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NEURO - ONKOLOGI

dr. TW. Yuliati Sp.S, M.Kes

Sifat Tumor :
1. Maligna
2. Benigna
Lokasi :
1. Sistem Saraf Pusat - 1.1. Otak
- 1.2. Med.
Spinalis
2. Sistem Saraf Tepi
Asal Tumor :
1. Primer
2. Metastasis

Tumor Otak : Tumor yang berkembang dalam


ruang kranium. Dapat berasal dari jaringan otak
itu sendiri maupun struktur sekitarnya, seperti:
selaput otak
pembuluh darah
sel-sel embrionik
tulang
saraf kranial
glandula pituitary
jaringan otak
Frekuensi tumor berbeda tgt jenisnya
Ada predileksi ttt yang menimbulkan sindrome ttt.
Pertumbuhan dan invasivitas mempengaruhi penampilan klinis

Tabel 1. Tipe Tumor Jaringan Saraf


Tumor
Glioma (41%)
Glioblastoma multiforme
Astrocytoma
Ependymoma
Medulloblastoma
Oligodendrocytoma
Meningioma (17%)
Pituitary adenoma (13%)
Neurinoma (Schwannoma) (12%)
Metastatic carcinoma
Craniopharyngioma, dermoid, epidermoid, teratoma
Angioma
Sarcoma
Unclassified (mostly glioma)
Miscellaneous (pinealoma, chordoma, granuloma, lymphoma)
Total

Persentase
20
10
6
4
5
15
7
7
6
4
4
4
5
3
100

TANDA & GEJALA

MEKANISME TANDA KLINIK TUMOR

1. Kompresi pd jaringan neuronal


2. Infiltrasi / invasi langsung pd jar neuronal
3. Gangguan pembuluh darah
4. Gangguan eksitabilitas
5. Penekanan efek massa
6. Gangguan sirkulasi aliran LCS
(Spencer, 1989)

Mechanism
1. Space occupying lesion
2. Ventricle compression
3. Destruction

Cerebral oedem
Vasogenic
Sitotoksik
Interstitial

EDEMA OTAK (Padmosantjojo, 2000)


Vasogenik: Kerusakan vaskulatur endotel kapiler,
gangguan Tight Junctions, permeabilitas naik
Sitotoksik: Intact Barier Edema, Gangguan pompa
Na-K-ATPase, Natrium intrasel naik
Interstisial: Transudasi
TIK Meningkat (Padmosantjojo, 2000)
Doktrin Monroe Kellie VKS:
V darah (150) + VLCS (150) + V otak (1200)
TIK meningkat bila tidak ada keseimbangan
Volume KS dengan wadahnya

BRAIN SWELLING

HYPODENSE SWELLING
VASOGENIC
OEDEMA

ISODENSE SWELLING
DYSAUTOREGULATION

Gejala Tumor Supratentorial


Due to increase ICP
- From mass effect of tumor and/or edema
- From blockage of CSF drainage(hydrocephalus)
Focal deficit: weakness, dysphasia
- Due to destruction of brain parenchym
- Due to compression of brain parenchyma
- Due to compression of cranial nerve
Headache
Seizure
Mental status changes (depression, lethargy,
apathy, confusion)
Symptoms suggestive of a TIA

Gejala Tumor Infratentorial


Peningkatan tek.intrakranial krn hidrosefalus:
Nyeri kepala
Mual / muntah : akibat peningkatan TIK
dari hydrosefalus atau penakanan langsung pada
nukleus vagal atau area postrema (pusat muntah)
Papilledema
Ataxia / ggn berjalan
Vertigo
Diplopia : nervus VI palsy

Mechanism of symptoms and signs


Invasion, irritation, replacement of normal tissue
Probably accounts for a minority of symptoms
Characteristic of low-grade infiltrating gliomas
Tumor growth compresses normal tissues
Shifts of normal brain structures
Compression of blood vessels causes ischemia
New vessels formed with no bloodbrain barrier

Symptoms and signs caused by brain tumors depend on


the location of the tumor and histopathology (rapidity of
growth) What are these signs and symptoms?
Generalized largely due to increased ICP
Focal result of compression and/or ischemia of normal brain
at the site of the tumor
False localizing neurologic abnormalities occurring at a
distant site from the tumor due to shifts of cerebral structures

Gejala Tumor otak (Crow, 2001)


Def.Neurologis
Neurologis
Def.
progresif(70%)
(70%)
progresif

Destruksiatau
atau
--Destruksi
kompresilangsung
langsung
kompresi
Kompresiakibat
akibat
--Kompresi
massa,edema
edema
massa,

Nyerikepala
kepala
Nyeri
(>50%)
(>50%)

Memburukdidi
Memburuk
pagihari
hari
pagi

Invasiatau
ataukompresi
kompresi
--Invasi
TIKtinggi
tinggi
--TIK
Sekunderatau
atau
--Sekunder
psikogenik
psikogenik

Kejang(15(15Kejang
20%)
20%)

Gangguan
Gangguan
eksitabilitasneural
neural
eksitabilitas

Gejala Klinik Tumor otak (DeAngelis, 2001)

- Demensia
- Ggn mood
- Ggn perilaku
- Inkontinensia
- disfungsi olfaktorius
- Disfungsi opticus

- Contralateral limb weakness


- Contralateral sensory loss
- Disfasia
- Disleksia, disgrafia, diskalkulia
- Disorientasi spasial

Hemianopsia
Homonim
Kontralateral

- Ggn bahasa
- Ggn memori
- Ggn mood
- Ggn perilaku
- Hearing & vision
pathways

- Ggn saraf kranial


- Ggn fx vital

Nistagmus
Disartria
Ataksia

(Wilkinson, 1997)

Headache features suggestive of a spaceoccupying lesion (Dodick, 1997)


Subacute and progressive
New onset in adult life (>40 yr of age)
Association with any of the following:
Nausea/ vomiting
Nocturnal occurrence or morning awakening
Worsening by changes in posture
Confusion, seizures, or weakness
Any abnormal neurologic sign

KARAKTERISTIK NYERI KEPALA SOP

1.Tidak terlokalisir dengan baik


2.Perjalanan penyakit subakut progresif
3.Intensitas sedang sampai berat
4.Resisten terhadap analgetik biasa
(Dodick, 1997)

KARAKTERISTIK NYERI KEPALA SOP


1. memberat pada pagi hari
(akibat hipoventilasi selama tidur)
2. memberat dengan batuk, ketegangan
3. kepala harus diposisikan tertentu (30% kasus)
4. disertai dengan mual dan muntah (40% kasus)
( stl muntah, akibat hiperventilasi)
(Greenberg, 2001)

NYERI KEPALA YG PERLU PERHATIAN


1. Perjalanan penyakit subakut progresif
2. Onset usia dewasa tua ( > 40 tahun )
3. NK disertai tanda-tanda:
- mual/muntah tanpa peny.sistemik
- memberat pada dini hari
- memberat dengan perubahan posisi
- disertai kejang, kelemahan, pe
kesadaran, tanda neurologis abnormal
(Dodick, 1997)

STRUKTUR PEKA NYERI DI KEPALA


1. Sinus venosus dan cabang kortikalnya
2. Arteria besar di otak
3. Duramater yang melingkupi dasar anterior &
fossa posterior
4. N. craniales V, IX, X
5. Saraf spinal: n. cervical I, II, III
(Gilroy, 2000)

Gejala Tumor Otak


Gangguan kesadaran
Gejala umum (muntah, kejang, perasaan
abnormal pada kepala, dan gangguan mental)
Tanda lokalisatorik yg menyesatkan
paresis N. cranial (tersering n III, IV,VI),
refleks patologis positif
gangguan mental
gangguan endokrin dan ensefalomalasia
Tanda lokalisatorik yg benar / gejala fokal
kejang fokal
gangguan penghiduan dan pengecapan
tinitus, afasia, apraksia, astereognosis,
gangguan penglihatan / medan penglihatan

Gejala saat px
Defisit neurologis

Persentase
pasien
Persentase

Hemiparesis

61 - 83 %

Papiledema

32 - 66 %

Gangguan kesadaran

18 - 40 %

Afasia

25 - 32 %

Headache
Increased ICP : tumor mass effect,
hydrocephalus, mass effect from associated
edema or hemorrhage
Invasion or compression of pain sensitive
structures : dura, blood vessels, periosteum
Secondary to difficulty with vision : diplopia,
difficulty focusing
Greenberg (2001)

Etiology and Risk Factors


Genetic
Familial
Several inherited disease

Environmental
Irradiation
Severe head trauma
Chronic exposure of the petrochemicals

ETIOLOGI TUMOR GANAS (Tjokronagoro, 2000)


Kongenital
Onkogen sejak lahir (retinoblastoma)
Karsinogenik
Benzopyren, Nitrosamine, alfatoxin
Virus
Ca. Nasofaring, Ca. Hepar, Ca. Cervix
Trauma Kronis Sinar radiasi dan ultraviolet
ASSOCIATION WITH HUMAN CANCERS
1. Growth Factor Receptor
Increased numbers in 20 percent of breast cancers

2. Ras Protein
Activated by mutations in 20 to 30 percent of cancers

3. Abl Kinase
Activatied by abnormal chromosomes in chronic myelogenous leukemia

4. Src Kinase
Activated by mutations in 2 to 5 percent of cancers

5. pRB Protein
Mutated or deleted in 40 percent of cancers

6. p53 Protein
Mutated or deleted in 50 percent of cancers

Treatment
Supportive
Corticosteroid
Anticonvulsant

Definitive
Surgery
Radiation
Radionecrosis
Chemotherapy

Treatment method for Brain Tumor (Flower, 2000)

Corticosteroids
These agents reduce edema around tumor, frequently leading to
symptomatic and objective improvement in symptoms

Drug Name

Dexamethasone (Decadron, Dexasone) -- Postulated


mechanisms of action of corticosteroids in brain tumors
include reduction in vascular permeability, cytotoxic
effects on tumors, inhibition of tumor formation, and
decreased CSF production.

Adult Dose

16 mg/d PO/IV divided q6h in significant peritumoral


edema; continue until patient shows improvement; taper
to discontinue or to minimum effective dose

Pediatric Dose

Contraindications

0.15 mg/kg/d PO/IV divided q6h

Documented hypersensitivity; active bacterial or fungal


infection; peptic ulcer disease; psychosis; hypertension

Estrogen antagonists
Inhibit effects of estrogen by competitively binding to estrogen
receptor
Drug Name

Tamoxifen (Nolvadex) -- Competitively binds to estrogen


receptor, producing a nuclear complex that decreases
DNA synthesis and inhibits estrogen effects.

Adult Dose

Reports of tamoxifen in malignant meningiomas


recommend 40 mg/m2 PO bid for 4 d; then, 10 mg PO bid
for 10 d (not a standard protocol but in the treatment of
meningiomas remains experimental)

Pediatric Dose

Contraindications

Not established

Documented hypersensitivity; leukopenia,


thrombocytopenia, or on anticoagulant therapy (can
increase prothrombin time); women with dysmenorrhea,
cataracts secondary to risk of corneal and retinal damage;
hyperlipoproteinemia; menstrual irregularity;
thromboembolic disease; or visual disturbance

Progesterone antagonists
RU-486 has been used experimentally in the treatment of this
medical condition

Drug Name

RU-486 -- Experimental antiprogesterone agent.


Used in patients with recurrent benign
meningiomas; in one study of 14 patients, tumor
regression was reported in 5 of 14 patients.

Adult Dose

200 mg PO bid

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Tumor yang metastasis ke otak berasal dari:


lung cancer
>40%
breast
40%
renal cell
7%
GI
6%
melanoma
3%
Undetermined
4%

Most common tumor is lung cancer small cell


tumors metastasize more commonly
Metastases to the dura more frequently from
breast, prostate or lymphoma
Leptomeningeal mets often from breast, lung,
melanoma, lymphoma
Melanoma higher frequency of hemorrhagic
tumors, higher frequency of presentation with a
met, commonly results in multiple mets
Breast cancer is the most frequent tumor to
metastasize to the pituitary gland
The most common way of metastatic spread is hematogenous

Inherent chemoresistance of tumors :


Primary tumors less responsive than metastatic
Specific metastases differ in response:
melanomas very radioresistant
breast or lung metastases show better response
Possible clonal selection in metastatic lesions of
previously treated systemic tumors

Approach to Treatment
Medical treatment
Surgery
Radiation
Chemotherapy
Palliative treatment

Approach to Treatment

The most important factors


determining the options for treatment
of brain metastases are:

Number of metastases
Control of the primary tumor
Extent of the extracranial metastases
Age
Performance Status (Karnovsky)

Medical treatment
Anticonvulsants
When seizures are a symptom of disease
Little role as prophylaxis
Steroids
Important in treatment, help relieve symptoms of mass effect
Minimize long term use given side effects

Surgical treatment
Biopsy:
Open brain biopsy
Stereotactic biopsy
Frame-based: BRW, CRW, Leksell
Frameless

Advantage:
Diagnosis:
No known primary
Known primary Important role for bx

Low morbidity

Surgery
Tumor resection best recommended in:
Surgically accessible lesions, particularly if >3cm
Symptomatic lesions with evidence of mass effect
Posterior fossa lesions
single, accesible brain met with no LM dissemination
life expectancy > 3mths
Karnofsky >70
not a radiosensitive tumour (e.g., small cell)

Biopsy or Resection?
Biopsy indicated for:
Deep lesions
Multiple lesions
Patients otherwise too debilitated, medically unfit
Poor Karnofsky performance score

Advantages:
Diagnosis
Relief of mass effect
Improved outcomes over biopsy alone, and when used in conjuction with
radiation

Disadvantages:
Morbidity of procedure
Morbidity minimized with the use of intraoperative aids:
Intraoperative image guidance
Awake craniotomi

Radiation
Whole Brain radiation
Radiosurgery

Whole Brain Radiation


Commonest treatment particularly since majority of patients
present with multiple lesions
Several large scale multi-institutional trials by the Radiation
Oncology Therapy Oncology (RTOG) studying the effect of dose
and schedule
No significant difference in frequency and duration of response for
total radiation doses between 20 Gy/1wk to 50 Gy/4wk
Effectiveness depends partly to tumor histology poorer
response in radioresistant tumors eg. melanoma, renal cell ca

Side Effects
Exposure of radiation to the whole brain
Acute:
Transient worsening of neurological symptoms
Nausea, vomiting
Dry desquamation, hair loss, otitis
Thought to be due to distorted cerebrovascular autoregulation and increased
capillary permeability

Somnolence syndrome: 1-4 months post Rx


Delayed:
Long term survivors may develop neurological symptoms related to radiation
necrosis
Seen more frequently with high dose per fractions
Leukoencephalopathy
Dementia, ataxia

Chemotherapy
Effectiveness of chemotherapeutic agents depends on
Ability to treat specific tumor
Ability to cross the BBB

Timozolamide
Alkylating agents with better BBB penetration
Additive/synergistic activity in combination with other chemo
agents

Recurrent Metastases
Further CNS progression often accompanied by decline in KPS
More limited therapeutic options
Surgery
Radiation

Role of surgery for treatment of recurrent metastatic disease


controversial

Single lesion
Surgically
accessible

Surgery
WBRT

Deep lesion
>3cm, multiple lesions,
poor KPS

WBRT

Deep lesion
<3 cm

Radiosurgery
+/- WBRT

Imaging

Low-grade astrocytoma
T2-weighted image shows a
high-signal-intensity lesion
with well-defined margins,
no surrounding edema, and
little mass effect

Glioblastoma crossing the


corpus callosum
Coronal T2-weighted scan
shows high intensity in the left
and right centrum semiovale
(white arrows) and extension of
tumor across the corpus
callosum (open arrows)

Metastases
Axial T2-weighted scan
demonstrates three large
masses (arrows) surrounded
by extensive high-signal
edema

Eisenberg & Ronald (2003)

Imaging

Glioblastoma multiforme
Thick irregular ringenhancing lesion
associated with a large amount of
surrounding low-attenuation edema

Cystic astrocytoma
Hypodense mass with a thin rim of contrast
enhancement

Eisenberg & Ronald (2003)

Summary
Prognosis for patients with brain metastases remains poor
Single lesions in patients with good prognostic factors should
preferably be treated surgically, followed by Rx
Surgically inaccessible lesions benefit from radiosurgery
Multiple controversies remain, for which adequate randomized
controls are necessary
Upcoming role for new chemotherapeutic agents (Timozolamide)

Metastatic Tumor of
Spine

Metastasis
Cancer metastasis: lung, liver, bone
bone metastasis origin: lung, breast, prostate, renal,
thyroid
Spine is the most common site of bone metastasis
L-spine: most common
Batsons plexus

Metastasis
Pathway of Metastasis:
arterial, direct extension, lymphatic, venous
epidural venous plexus--Batsons plexus
cancellous bone micro-environmental necessary
cortical bone invasion secondarily

Diagnosis
Bone scan:
nonspecific, identify for biopsy position

MRI: (take place myelography)


most complete information
T1 low signal; T2 slight higher sign (loss of fatty marrow)

Biopsy:
suspecious x-ray; tissue for hormonal evaluation
95% accuracy; 75% success rate
complication:
pneumo- / hemo- throax
excessive bleeding
neurologic injury

Diagnosis

winkling owl sign

Melanoma with T-spine metastasis

From Essential of Skeletal Radiology p986

Non-Operative Treatment
Steroid:
reduce edema, pain relief; not motor recovery
dexamethasone IV bolus 100mg
followed by 96mg/day in four divided doses for 3
days
tapered over 2 weeks; > 3 weeks, steroid toxicity

Radiotherapy: pain relief: 80-90%

Operative Treatment
Indications and Goals:
intractable pain unresponsive to nonoperative
progressive neurologic change
radioresistant tumor
specimen for histologic diagnosis
decompression with debulking of tumor mass
spinal instability, body major destruction
collapse > 50%, body involve > 50%, posterior element

Kemoterapi Temozolomide

Farmakokinetik

Hvizdos & Goa (1999)

Semoga Bermanfaat
Jazakumulloh Khoiron