C, Demeocq F, et al.
Radiotherapy followed by high dose busulfan and thiotepa: a pro-
spective assessment of high dose chemotherapy in children with
diffuse pontine gliomas. Cancer 2000;88(3):685–92.
[60] Broniscer A, Iacono L, Chintagumpala M, Fouladi M, Wallace D,
Bowers DC, et al. Role of temozolomide after radiotherapy for newly
diagnosed diffuse brainstem glioma in children: results of a multiin-
stitutional study (SJHG-98). Cancer 2005;103(1):133–9.
[61] Allen JC, Helson L. High-dose cyclophosphamide chemotherapy for
recurrent CNS tumors in children. J Neurosurg 1981;55(5):749–56.
[62] Gaynon PS, Ettinger LJ, Baum ES, Siegel SE, Krailo MD,
Hammond GD. Carboplatin in childhood brain tumors. A Children’s
Cancer Study Group Phase II trial. Cancer 1990;66(12):2465–9.
[63] Chamberlain MC. Recurrent brainstem gliomas treated with oral
VP-16. J Neurooncol 1993;15(2):133–9.
[64] Rodriguez LA, Prados M, Fulton D, Edwards MS, Silver P, Levin V.
Treatment of recurrent brain stem gliomas and other central nervous
system tumors with 5-fluorouracil, CCNU, hydroxyurea, and
6-mercaptopurine. Neurosurgery 1988;22(4):691–3.
[65] Kalifa C, Hartmann O, Demeocq F, Vassal G, Couanet D, Terrier-
Lacombe MJ, et al. High-dose busulfan and thiotepa with autologous
bone marrow transplantation in childhood malignant brain tumors: a
phase II study. Bone Marrow Transplant 1992;9(4):227–33.
[66] Dunkel IJ, Garvin JH, Goldman S, Ettinger LJ, Kaplan AM, Cairo M,
et al. High dose chemotherapy with autologous bone marrow rescue
for children with diffuse pontine brain stem tumors. Children’s
Cancer Group. J Neurooncol 1998;37(1):67–73.
[67] Hashizume R, Ozawa T, Gryaznov SM, Bollen AW, Lamborn KR,
Frey WH, et al. New therapeutic approach for brain tumors: Intra-
nasal delivery of telomerase inhibitor GRN163. Neuro Oncol
2008;10(2):112–20.
[68] Anderson RCE, Kennedy B, Yanes CL, Garvin J, Needle M, Canoll P,
et al. Convection-enhanced delivery of topotecan into diffuse
intrinsic brainstem tumors in children. J Neurosurg Pediatr 2013;11
(3):289–95.
[69] Sewing ACP, Caretti V, Lagerweij T, Schellen P, Jansen MHA, van
Vuurden DG, et al. Convection enhanced delivery of carmustine to
the murine brainstem: a feasibility study. J Neurosci Methods
2014;238:88–94.
[70] Zhou Z, Ho SL, Singh R, Pisapia DJ, Souweidane MM. Toxicity eval-
uation of convection-enhanced delivery of small-molecule kinase
inhibitors in naı̈ve mouse brainstem. Childs Nerv Syst 2015;31
(4):557–62.
[71] Zhou Z, Singh R, Souweidane MM. Convection-enhanced delivery
for diffuse intrinsic pontine glioma treatment. Curr Neuropharmacol
2017;15(1):116–28.
[72] Geoerger B, Hargrave D, Thomas F, Ndiaye A, Frappaz D,
Andreiuolo F, et al. Innovative therapies for children with cancer
pediatric phase I study of erlotinib in brainstem glioma and
relapsing/refractory brain tumors. Neuro Oncol 2011;13(1):109–18.
[73] Bartels U, Wolff J, Gore L, Dunkel I, Gilheeney S, Allen J, et al.
Phase 2 study of safety and efficacy of nimotuzumab in pediatric
patients with progressive diffuse intrinsic pontine glioma. Neuro
Oncol 2014;16(11):1554–9.
596 SECTION V Chemotherapy for Specific Tumors—Pediatrics
[74] Pollack IF, Jakacki RI, Blaney SM, Hancock ML, Kieran MW,
Phillips P, et al. Phase I trial of imatinib in children with newly diag-
nosed brainstem and recurrent malignant gliomas: a Pediatric Brain
Tumor Consortium report. Neuro Oncol 2007;9(2):145–60.
[75] Narayana A, Kunnakkat S, Chacko-Mathew J, Gardner S,
Karajannis M, Raza S, et al. Bevacizumab in recurrent high-grade
pediatric gliomas. Neuro Oncol 2010;12(9):985–90.
[76] Gururangan S, Chi SN, Young Poussaint T, Onar-Thomas A,
Gilbertson RJ, Vajapeyam S, et al. Lack of efficacy of bevacizumab
plus irinotecan in children with recurrent malignant glioma and
diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study.
J Clin Oncol 2010;28(18):3069–75.
[77] Felix FHC, de Araujo OL, da Trindade KM, Trompieri NM,
Fontenele JB. Retrospective evaluation of the outcomes of children
with diffuse intrinsic pontine glioma treated with radiochemotherapy
and valproic acid in a single center. J Neurooncol 2014;116
(2):261–6.
[78] Hennika T, Hu G, Olaciregui NG, Barton KL, Ehteda A,
Chitranjan A, et al. Pre-clinical study of panobinostat in xenograft
and genetically engineered murine diffuse intrinsic pontine glioma
models. PLoS ONE 2017;12(1).
[79] Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A,
Potter DM, et al. Antigen-specific immune responses and clinical
outcome after vaccination with glioma-associated antigen peptides
and polyinosinic-polycytidylic acid stabilized by lysine and carboxy-
methylcellulose in children with newly diagnosed malignant brainstem
and nonbrainstem gliomas. J Clin Oncol 2014;32(19):2050–8.
[80] Ardon H, De Vleeschouwer S, Van Calenbergh F, Claes L,
Kramm CM, Rutkowski S, et al. Adjuvant dendritic cell-based
tumour vaccination for children with malignant brain tumours.
Pediatr Blood Cancer 2010;54(4):519–25.
[81] Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A,
et al. Regression of glioblastoma after chimeric antigen receptor
T-Cell therapy. N Engl J Med 2016;375(26):2561–9.