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Mostafa EL-Haddad, Msc., MD., FRCR(UK)., Kasr El-Ainy Hospital Cairo University (NEMROCK) 2012.

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Presentation on theme: "Mostafa EL-Haddad, Msc., MD., FRCR(UK)., Kasr El-Ainy Hospital Cairo University (NEMROCK) 2012."— Presentation transcript:

1 Mostafa EL-Haddad, Msc., MD., FRCR(UK)., Kasr El-Ainy Hospital Cairo University (NEMROCK) 2012

2 Genetic Syndromes

3 SyndromeTumors Other Asso. Genetics -Turcots - Glioblast. - Medullobla. - Colon ca APC gene (5q) A. Dominant -Tuberous Sclerosis -Subependymal giant cell astrocytoma. -Hamartomas.-Angiofibromas. -Hypomelanotic patches. -M retardation. -TSC1 and TSC2 -9q and 16p. -A.D NF I NF I (commonest of these rare syndromes)-Neurofibromas.-Gliomas.-Sarcomas. -Café au lait patches. -Lish nodules. -Neural crest tumors. NF I Ch 17. A.D. NF II Meningiomas.Shwannomas(AN) Gliomas(spinal mainly) Lens opacity. Cerebral calcifications NF2 on ch22

4 SyndromeTumors Other Asso. Genetics Cowden Dysplastic gangliocytoma of cerebellum -Peripheral hamartomas. -Breast ca. -Thyroid ca -Colorectal ca. PTEN/MMAC1 10q. A.D. Basal Naevus (Gorlins)-Medulloblas. Basal cell cas. Bone ablnormalities Palmar pits PTCH ch 9q. A.D. Von-Hipple lindau Cerebral and spinal haemangiobla stomas Wilms VHL g Li-Fraumeni-Gliomas.-PNETS-Sarcomas. -Breast. P53.A.D.

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

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

7 Anatomy Circle of Willis. Optic Chiasma.






















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

30 Commonest Brain Tumor? Brain Metastasis.

31 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.

32 WHO Grading Classification idea: -Neuroepithelial. -Germ cells. -Meningeal. -Etc……… OLIGODENDROGLIOMA WHY SPECIAL?

33 Brain Alpha-Beta ratio Implication in Dose and fractionation.

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

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

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

37 Define your target Margin for Low grade tumors Margin in High grade tumors.

38 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

39 GTV In High Grade Glioma MRI or CT? both with contrast. Best with T1 MRI with contrast.

40 GTV in Low grade Glioma CT in Low grade glioma, tumor is non enhancing so its very difficult to delineate. MRI T1 or T2?

41 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?.

42 Brain Metastasis



45 RPA Class I KS70. Primary: controlled. Age 65. No extra- cranial metastasis. MS 7.1 RPA Class II KPS 70 Primary: Uncontrolled And/or Age 65 And/or Extra-cranial metastasis MS 4.3 RPA Class III KPS <70 MS 2.3 Gaspar et al IJROBP 1997

46 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.

47 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.

48 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

49 Value of Whole Brain Irradiation Increase Median Survival from 1 to 4 months.

50 Radio-surgery When? RTOG RPA class III. RPA class I. Single Mets.

51 Can we avoid WBI? EORTC: – The American Surgeons Oncology Group. Japanese Radiation Oncology Study Group.

52 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.

53 Whats 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 modied T2-weighted sequences on which uid in motion, such as cerebrospinal uid, remains dark, whereas tumor or edema remains white. This sequence is useful for the delineation of periventricular lesions.

54 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.

55 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.

56 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.

57 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.

58 58

59 59

60 60 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 16.Spinal Cord

61 High Grade Tumors Grade 3: Anaplastic astrocytoma and pure and mixed anaplastic oligodendroglioma Grade 4: Glioblastoma Multiforme

62 Survival in Months Anaplastic Oligodendroglioma ~60. Anaplastic Astrocytoma ~36. Glioblastoma Multiforme < 12.

63 63 Grade 4 Astrocytoma 6 cm right posterior parietal lesion Irregular margins, infiltrating tumour Rim-enhancing, central necrosis Mass effect / edema Beware corpus callosum involvement

64 64 High grade Astrocytoma: Differential Diagnosis Vs abscess

65 65 High grade astrocytoma: DD Abscess. Metastasis. Resolving hemorrhagic stroke. multiple sclerosis, giant plaque. Early-delayed radiation edema can mimic tumour progression

66 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. Calcication occurs only when the glioblastoma arose from a low-grade.

67 Types of GBM 1ry: 2 nd :

68 68 Prognostic Factors (for HG Gliomas) RTOG (Curran.1993 ) 1. Age 2. Histology 3. KPS 4. Mental status 5. Duration of symptoms 6. Neurologic functioning class, 7. Extent of surgery 8. 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%


70 RPA For GBM Class III Age: Tumor Type: Mental Status: Performance status: < 50 GBM KPS

71 RPA For GBM Class IV Age: Tumor Type: Mental Status: Performance status: < 50 GBM KPS <90

72 RPA For GBM Class IV Age: Tumor Type: Mental Status: Performance status: Treatment status : 50 GBM Good neurologic function Surgical resection

73 RPA For GBM Class V Age: Tumor Type: Mental Status: Performance status: Treatment status : 50 GBM Neurologic function that inhibits the ability to work Surgical resection or biopsy only followed by at least 54.4 Gy radiotherapy Good neurologic function Surgical resection

74 RPA For GBM Class V Age: Tumor Type: Mental Status: Performance status: 50 GBM Normal <70

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

76 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: , 1997.

77 Radiotherapy Initially 50 to 60Gy of whole-brain radiation following surgery signicantly increases the median survival of patients with malignant gliomas from 14 to 36. Partial Brain 60Gy is The Standard

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

79 Le risque dextension pour les formes profondes dans les noyaux gris et surtout les bres longues associatives (corps calleux et capsule) est important et peu évalué.

80 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.

81 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.

82 Edema or NOT


84 84 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) mg/m2 daily x 5 d, q 28 d ( 6cycles ).

85 Irradiation Volume in Stupp Trial GTV plus 2 to 3 tumor margin for CTV.


87 MGMT Story




91 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

92 92 Define Parinauds syndrome Parinauds syndrome Decreased upward gaze Dissociation 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

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



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

97 Meningioma Imaging: MRI? CT which is better?

98 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).


100 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.

101 Treatment Watch and Wait: s mall a s ymptomatic. Surgery: Complete is the Goal.

102 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).

103 Simpson Criteria

104 Radiotherapy GI completely resected GI incomplete resection GII or GIII

105 Partial resection plus RT equal to complete resection.

106 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 ndings of a contrast-enhanced MRI of the brain.

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

108 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.

109 Meningioma and Hormonal Therapy Approximately 70% of meningiomas are progesterone receptor positive and 30% are estrogen receptor positive (Sanson 2000). Should we use it??

110 Biotherapy and Chemotherapy FASHAL !!



113 Low grade Gliomas

114 114 LOW GRADE GLIOMAS PATHOLOGY (WHO) Astrocytic Tumors 1. Astrocytomas 70% i. fibrillary ii. protoplasmic iii. gemistocytic 2. Pilocytic astrocytomas 3. Pleomorphic xanthoastrocytomas 4. 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.

115 Histological Types GI: Pilocytic Astrocytoma. GII: mainly astrocytoma and oligodendroglioma. Median Survival ~ Low Grade Oligodendroglioma ~120 mo. Low Grade Astrocytoma ~60 mo.

116 116 Low Grade Glioma Little or no mass effect Absence of enhancement Sometimes better seen on T2 MRI

117 117 Low Grade glioma: T1 vs T2


119 119 Low Grade Oligodendroglioma Mass effect Enhancement

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

121 Ependymoma Story Infratentrial vs Supratentorial.

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

123 Radiotherapy EORTC 22845: Karim et al 2002 IJROBP.


125 EORTC PFS 37 % Vs 44 % p= Median time to progression was longer.

126 Low Vs High Dose of RT EORTC 22844

127 It was conducted during the same time interval as EORTC Believers in postoperative RT entered their patients on 22844, whereas RT nonbelievers entered patients on Eligibility criteria and stratication factors were the same as EORTC


129 NCCT Vs RTOG Vs ECOG 50.4Gy Vs 64.8 Gy.

130 Histology Differ

131 Size of The Tumor Differ

132 Radiotherapy Below 40 ys. Above 40 years. Chemotherapy When?

133 Tumor location and Manifestations Abulia: loss of ability to take independent decisions. Temporal Lobe tumors: memory loss.

134 Radiotherapy EORTC 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).

135 Dose of Radiotherapy IEORTC patients were randomized to receive 45 Gy in 5 weeks or 59.4 Gy in 6.6 weeks (Level I) (Karim et al. 1996).

136 Pilocytic Astrocytoma Surgery only. Radiotherapy in incomplete resection symptomatic progressive only.

137 Intracranial Germinoma Midline tumor. Pineal body, suprasellar. Disseminate.

138 Treatment strategy 1- Craniospinal irradiation. 2- Lower dose of CSI. 3- Reduce volume strategies: whole ventricular or localized plus chemotherapy.


140 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.



143 Proton Therapy

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