TEMOZOLOMIDE

IN CHILDHOOD BRAIN TUMOR

ANKY TRI RINI K.E.

Pediatric Oncology Department
“Dharmais” Cancer Hospital
PRIMARY BRAIN TUMOR

 One of the most common solid

malignancy of childhood, with
2,5 % cases/ 100.000 children
annually
 The majority 60-70 % are
gliomas
 Leading cause of cancer death
in children, the overall 5 years
survival rate being 50 %
( Bleyers WA, Nerv Syst 1999 and

Potter R et all, SIOP 2005)

CLASSES OF BRAIN TUMORS:

WHO recognize 120+ different types

of brain tumors
The 4 major classes:
1. Glioma
2. Neuronal tumors
3. Poorly differentiated neoplasms
4. Meningiomas
 Cont….…

 There are 3 basic types:

1. Tumors of the brain  gliomas
2. Tumors to the brain  metastases
3. Tumors on the brain  meningiomas,
pituitary tumors
TUMOR SITES

 Adult : predominantly (70%) in the

supratentorial ( cerebral hemisphere/
cerebrum )
 Children : 50 % in the infratentorial
( cerebellum and brain stem )

Becker LE, Neuroimaging. Clin N Am 1999 and Lee WH,

Neuro oncology clinical tials investigator training 2009.
CHARACTERISTIC OF BRAIN
TUMORS

 Biologic malignancy
 Limited surgery to prevent neurologic deficits
 Specific anatomic site: meningioma (benign)
compressing medulla of brain (fatal outcome)
 CSF seeding
 Rare extracranial metastases, Glioblastoma
multiforme (GBM ) and Medulloblastoma mostly
post operative procedure
 Gliomas: Signs and Symptoms

 Highly variable
 Seizures/headache
 Motor deficits
 Nausea/vomiting
 Personality changes
 Slowing of cognitive function
– Patients may sleep longer at night
– Nap more during the day
– Loss of memory
7
TEMOZOLAMIDE (TMZ)

 TMZ, an oral alkylating agent is rapidly

absorbed and excellent oral
bioavailability
 Good penetration across the blood
brain barrier and low toxicity profile.
 Maximum plasma concentrations are
observed 30 -90 minutes after oral
intake
 Plasma half life approximately 2 hours
 Cont….

 Used in single agent or combination

regimen are key components in the
chemoteraphy of primary brain tumors.
 Should be administered in the fasting
state
 Must not be opened or chewed, but are
to be swallowed with water
THERAPY

 Standard therapy invollves surgical

resection, radiotherapy and
chemotherapy.
 The addition of radiotherapy to surgery
increase survival
 The concomitant treatment: combination
of radiotherapy and ajuvant TMZ
(6 weeks) followed by TMZ (5 days every
28 days for 6 cycles) increased the
median survival.
 Volume 352:987-996 March 10, 2005 Number 10

Radiotherapy plus Concomitant

and Adjuvant Temozolomide
for Glioblastoma
 Roger Stupp, M.D., Warren P. Mason, M.D., Martin J. van den Bent, M.D., Michael Weller, M.D.,
Barbara Fisher, M.D., Martin J.B. Taphoorn, M.D., Karl Belanger, M.D., Alba A. Brandes, M.D.,
Christine Marosi, M.D., Ulrich Bogdahn, M.D., Jürgen Curschmann, M.D., Robert C. Janzer,
M.D., Samuel K. Ludwin, M.D., Thierry Gorlia, M.Sc., Anouk Allgeier, Ph.D., Denis Lacombe,
M.D., J. Gregory Cairncross, M.D., Elizabeth Eisenhauer, M.D., René O. Mirimanoff, M.D., for
the European Organisation for Research and Treatment of Cancer Brain Tumor and
Radiotherapy Groups and the National Cancer Institute of Canada Clinical Trials Gro

11
12
 Radiotherapy plus
Concomitant and Adjuvant
Temozolomide for Glioblastoma

13
MGMT
( Methylguanine methyltransferase)

 Is an important tumor cell repair

enzyme that contributes to alkylating
agent resistence
 High level of MGMT activity in cancer
cells create a resistant phenotype
 Study of combinations of TMZ with
MGMT inhibitors is in progress
 “DHARMAIS”
CANCER HOSPITAL
EXPERIENCE
 BACKGROUND

• Management of childhood brain

tumour (CBT)  change
dramatically in the next years
• CBT is usually rapidly fatal
• Surgery, Radiotherapy,
Chemotherapy
Combination  increase survival
Cancer Distribution on Children < 15 yrs old
(RSCM, Jakarta, 2006)
 Incident of Childhood Cancer in
“Dharmais” Cancer Hospital 2007-2008

Cancer 2007 2008

 Leukemia 6 16
 Retinoblastoma 6 7
 Brain Cancer 5 7
 Neuroblastoma 4 8
 Osteosarcoma 3 7
 Hepatoblastoma 3 5
 Ewing Sarcoma 2 3
 Yolc Sac Tumour 2 3
 Others 7 10
Source: Cancer Registry, Pediatric Oncology Dept., DCH
 PURPOSE

• To determine the clinical features

• To review treatment response
METHODS

 The study was conducted

retrospectively based on medical
record of 11 patients with brain tumors
treated with temolozomide in DCH
between January 2003 – December
2008
 The data were collected for
clinicoepidemiology features and
response of treatment
METHODS . . . . .

 The treatment: radiotherapy plus continuous daily

temozolomide (75mg/m²/day, 7 day/week from the first
to the last day of radiotherapy), followed by 6 cycles of
adjuvant temozolomide (200mg/m² for 5 days during
each 28 days cycles)
 It should be administered in the fasting state at least 1
hour before meal.
 Capsule mustn’t be opened or chewed. For a child who
can not swallow capsule, open the capsule and put the
temozolomide straight to a cup filled with orange juice
and can be given through a gastric tube
PROTOCOL

TEMOZOLOMIDE : 75 mg/ m²/ day

↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓
 Day 1 2 3 4 5 6 7 . . . ………… ….n
RADIOTHERAPY…………………

FOLLOWED 6 CYCLES,
TEMOZOLOMIDE : 200 mg/ m²/day, 28 DAYS CYCLE
↓ ↓ ↓ ↓ ↓
Day : 1 2 3 4 5…………28
Result :
SEX DISTRIBUTION (n=11)

girls, 4
boys, 7
AGE DISTRIBUTION (n=11)

< 5 years old 6-10 years old > 11 years old

B
ra
in
S
te
m
C

2
er
eb
el
lu
m
4

Fo
ss
a 2
M
id
b ra
in
1
TUMOR SITES (n=11)

P
on
s
1

un
kn
o w
n
1
A
na
pl
as
tik
ep
en
d

1
G
er
m
in
om
a

1
G
l io
m
a
5

G
l io
sa
rc
om
a
1

M
ed
ul
lo
b
la
st
o
m
a
3
HISTOPATHOLOGY TYPES (n=11)
TREATMENT MODALITIES (n=11)

1
2

7
2

chemo,radio,acup chemo,radio
serg,chemo,acup serg,chemo,radio
TOXIC EFFECT (n=11)

3 3

3 5

Ane m ia

Le uk ope nia

Trom bocytope nia

Ele ctrolyte im balance
TREATMENT RESPONSE (n=11)

Die
3 Survive
4

Loss to follow up
4
 CONCLUSION

 CBT mostly found in children age

6-10 years old
 The treatment clinically has a good
response
 Temozolomide is well tolerated with
only minimal non cumulative
myelosupresion
SUGGESTION

 Pathology examination should be performed in

every brain tumor surgery
 More study is needed, especially MGMT
(Methyl Guanine Methyl Transferase)
regarding resistance to TMZ