TEMOZOLOMIDEIN 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

7

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

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.

11

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

Volume 352:987-996 March 10, 2005 Number 10

12

13

Radiotherapy plus Concomitant and Adjuvant

Temozolomide for Glioblastoma

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)

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

Incident of Childhood Cancer in

“Dharmais” Cancer Hospital 2007-2008

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, 4boys, 7

AGE DISTRIBUTION (n=11)

1

7

3

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

TUMOR SITES (n=11)

2

4

2

1 1 1

Brain

Ste

m

Cerebel

lum

Fossa

Mid

brain

Pons

unknow

n

HISTOPATHOLOGY TYPES (n=11)

1 1

5

1

3

Anapla

stikep

end

Germ

inom

a

Glio

ma

Glio

sarcom

a

Medullo

blast

oma

TREATMENT MODALITIES (n=11)

1

2

7

2

chemo,radio,acup chemo,radio

serg,chemo,acup serg,chemo,radio

TOXIC EFFECT (n=11)

5

33

3

Anemia

Leukopenia

Trombocytopenia

Electrolyteimbalance

TREATMENT RESPONSE (n=11)

Survive

4

Loss to follow up

4

Die

3

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