Mostafa EL-HaddadMostafa EL-HaddadM.B.B.ch., Msc., MD., FRCR(UK)., M.B.B.ch., Msc., MD., FRCR(UK).,

Kasr El-Ainy Hospital Cairo University Kasr El-Ainy Hospital Cairo University (NEMROCK(NEMROCK))

20122012

Genetic Syndromes

SyndromeSyndrome TumorsTumors Other Asso.Other Asso. GeneticsGenetics

-Turcot’s-Turcot’s - Glioblast.- Glioblast.

- Medullobla.- Medullobla.

- Colon ca- Colon ca APC gene (5q)APC gene (5q)

A. DominantA. Dominant

-Tuberous -Tuberous SclerosisSclerosis

-Subependymal -Subependymal giant cell giant cell astrocytoma.astrocytoma.

-Hamartomas.-Hamartomas.

-Angiofibromas.-Angiofibromas.

-Hypomelanotic -Hypomelanotic patches.patches.

-M retardation.-M retardation.

-TSC1 and -TSC1 and

TSC2TSC2

-9q and 16p.-9q and 16p.

-A.D-A.D

NF I NF I (commonest of these rare syndromes)

-Neurofibromas.-Neurofibromas.

-Gliomas.-Gliomas.

-Sarcomas.-Sarcomas.

-Café au lait patches.-Café au lait patches.-Lish nodules.Lish nodules.-Neural crest tumors.Neural crest tumors.

NF I Ch 17.NF I Ch 17.

A.D.A.D.

NF IINF II Meningiomas.Meningiomas.

ShwannomasShwannomas

(AN)(AN)

Gliomas(spinal Gliomas(spinal mainly)mainly)

Lens opacity.Lens opacity.

Cerebral calcificationsCerebral calcifications

NF2 on ch22NF2 on ch22

SyndromeSyndrome TumorsTumors Other Asso.Other Asso. GeneticsGenetics

Cowden Cowden Dysplastic Dysplastic gangliocytoma gangliocytoma of cerebellumof cerebellum

-Peripheral -Peripheral hamartomas.hamartomas.

-Breast ca.-Breast ca.

-Thyroid ca -Thyroid ca

-Colorectal ca.-Colorectal ca.

PTEN/MMAC1 PTEN/MMAC1 10q.10q.

A.D.A.D.

Basal NaevusBasal Naevus

(Gorlin’s)(Gorlin’s)

-Medulloblas.-Medulloblas. Basal cell cas.Basal cell cas.

Bone Bone ablnormalitiesablnormalities

Palmar pitsPalmar pits

PTCH ch 9q.PTCH ch 9q.

A.D.A.D.

Von-Hipple lindauVon-Hipple lindau Cerebral and Cerebral and spinal spinal haemangioblahaemangioblastomasstomas

Wilm’sWilm’s VHL g VHL g

Li-FraumeniLi-Fraumeni -Gliomas.-Gliomas.

-PNETS-PNETS

-Sarcomas.-Sarcomas.-Breast.Breast.

P53.P53.

A.D.A.D.

Infratentorial tumors more common in children (infants). Also in midline.

in adults Supratentorail more.

Sex In general male more. Meningioma and Shwannomas more in female Ependymoma and nerve sheath equally

distributed.

Anatomy Circle of Willis. Optic Chiasma.

ANATOMY

Staging AJCC 2002: NO Old TNM M staging and medulloblastoma Biopsy no biopsy.

Commonest Brain Tumor? Brain Metastasis.

Imaging T2 and FLAIR (fluid-attenuated inversion

recovery) images are more sensitive for detecting edema.

For nonenhancing tumors, especially glial neoplasms, the FLAIR sequence and T2 sequences are best for the definition of tumor extent.

WHO Grading Classification idea:

-Neuroepithelial.

-Germ cells.

-Meningeal .

-Etc………

OLIGODENDROGLIOMA WHY SPECIAL?

Brain Alpha-Beta ratio Implication in Dose and fractionation.

General Management

Newer generation anticonvulsants, such as levetiracetam, lamotrigine, and pregabalin that do not affect cytochrome P450 activity are now preferred.

Choose Your Patient Low Grade. High grade. Children.- Boost or No Boost?- Dose escalation in low and High grade

gliomas.- Risk structures.

CT-Simulator

Patient preparation. IV contrast. Treatment position: Supine? Prone?. Neck flexed or extended .WHEN? Fixation methods

Define your target

Margin for Low grade tumors Margin in High grade tumors.

GTV

A central low-density area is evaluated as necrosis and is surrounded by an annular enhancing area corresponding to a densely cellular zone of viable neoplasm called the “rim.” (IF any) The external limit of the rim corresponds to the GTV

GTV In High Grade Glioma

MRI or CT? both with contrast. Best with T1 MRI with contrast.

GTV in Low grade Glioma

CT in Low grade glioma, tumor is non enhancing so its very difficult to delineate.

MRI T1 or T2?

CTV in High Grade Glioma

2-3 cm beyond any existing edema. Which imaging study will you use to

adequately define your edema?? MRI ?? T1 or T2? .

Brain Metastasis

Brain Metastasis

Gaspar et al IJROBP 1997

Factors NOT in The RTOG Prognostic Factors Number of the lesions. Primary site (breast, lung…). Time interval between the Metastasis

and the primary. Location. Neurologic Function. Radiation dose. Tumor response.

Karnofsky scale 100%: Normal no complaints; no evidence of

disease 90%: Able to carry on normal activity; minor

signs or symptoms of disease. 80%: Normal activity with effort; some signs

or symptoms of disease. 70%: Cares for self; unable to carry on

normal activity or to do active work. 60%: Requires occasional assistance, but is

able to care for most of his personal needs.

50%:Requires considerable assistance and frequent medical care.

40%: Disabled; requires special care and assistance.

30%:Severely disabled; hospital admission is indicated although death not imminent.

20%: Very sick; hospital admission necessary; active supportive treatment necessary.

10%: Moribund; fatal processes progressing rapidly.

0 Dead

Value of Whole Brain Irradiation

Increase Median Survival from 1 to 4 months.

Radio-surgery When?

RTOG 9508. RPA class III. RPA class I. Single Mets.

Can we avoid WBI?

EORTC: 22952 –26001. The American Surgeons Oncology

Group. Japanese Radiation Oncology Study

Group.

Landmarks Sella turcica is centrally located and marks

the lower border of the median telencephalon and diencephalon.

Reid's baseline and the Frankfort horizontal plane.

Optic canal runs at most 1 cm superior and 1 cm anterior to that point.

Pineal body 1 cm posterior and 3 cm superior to the external auditory meatus.

What’s FLAIR? Think of the FLAIR sequence as a bit of a

'negative', in that FLAIR will show areas of differing fluid concentration (not blood).

FlAIR are modified T2-weighted sequences on which fluid in motion, such as cerebrospinal fluid, remains dark, whereas tumor or edema remains white.

This sequence is useful for the delineation of periventricular lesions.

MR Spectroscopy

MR spectroscopy is a promising approach for both metabolic and functional evaluation of GTV and CTV. This technique provides information about tumor activity based on the levels of cellular metabolites.

Choline is a neurotransmitter and membrane component that is increased in glioma and the degree of elevation of the choline level correlates with elevation of tumor cell density.

N-acetylaspartate is a neuronal metabolite that is decreased in glioma implying an increase in the choline-to-N-acetylaspartate ratio.

Creatine indicates a cellular energetic process, and lactate is a catabolite of anaerobic metabolism that can be used as a surrogate marker for necrosis or hypoxia.

CT and MRI delineation of GTV and CTV for untreated glioma remains a controversial and difficult issue, mainly because of the discrepancy between real tumor invasion and that estimated by CT or MRI.

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Cranial structures

1.Hard Palate 2.Nasopharynx 3.Sphenoid air sinus 4.Pituitary gland 5.Frontal sinus 6.Frontal lobe 7.Corpus callosum 8.Septum pellucidum 9.Parietal lobe 10.Fourth ventricle 11.Occipital lobe 12.Cerebellum 13.Sinus Confluence 14.Pons 15.Medulla Oblongata •Spinal Cord

High Grade Tumors

Grade 3: Anaplastic astrocytoma and pure and mixed anaplastic oligodendroglioma

Grade 4: Glioblastoma Multiforme

Survival in Months

Anaplastic Oligodendroglioma ~60. Anaplastic Astrocytoma ~36. Glioblastoma Multiforme < 12.

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Grade 4 Astrocytoma 6 cm right posterior

parietal lesion Irregular margins,

infiltrating tumour Rim-enhancing, central

necrosis Mass effect / edema Beware corpus callosum

involvement

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High grade Astrocytoma:Differential Diagnosis Vs abscess

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High grade astrocytoma: DD Abscess. Metastasis. Resolving hemorrhagic stroke. multiple sclerosis, giant plaque. Early-delayed radiation edema can

mimic tumour progression

Glioblastoma Multiforme: 80% of all malignant glioma. Median survival is 9-10 months. 5 yr survival < 5%. Rarely metastasize. >80% failures within 2 cm of original

tumor. Calcification occurs only when the

glioblastoma arose from a low-grade.

Types of GBM

1ry: 2nd:

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Prognostic Factors (for HG Gliomas)

RTOG (Curran.1993)1. Age2. Histology3. KPS4. Mental status5. Duration of symptoms6. Neurologic functioning class,7. Extent of surgery8. Radiation dose All significant predictive factors of

outcome.

favorable group (classes I – II): 12% of all patients; 2YOS of ~ 70%

intermediate group (classes III – IV): 43% of all patients; 2YOS of 10 – 30%

unfavorable group (classes V – VI): 45% of all patients; 2YOS of ~ 5%

RPA For GBM Class III Age: Tumor Type: Mental Status: Performance status:

< 50 GBM KPS 90-100

RPA For GBM Class IV Age: Tumor Type: Mental Status: Performance status:

< 50 GBM KPS <90

RPA For GBM Class IV Age: Tumor Type: Mental Status: Performance status: Treatment

status :

≥50 GBM Good neurologic

function Surgical

resection

RPA For GBM Class V Age: Tumor Type: Mental Status: Performance status:

Treatment status :

≥50 GBM Neurologic function

that inhibits the ability to work

70-100 Surgical resection or

biopsy only followed by at least 54.4 Gy radiotherapy Good neurologic function

Surgical resection

RPA For GBM Class V Age: Tumor Type: Mental Status: Performance status:

≥50 GBM Normal <70

Why The Tumor Enhance? What decrease the enhancement? What increase?

Treatment Surgery: Controversy exists regarding the relationship

between the extent of surgery and survival.

Grossman R, et al: National Comprehensive Cancer Network adult brain tumor practice guidelines. Oncology 11: 237-277, 1997.

Radiotherapy Initially 50 to 60Gy of whole-brain

radiation following surgery significantly increases the median survival of patients with malignant gliomas from 14 to 36.

Partial Brain 60Gy is The Standard

Les études postmortem montrent que dans l’œdème, le risque de présence de cellules tumorales est surtout important dans les 20 mm avoisinant le volume tumoral macroscopique.

Le risque d’extension pour les formes profondes dans les noyaux gris et surtout les fibres longues associatives (corps calleux et capsule) est important et peu évalué.

The exact volume of treatment is controversial and may be based either on contrast- enhancing disease or T2 changes with a margin or a combination of both.

Unit A Protocol

A typical treatment schema might include 45 to 46Gy administered to T2 changes on MRI with a 1- to 2-cm margin, with an additional boost of 14 to 15Gy to the area of contrast enhancement with a margin.

Edema or NOT

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Temozolamide

ASCO 2004 NEJM (Stupp et al) RCT (concomitant + adjuvant TMZ and RT versus RT

alone) RT (6000 cGy in 30 fractions - retina limited to 50 Gy,

brainstem and chiasm limited to 54 Gy) TMZ (concomitant) 75 mg/m2

(weekly CBC; Septra prophylaxis for PCP-consider for lymphocyte count <500)

TMZ (adjuvant) 150-200 mg/m2 daily x 5 d, q 28 d

( 6cycles ).

Irradiation Volume in Stupp Trial

GTV plus 2 to 3 tumor margin for CTV.

MGMT Story

Temozolamide

DNA

YEBAWAZOH

YENKEZOH

MGMT

LAW BAwaZ MYNE YENKEZ DNA

YEMOUT

Adjuvant Chemotherapy Rules of Adjuvant Treatment: 1- All known tumor should be removed. 2- Effective chemotherapy must be

available 3- Chemotherapy Start as soon as

possible after surgery Give at maximum tolerated dose Continue for limited time

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Define Parinauds syndrome

Parinaud’s syndromeDecreased upward gazeDissociation near-light (i.e., limited restriction to light

but retained response to accommodation)Diminished convergence

caused by pressure into superior colliculi and lateral geniculate nuclei.

Other signs of pineal gland tumor: diplopia, visual defect, papilledema, ↓visual activity

Hypofractionation schedules are also used in selected patients. This approach shortens the treatment time without substantially compromising survival.

Treatment Challenges

The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium

Meningioma Imaging: MRI? CT which is better?

WHO Classification

Grade I or benign meningiomas:

low mitotic index (90% of all meningiomas). Grade II or atypical meningiomas:

higher mitotic index (>4 mitosis per 10 HPF) (5%–7% of all meningiomas).

Grade III or malignant meningiomas:

highest mitotic index (>20 per 10 HPF)

(1%–3% of all meningiomas).

Grade I meningioma does not metastasize. Rarely grade II and III meningioma may

metastasize outside of the central nervous system, especially in advanced or recurrent diseases.

Treatment

Watch and Wait: small asymptomatic. Surgery: Complete is the Goal.

Simpson Criteria

The 10-year recurrence rate is 9% for patients with a Simpson Grade of 1, compared to a 10-year recurrence rate of 29% for patients with a Simpson grade of 3 (Level IV) (Simpson 1957).

Simpson Criteria

Radiotherapy

GI completely resected

GI incomplete resection

GII or GIII

Partial resection plus RT equal to complete resection.

Technique

The gross tumor volume (GTV) should be determined by fusion of the T1-weighted contrast- enhanced MRI with the planning CT (Grade B).

The tumor volume is best determined by comparing preoperative and postoperative findings of a contrast-enhanced MRI of the brain.

MRI defined meningioma volumes could be larger but not inclusive of CT defined volumes, thus CT scan and MRI are complementary for the purpose of tumor delineation (Khoo et al. 2000).

Adjuvant radiation therapy The GTV for adjuvant radiation of WHO Grade I meningioma can include the postoperative residual tumor only.

For atypical and malignant meningioma (i.e., WHO

grade II and III), GTV should include the entire tumor bed on the pre- operative MRI.

Dose: 50 to 54Gy for GI.

Up to 60 for GII and III.

Meningioma and Hormonal Therapy

Approximately 70% of meningiomas are progesterone receptor positive and 30% are estrogen receptor positive (Sanson 2000).

Should we use it??

Biotherapy and Chemotherapy

FASHAL !!

Low grade Gliomas

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LOW GRADE GLIOMAS

PATHOLOGY (WHO) Astrocytic Tumors1. Astrocytomas 70%

i. fibrillaryii. protoplasmiciii. gemistocytic

2. Pilocytic astrocytomas3. Pleomorphic xanthoastrocytomas4. Subependymal giant cell 5. astrocytomas Oligodendroglial Tumors Mixedoligoastrocytoma

Grade (based on):

1. nuclear abnormalities

2. Mitoses

3. endothelial proliferation

4. necrosis. Mayo system adds the

number of features found above. I=0, II=1, III=2, IV=3-4.

Kernohan is another major grading system.

Histological Types

GI: Pilocytic Astrocytoma. GII: mainly astrocytoma and

oligodendroglioma.

Median Survival ~ Low Grade Oligodendroglioma ~120 mo.

Low Grade Astrocytoma ~60 mo.

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Low Grade Glioma

Little or no mass effect

Absence of enhancement

Sometimes better seen on T2 MRI

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Low Grade glioma: T1 vs T2

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Low Grade Oligodendroglioma

Mass effect

Enhancement

Oligodendroglioma Story

May survive up to 10 years. 40 to 80% may have 1p 19 q loss. Tumor without the loss ……lost. Oligodendroglioma, oligoastrocytoma?.

Ependymoma Story

Infratentrial vs Supratentorial.

Treatment Watch and Wait. Surgery. Radiotherapy? Immediate Vs deferred.

Radiotherapy

EORTC 22845: Karim et al 2002 IJROBP.

EORTC 22845 OAS

EORTC 22845 PFS

37 % Vs 44 % p= 0.02. Median time to progression was longer.

Low Vs High Dose of RT

EORTC 22844

It was conducted during the same time interval as EORTC 22845. “Believers” in postoperative RT entered their patients on 22844, whereas RT “nonbelievers” entered patients on 22845.

Eligibility criteria and stratification factors were the same as EORTC 22845.

NCCT Vs RTOG Vs ECOG 50.4Gy Vs 64.8 Gy.

Histology Differ

Size of The Tumor Differ

Radiotherapy

Below 40 ys. Above 40 years. Chemotherapy When?

Tumor location and Manifestations

Abulia: loss of ability to take independent decisions.

Temporal Lobe tumors: memory loss.

Radiotherapy EORTC 22845 is the only randomized

trial in low- ]grade glioma to compare immediate RT with deferred treatment (including radiotherapy) at the time of progression (Level I)

(Van den Bent et al. 2005).

Dose of Radiotherapy

IEORTC 22844 379 patients were randomized to receive 45 Gy in 5 weeks or 59.4 Gy in 6.6 weeks (Level I)

(Karim et al. 1996).

Pilocytic Astrocytoma

Surgery only. Radiotherapy in incomplete resection

symptomatic progressive only.

Intracranial Germinoma

Midline tumor. Pineal body, suprasellar. Disseminate.

Treatment strategy

1- Craniospinal irradiation. 2- Lower dose of CSI. 3- Reduce volume strategies: whole

ventricular or localized plus chemotherapy.

Dose reduced from 30Gy to 24 Gy in 15 fractions of 1·6Gy followed by a focal boost to the primary tumour area of either 15 Gy or 16 Gy in ten fractions, which lowered the total primary tumour dose from 45 Gy to 40 Gy

The national recommended approach in Germany and the UK.

Proton Therapy