Medulloblastoma is a rare tumor in central nervous system, with an even rarer occurrence in adulthood. The management of a recurrent disease is a medical challenge; chemotherapy has been used as the treatment of choice, while reirradiation has been employed in selected cases. We report the case of a 51-year-old man with recurrent medulloblastoma. He was treated with local reirradiation, chemotherapy, and antiangiogenic drug, with the latter giving the longer progression-free interval. The aim of this report is to show that recurrent medulloblastoma in adults can be approached with a multimodality treatment and that antiangiogenic therapy should have a role in the management of this disease

Acquaviva, Grazia

Ettorre, Giovanni Carlo

Privitera, Giuseppe

Spatola, Corrado

Journal of Oncology

English

PubMed

Giuseppe Privitera

Grazia Acquaviva

Giovanni Carlo Ettorre

Corrado Spatola

Crossref

Hindawi Publishing Corporation
Journal of Oncology
Volume 2009, Article ID 247873, 4 pages
doi:10.1155/2009/247873
Case Report
Antiangiogenic Therapy in the Treatment of
Recurrent Medulloblastoma in the Adult: Case Report and
Review of the Literature
Giuseppe Privitera, Grazia Acquaviva, Giovanni Carlo Ettorre, and Corrado Spatola
U.O. Radiodiagnostica e Radioterapia Oncologica, AOU Policlinico “G. Rodolico”—Catania, Via Santa
Sofia 78-95125—Catania, Italy
Correspondence should be addressed to Corrado Spatola, cor spatola@hotmail.com
Received 27 May 2009; Revised 9 August 2009; Accepted 3 November 2009
Recommended by David Ball
Medulloblastoma is a rare tumor in central nervous system, with an even rarer occurrence in adulthood. The management of
a recurrent disease is a medical challenge; chemotherapy has been used as the treatment of choice, while reirradiation has been
employed in selected cases. We report the case of a 51-year-old man with recurrent medulloblastoma. He was treated with local
reirradiation, chemotherapy, and antiangiogenic drug, with the latter giving the longer progression-free interval. The aim of
this report is to show that recurrent medulloblastoma in adults can be approached with a multimodality treatment and that
antiangiogenic therapy should have a role in the management of this disease.
Copyright © 2009 Giuseppe Privitera et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
1. Background
Medulloblastoma is a rare embryonal neuroepithelial tumor
in central nervous system. It occurs most frequently in
the cerebellum of children, but almost 20% of the medul-
loblastomas develop in adulthood. The overall frequency of
medulloblastoma/PNET is very low, with the Central Brain
Tumour Registry of the USA reporting that this disease is
0.9% of all reported brain tumours, with an incidence of 0.24
per 100000 person-years. The peak age group is 0–4 years,
progressively declining to 0.05/105person-years for the 65-
to-74 year age groups. This tumor occurs most frequently in
men than women [1].
Whether medulloblastoma is the same tumor in adults
and in children is an open question in the adult population.
The standard therapy for medulloblastoma has been
surgical resection followed by craniospinal irradiation (CSI).
The role of adjuvant chemotherapy is unclear in the adult
population.
The management of a recurrent disease is a medical
challenge; chemotherapy has been used as the treatment of
choice, while reirradiation has been utilized in selected cases
[2]. The advent of new anticancer drugs tested in brain
tumors, as for antiangiogenetic molecules, has only recently
been employed in the treatment of medulloblastoma and it
is to be expected that their use will increase in the future, in
the light of a personalized therapy.
2. Case Report
We report the case of a 51-year-old man with recurrent
medulloblastoma. His clinical history began in 1999, when
he developed symptoms of raised intracranial pressure with
dizziness and headache. A brain MR revealed a tumor in the
region of right ponto-cerebellar angle, 3 cm in maximum
diameter. The patient underwent a complete surgical resec-
tion, confirmed by a postsurgery MR, and a diagnosis of
classic medulloblastoma, G IV WHO was performed.
He received craniospinal irradiation (36 Gy), followed by
a primary boost to the posterior fossa (18 Gy) with a total
dose to that region of 54 Gy.
After a 6-year period of event-free follow-up, in March
2005 a surveillance MRI showed recurrent disease in cervical
and thoracic spinal cord. Thus, he received chemotherapy
2 Journal of Oncology
A
(a)
A
(b)
Figure 1: Spine MR showing the diﬀuse recurrent disease in the
cervical spine (on the left) and the complete response during the
treatment with bevacizumab (on the right).
with dacarbazine-etoposide-cisplatin (DEC) for 6 cycles;
after four cycles of this treatment a grade III-IV neurotoxicity
was developed, so carboplatin was introduced in the place of
cisplatin.
In November 2005 a disease progression was diagnosed,
with the evidence of recurrence in brainstem and cervical
spinal cord: the patient was treated with procarbazine
(60 mg/m2) and lomustine (110 mg/m2) for 2 cycles.
After that, he underwent a reirradiation limited to the
sites of recurrence (brainstem and cervical spinal cord)
to a total dose of 24 Gy, with concomitant temozolomide
75 mg/m2. Adjuvant temozolomide 200 mg/m2 was started
after irradiation.
A complete remission of the disease was demonstrated in
February 2006 and, for that reason, the same treatment was
continued for 13 cycles, until December 2006. During this
period, the patient experienced a good quality of life and the
progression-free interval was almost one year (Figure 1).
In January 2007 he had an MRI of the brain and of the
spinal axis that showed recurrence in sacral spine (S1), thus
we planned a new chemotherapeutic schedule, vincristine-
etoposide-ifosfamide, for 2 cycles, without any evidence of
response. A new control MRI evidenced a relapse in the
brain and a stable disease to the spinal axis. For that reason,
in view of the short relapse-free interval and of the lack of
response to the conventional chemotherapeutic drugs, we
decided to enter the patient into an oﬀ-label treatment with
bevacizumab. Thus, in July 2007 he started this treatment
with a dose of 5 mg/kg every 14 days.
After three months on bevacizumab, the restaging MR
showed a complete disease regression, without any evidence
of disease in the brain and in the spinal axis. Therefore,
he continued the same treatment schedule for further 4
months. During this period, the patient experienced only a
mild hypertension, treated with ACE-inhibitors and a pro-
longation of the infusion interval, with the administration of
bevacizumab at a dose of 5 mg/kg every 21 days.
In February 2008, the control MRI demonstrated a slight
progressive disease in the cervical spine, consequently we
returned to the previous treatment schedule of drug infusion
every 14 days. After 3 months, the control MRI showed
a reduction of the pathologic enhancement to the cervical
spine. Thus, the treatment was continued for further 4
months until September 2008, without any relevant side
eﬀects.
In October 2008, as eﬀect of a cranial trauma, the patient
was referred to the hospital for the appearance of clinical
signs of raised intracranial pressure, with sleepiness and
headache, epilepsy with continuous crisis, and oliguria. A
brain CT showed a subarachnoid frontal cerebral higroma,
without the evidence of any vascular damage. For that
reason, the patient was referred to the neurosurgeon, who
performed a cerebro-spinal fluid drainage, and then to
the intensive care unit for the life-saving treatments. The
cytological study of the liquor was negative for cancer.
During the hospitalization there was no regression of the
clinical symptoms, so the patient died after 10 days from the
admission (Table 1).
3. Discussion and Conclusions
Medulloblastoma of the cerebellum is an embryonal tumor,
with a peak of incidence in children.
Not infrequently, about 20% of cases, it arises in adult-
hood. There is the question as to whether the pathogenesis
is the same in the adult form of the disease as the childhood
one [1–3]. This suggests that the prognosis and therapy of
medulloblastoma could not be the same in all ages, but it is
necessary to personalize the treatment approach.
The standard therapy for medulloblastoma has been
surgical resection followed by craniospinal irradiation (CSI).
Surgery plays a critical role in the management of this
malignancy from both a diagnostic and therapeutic point
of view, since the importance of complete resection is well
recognized [4].
Cranio-spinal irradiation plays a key role in the manage-
ment of patients with this disease for many years, because
it was the only treatment available and eﬀective, but also
because of the recognition that many chemotherapy drugs
have diﬃculties to pass through the blood-brain barrier.5
The standard radiotherapy treatment counts a dose of 35 Gy
to 36 Gy with boost to the posterior fossa, thus giving a total
of 55-56 Gy with a 5-year progression-free survival (PFS) and
overall survival of 50 to 65% [5, 6].
The role of adjuvant chemotherapy is unclear, because
it was associated with a nonsignificant trend to prolonged
survival. Several randomized and nonrandomised studies
have demonstrated a survival benefit in pediatric medul-
loblastoma treated with chemotherapy, given after radiother-
apy [7–9] or before it [10, 11]. Adjuvant or neoadjuvant
chemotherapy plays also a key role in permitting a reduction
in the dose of cranio-spinal irradiation; thus, chemotherapy
Journal of Oncology 3
Table 1: Patient natural history.
Date Treatments Comments
April 1999 Surgery (total resection)- DFI/6 years
Craniospinal irradiation (35 Gy) + boost PCF (18 Gy) total dose
54 Gy
March 2005 Relapse (cervico-dorsal spinal cord) Progression after 8 months
Chemotherapy (dacarbazine-vp16- CDDP/carboplatin 6 cycles)
November 2005
Relapse (brain stem and cervical spinal cord)
Partial response PFI 13 monthsChemotherapy (procarbazine-lomustine 2 cycles)
Reirradiation (brainstem and spinal cord 24 Gy) plus
concomitant temozolomide
Temozolomide (13 cycles until December 2006)
January 2007 Relapse (sacral spinal) Progressive disease
Chemotherapy (vincristine-VP16-ifosfamide-2 cycles)
April 2007 Relapse (brain) Complete response
Targeted therapy (bevacizumab q.14 3 months)
October 2007 Arterious hypertension Progressive disease
Targeted therapy (bevacizumab q.21 4 months)
February 2008 Relapse (cervical spinal cord) Partial response
Targeted therapy (bevacizumab q.14 7 months until September
2008)
October 2008 Cerebral hygroma/epileptic syndrome Death
is to date a standard of care in pediatric medulloblastoma,
whereas its role in adult setting is not determined due to the
rarity of the disease.
The management of recurrent medulloblastoma is based
on the use of systemic chemotherapy. The role of reirra-
diation is still unclear. It has been employed in selected
cases, as for patients with good performance status, longer
progression-free interval, and who are not amenable to
stereotactic radiotherapy. The major argument against reir-
radiation with fractionated external beam radiotherapy
within the central nervous system is the cumulative CNS tox-
icity. In the recent years, brain and spinal cord reirradiation
has had a reappraisal: several studies have shown a lower
incidence of severe complication than previously reported
[2].
The main factors determining tolerance of the CNS to
irradiation seem to be total dose, interval to re-treatment,
volume of brain irradiated, fraction size, use of chemother-
apy, and age of patient.
There is not a gold standard chemotherapy treatment for
adult medulloblastoma. Multiagent treatment with CDDP,
Carboplatin, CCNU, and vincristine is the more commonly
utilized treatment in high risk patients, demonstrating to
increase the 5-year progression-free survival rate in children
to 85 % [6, 12].
Herrlinger et al. [4] suggest that the second-line and
third-line therapes should be oﬀered to adult medulloblas-
toma patients. A small but significant survival benefit was
demonstrated for the use of chemotherapy for high risk
patients [4].
The novel approaches such as small molecules, mon-
oclonal antibodies, and antiangiogenic therapies support
the conventional treatment and they will increasingly allow
personalized medical care.
The advent of new anticancer drugs tested in brain
tumors has important consequence for personalized therapy.
Tumor vasculature is emerging as an important target
for antiangiogenic therapy. Slongo et al. demonstrated the
expression of VEGF, VEGFR-1, and VEGFR-2 in human
medulloblastoma cell lines and the possible autocrine
mechanism of VEGF on medulloblastoma cell proliferation.
Medulloblastoma cell lines present both VEGFR-1 and
VEGFR-2. Targeting VEGF signaling may represent a new
therapeutic option in the treatment of medulloblastoma
[13, 14].
In the case presented, the patient had a first recurrence
after a disease-free interval of 6 years. The patient was
approached initially by means of systemic chemotherapy,
with dacarbazine, etoposide and platin compounds, which
results in a disease progression after 8 months, at the
expenses of moderate neurotoxicity. Reirradiation was car-
ried out after an interval of about 7 years, employing a
standard fraction size and a low total dose, with concomitant
and adjuvant temozolomide. It results in a partial response
with a long progression-free interval of 13 months, without
major side eﬀects, with the exception of a moderate cerebral
atrophy showed by the follow-up MR.
The use of systemic chemotherapy at the third relapse has
not led to clinical benefit; for that reason we decided to make
use of an oﬀ-label targeted therapy with an antiangiogenic
4 Journal of Oncology
molecule, such as bevacizumab. This treatment results in
a rapid and complete disappearance of brain and spinal
cord localizations. The only clinical relevant side eﬀect
was a moderate hypertension, which leads us to increase
the interval between administration, from every 14 days
to every 21 days. The every-three weeks schedule has not
maintained the complete response gained by the every-
two weeks schedule, so the treatment was restarted at the
previous schedule, with a new antihypertensive therapy.
Consequently, the follow-up MR showed again a response in
the spinal cord.
During the treatment with bevacizumab, the patient
experienced a good quality of life, with a progression-free
interval of almost 17 months. The death was not attributable
to a disease progression, neither to a treatment side eﬀects.
The aim of this case report is to show that recurrent
medulloblastoma in adults can be approached with a mul-
timodality therapy by means of radiotherapy, chemotherapy,
and targeted therapy.
In conclusion, angiogenesis seems to play a key role in the
progression of medulloblastoma, and clinicians have sought
to develop eﬀective and less toxic antiangiogenic strategies,
including the inhibition or destruction of abnormal blood
vessels using either antiangiogenic or vascular disrupting
agents [15].
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Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature

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CBTRUS Executive Team Central Brain Tumor Registry of the United States, “Primary brain tumors in the United States,

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P a c k e r ,L .N .S u t t o n ,J .W .G o l d w e i n ,e ta l . ,“ I m p r o v e d survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma,”

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Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature

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