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APPROACHING TOWARDS
NEURO-ONCOLOGY & ROLE OF
RADIOTHERAPY
6/24/2018 1
DR KANHU CHARAN PATRO
RADIATION ONCOLOGIST
M.D,D.N.B[RT],FAROI[USA],MBA[ICFAI],PDCR,CEPC
6/24/2018 2
O
N
O L
Y
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M
G
C
H
R
I
C
G
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P
E
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S P E C I
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VISAKHAPATNAM,1/7-MVP[AP]
36/24/2018
46/24/2018
Statistics
• Near 10 million new cases are
detected each year
• Near 20 million people living with
cancer in the world today
• Near 7 million people will die from
cancer
• Every day, around 1700 Americans
die of the disease
• 1 in 3 people will be diagnosed with
cancer in the UK and
• 1 in 4 will die from their disease
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Lung
Breast
Colon/Rectum
Stomach
Liver
Prostate
Cervix uteri
Oesophagus
Bladder
Non-Hodgkin
Lymphoma
Leukaemia
Oral cavity
Pancreas
Kidney
Ovary
1000 800 600 400 200 0 200 400 600 8001000
Men Women
From: D.M. Parkin The Lancet Oncology 2: 533-543 (2001)
(Thousands)
Incidence
Mortality
337
293
105
0370
241
318
446
234
165
166
471
233
133
111
76
33
121
68
113
86
47
97
101
101
34
71
192
114
810
902
558
405
255
499
398
384
204
543
279
260
227
99
93
167
144
109
81
170
116
112
57
119
5.3 million cases
3.5 million deaths
4.7 million cases
2.7 million deaths
The Global Burden of Cancer 2000
66/24/2018
Levels of evidence
 Level I=large double blind RCTs, or, meta-analysis of sma
RCTs , with clinically relevant outcomes
I a=evidence from meta-analysis of RCT
I b=evidence from at least 1 RCT
 Level II=small RCTs, non-blinded RCTs
II a=evidence from one well designed non-RCT
II b=evidence from one well-designed quasi-
experimental study
 Level III=observational [cohort ] studies , case-
control studies , non-RCTs
 Level IV=opinion of expert committees,
or Rspected authorities
 Level V=expert opinion
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? ?
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Neuro-oncology team
• Neurosurgery
• Radiation Oncology
• Paediatric Medical Oncologist
• Adult Medical Oncologist
• Neurology
• Neuro Radiology
• Neuro-Pathology
• Occupational Therapy
• Physiotherapy
• Clinical Psychology 126/24/2018
Just a look
13
• Brain tumors account for 85% to 90% of all primary central nervous system (CNS)
tumors
• Anaplastic astrocytoma and glioblastoma account for approximately 38% of
primary brain tumors
• Meningiomas and other mesenchymal tumors account for approximately 27%
• Other less common primary brain tumors include
– PITUITARY TUMORS,
– SCHWANNOMAS,
– CNS LYMPHOMAS,
– OLIGODENDROGLIOMAS,
– EPENDYMOMAS,
– LOW-GRADE ASTROCYTOMAS,
– MEDULLOBLASTOMAS, IN DECREASING ORDER OF FREQUENCY.
• Spinal tumors.
– Schwannomas,
– Meningiomas, and e6/24/2018
WHY
• Exposure to vinyl chloride may predispose to the
development of glioma
• Epstein-Barr virus infection has been implicated in the
etiology of primary CNS lymphoma
• Transplant recipients and patients with the acquired
immunodeficiency syndrome have substantially increased
risks for primary CNS lymphoma.
• The familial tumor syndromes
• Prior radiation
• Mobile phones-?
146/24/2018
The familial tumor syndromes
• Neurofibromatosis type i (17q11)
• Neurofibromatosis type ii (22q12)
• Von hippel-lindau disease (3p25-26)
• Tuberous sclerosis (9q34, 16p13)
• Li-fraumeni syndrome (17p13)
• Turcot syndrome type 1 (3p21, 7p22)
• Turcot syndrome type 2 (5q21)
• Nevoid basal cell carcinoma syndrome (9q22.3
• Multiple enchondromatosis (Maffucci/Ollier )
156/24/2018
Clinical behavior
• Raised ICT
• Pressure effect
• Deficits
• Other nonspecific symptoms
• Seizures are a presenting symptom in approximately
20% of patients with supra-tentorial brain tumors
• 70% with primary parenchymal tumors and 40% with
metastatic brain tumors develop seizures at some
time during the clinical course
166/24/2018
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Neuro-radiology
• CT scan
• MRI
• MRS
• Contrast scan
• PERFUSION
• DTI
• PET scan
18
Anatomic assessment
1. Location
2. size
3. Contrast characterstics
4. Edema
5. Calcification
6. Hemorrhage
7. Extent of the mass effect of the tumor
8. Shift of midline structures
9. Intracranial herniation
10. CSF obstruction- hydrocephalu
6/24/2018
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MRS
METABOLITE VALUE TUMOR
CHOLINE INCREASED HIGH GRADE GLIOMAs
CREATININE INCREASED HIGH GRADE GLIOMAs
NAA INCREASED NEUROGENIC TUMORs
LIPID INCREASED RADIONECROSIS
LYMPHOMA
METASTASIS
LACTATE INCREASED RADIONECROSIS
LYMPHOMA
METASTASIS
CH/CITRATE INCREASED HIGH GRADE GLIOMAs
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Radionecrosis/LYMPHOMA
6/24/2018 21
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What else
• Histopathology
• Immuno-histochemistry[IHC]
• Genetic –chromosomal study
• Intra-operative diagnosis
Sampling done by
-smear cytology,
-imprint cytology
-cryostat sections.
Smear preparations
-cytological & nuclear characteristics
-vasculature (capillary endothelial hyperplasia)
Cryostat sections-tumor architecture
236/24/2018
IHC
ANTIBODY USE
GLIAL FIBRILLARY ACIDIC
PROTEIN
LABELS ALMOST ALLASTROCYTIC AND
EPENDYMAL TUMOURS AND SOME OLIGODENDROGLIAL
TUMOURS
ALPHA INTERNEXIN LABELS SOME OLIGODENDROGLIALTUMOURS
S100 PROTEIN LABELS MOST EPENDYMOMAS & SOME ASTROCYTIC AND
OLIGODENDROGLIAL TUMOURS
KI-67/MIB-1 LABELS PROLIFERATING CELL NUCLEI IN GLIOMAS
GERMINOMA  PALP (PLACENTAL ALKALINE PHOSPHATASE)
 C-KIT (CD117)
 OCT4
CAPILLARY HEMANGIOBLASTOMA  INHIBIN (INHIBIN A)
 D2-40
MENINGIOMA  PHOSPHOHISTONE-H3
 MIB-1/KI-67
 CLAUDIN-
ASTROCYTOMA  PHH3,MIB-1/KI-67,P53,GFAP
MEDULLOBLASTOMA  SYNAPTOPHYSIN,
 MICROTUBULE-ASSOCIATED PROTEIN 2,
 NEUROFILAMENT PROTEIN,
 NEURONAL NUCLEI
EPENDYMOMA  EMA
(ATRT)  INI1
VASCULAR TUMOR  CD34
6/24/2018 24
Neuro-axis imaging
• Medulloblastoma
• PNET
– pineoblastoma,
– ependymoblastomas,
– unclassified
• Germ Cell tumour with CSF and/or MRI positive
for malignant cells.
• Non Hodgkins Lymphoma with CSF positive for
malignant cells.
• Pure germinoma.
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MEDULLOBLASTOMA WITH SPINAL TUMORS
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Spine germinoma with mets
6/24/2018 27
Surgery
• Maximal safe resection with the aim of total
excision whenever feasible.
• Open or stereotactic biopsy for very extensive
and diffuse tumours or those in eloquent
areas where near total excision could result in
significant deficit.
• Histological proof may not be required in
diffuse pontine gliomas or Neurofibromatosis
type 1 associated optic pathway gliomas
286/24/2018
Role of chemotherapy
• Children < 3 years of age: Partially excised or only
biopsied tumours in critical sites such as optic
pathway, hypothalamus or thalamus, or presence
of neurological deficit or mass effect: Initial
chemotherapy (Packer’s regimen or ICE) for 6 – 12
months and to defer radiotherapy till the age of 3
years for minimising the late radiation sequelae.
296/24/2018
WHO grading-Gliomas
• Grade I –
– Pilocytic Astrocytoma
– SEGA
• Grade II-
– Fibrillary
– Protoplasmic
• Anaplastic astrocytoma (AA) grade III
• Glioblastoma multiforme (GBM) grade IV
• Gemistocytic astrocytoma equivalent to AA
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Age factor
• Paediatrics
– Medullobalstoma
– ATRT
– Fourth vntricle
ependymomas
– Pilocytic astrocytomas
– Brain stem Gliomas
– PNETs
– Young age
• Oligodendrogliomas
• Gangliogliomas
• DNET
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Age factor –contd.
• Adults
– Anaplstic oligos/astros/
– GBM
– Primary CNS lymhoma
– Metastatic
326/24/2018
Sex factor
• Meningiomas
• Pituitaries
• craniopharyngiomas
336/24/2018
Mode of presentation
• Small duration of headache
– LOW GRADE GLIOMA
• Long duration of headache AND acute presentation
– Transformed Gliomas/Anaplastic Gliomas
• Sudden onset of headache
– HIGH GRADE GLIOMAS
• Spinal pain
– Spinal tumors
– PNETs with spinal mets
346/24/2018
Site factors
• Posterior fossa
– Pilocytic astrocytoma
– Ependymomas
– Medulloblastoma
– PNET
– ATRT
Any site
• Gliomas
• Temporal lobe
– DNET
– Ganglioglioma
– Ganglioneuroma
356/24/2018
Surgery
Maximal safe resection with the aim of total
excision whenever feasible.
Open or stereotactic biopsy for very extensive
and diffuse tumours or those in eloquent areas
where near total excision could result in
significant deficit.
Histological proof may not be required in
diffuse pontine gliomas or Neurofibromatosis
type 1 associated optic pathway gliomas
366/24/2018
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Surgery/MEDULLOBLASTOMA
• Goal
– Total or near total excision
– Normalization of ICP
– Ext ventricular drainage
– VP shunt→ resection (not recommended)?
6/24/2018 39
Surgical resection
Albright et al Neurosurgery. 1996 Feb;38(2):265-71.
• T 3b, T4,residual > 1.5 cm, M+
– PFS was 20% better at 5yr in pts with < 1.5cm residual disease
– PFS was 20% better at 5yr in pts with M0 disease
– Extent of residual tumor does correlate with prognosis in certain children
especially those who are > 3 years old, with no tumor dissemination
Jenkin et al IJROBP 1990 Aug;19(2):265-74
• Post-operative meningitis, a residual disease on PO scan, disseminated disease
were unfavorable factors
• Five-year DFS
– Stage I (total resection, no adverse factor) 100%
– Stage II (total resection with one or more adverse factor or less than total
resection with no other adverse factor) 78%
– Stage III (less than total resection with one or more adverse factor) 18%.
6/24/2018 40
Extent of Surgery
• Total – No visible tumour in operative bed and
on post op scan
• Near Total– post op scan reveals a nodular
enhancement in the surgical bed
• Sub total– 51%-90% resection done
• Partial-11%-50% resection done
• Biopsy-<10%
6/24/2018 41
CHEMOTHERAPY
• COMPARING TO SX/RT ,CHEMO HAS MINIMAL
ROLE
• TEMOZOLAMIDE SHOWED THE SURVIVAL 2YR
AND 5YR BENEFIT IN GLIOBLASTOMA
• NOW SOME NEW DRUGS LIKE AVASTIN
APPROVED
• PCV[PROCARBAZINE+CCNU+VINCA] IN OLIGOS AS
ADJUVANT AND RECURRENT TUMORS
• IN CHILDREN BELOW 3 YEAR OLD
• METHOTREXATE IN CNS LYMPHOMAs
426/24/2018
ROLE OF RADIOTHERAPY
• IN HIGH GRADE GLIOMAs AS ADJUVANT
• IN GRADE II GLIOMAs AS PER PIGNATTIS CRITERIA
• UNRESECTABLE/RESIDUAL LOW GRADE GLIOMAS
• ALL BRAIN STEM GLIOMAs
• ALMOST PAEDIATRIC BRAIN TUMORS
• SPINAL CORD TUMORS
• METASTATIC BRAIN TUMORS
• GERM CELL TUMORS
436/24/2018
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Radiation –Part of life
6/24/2018 45
Wilhelm Conrad Rontgen
History - radiation
1896 – Becquerel - Radioactivity
1898 – Madam Curie / Pierre Curie - Radium
1903 – Nobel Prize for Curie’s & Becquerel
1903 – First successful case of malignancy basal
cell carcinoma of face
6/24/2018 46
GOALS
 High dose to tumor tissue-Tumor control
 Normal tissue sparing
 Minimize long and short term toxicities
 Better Quality of life
6/24/2018 47
Treatment
• Delivered 5 days per week over 6-8 weeks
• Typical treatment takes around 5 minutes
• Treatment is painless--like having an X-ray taken
• No radioactive substances involved; beam goes
on/off
• Side effects usually temporary; controlled with
medication/diet
• Covered by Medicare and many other insurance
companies
•
6/24/2018 48
Role of radiation
S- Size >6cm
A- ASTRO component
D- Deficit
A- Age >40
M- midline shift
49
 S-MRS activity
 W-Wish
 MIB index>6%
 P- perfusion
 E-Enhancement
•Pignatti’s criteria are used to assist in
decision making for observation:
•If more than 2 criteria are present
then patients to be offered immediate
radiotherapy
6/24/2018
Evolution of Treatment Techniques
CONVENTIONAL RT
Collimator shapes Beam
Rectangular Treatment Field
Shaped Treatment Field
1970s and earlier
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• CONVENTIONAL
• 3DCRT
• IMRT
• IGRT
• DART
• SRS
• SRT
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Immobilization for Stereotactic Radiosurgery
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WHO grading-Gliomas
 Grade I –
 Pilocytic Astrocytoma
 SEGA
 Grade II-
 Fibrillary
 Protoplasmic
 Anaplastic astrocytoma (AA) grade III
 Glioblastoma multiforme (GBM) grade IV
 Gemistocytic astrocytoma equivalent to AA
596/24/2018
MENINGIOMA
• Grade -1
– Surgery
– Surgery plus radiation therapy
is used in selected cases, such
as for patients with known or
suspected residual disease or
with recurrence after
previous surgery.
– Radiation therapy for patients
with unresectable tumors
6/24/2018 60
ATYPICAL MENINGIOMA
• WHO grade II meningiomas (i.e.,
atypical, clear cell, and chordoid)
• WHO grade III meningiomas (i.e.,
anaplastic/malignant, rhabdoid,
and papillary), and
hemangiopericytomas are
• worse than for patients with low-
grade meningiomas because
complete resections are less
common and the proliferative
capacity is greater
• Surgery plus radiation therapy.
6/24/2018 61
GLIOBLASTOMA MULTIFORMAE
• WHO grade 4
• Commonest glial tumor & most
malignant form of diffuse
astrocytic glioma
• De-novo or tumor progression
from diffuse / anaplastic
astrocytoma (secondary)
• Male predominance
• Sixth decade
• Cerebral hemispheres (temporal,
parietal & frontal)
• Radiology :-large irregular mass
with a peripheral ring area of
contrast enhancement & a dark
hypodense centre representing
necrosis
6/24/2018 62
Sub categories
1. Giant cell glioblastoma- giant cells predominate
2. Epithelioid glioblastoma-
- large sheet like collections of cells with large nuclei & prominent nucleoli,
- mimic metastatic carcinoma,
- IHC is necessary
3. Small cell glioblastoma:-
- Predominantly small poorly differentiated cells
- Diagnostic difficulty with anaplastic oligodendroglioma & metastatic small
cell carcinoma
Gliosarcoma :-
- Evidence of mesenchymal differentiation in addition to typical features of
glioblastoma
- Generally sarcomatous
- Often has features of malignant fibrous histiocytoma or angisarcom or
fibrosarcoma
6/24/2018 63
Oligodendroglioma
• 4 - 5%, who grade 2.
• Fourth and fifth decades of life, with a
male predominance.
• Cerebral hemispheres, cerebellum,
brainstem and spinal cord.
• Focal neurological signs and seizures
accompanied by headaches.
• MRI scans show poorly defined
hypodense tumours in the subcortical
white matter with calcification.
• Older than those with
oligodendroglioma grade 2 tumours,
• There is no clear distinction between
grade 2 and grade 3 tumours, because
the criteria for differentiation are
controversial and ill defined.
• Similar clinical features
6/24/2018 64
Ependymomas
• Slow-growing tumours
• Walls of the cerebral ventricles, or
occasionally from the spinal canal.
• Children and young adults,
• Children-posterior fossa
• Adults-lateral ventricles and the
third ventricle
• Present with signs and symptoms
of raised intracranial pressure and
hydrocephalus
• MRI shows a well-circumscribed
lesion protruding into the ventricle,
often with areas of cyst formation
and haemorrhage
• Gross-soft grey-pink tissue with
areas of cyst formation and
occasional focal haemorrhage.
6/24/2018 65
CRANIOPHARYNGIOMA
• Surgery alone if the tumor is
totally resectable.
• Debulking surgery plus
radiation therapy if the
tumor is unresectable
6/24/2018 66
PITUITARY ADENOMA
• Surveillance after surgery
– Completely excised non
secretory adenoma--
• Radiation after surgery
– Incompletely excised non
secretry adenoma,
– Hormone secretory tumours
(Acromegaly, Cushings,
Prolactinoma, Nelsons
syndrome) not controlled
with surgery and /or medical
therapy
– Suprasellar extension
6/24/2018 67
GERM CELL TUMOR
6/24/2018 68
BRAIN METASTASIS
• Single lesion- Sx 
RADIATION
• Multiple lesion- RADIATION
• Role of chemotherapy–
• Temozolamide is
questionable
6/24/2018 69
Gliomatosis Cerebri
• Diffuse glial tumour infiltrating the
brain and extensively involving at
least two cerebral lobes
• Bilateral
• Adults - fifth decade
• GFAP-positive astrocytic cells with
an elongated morphology that
typically infiltrate the white matter in
parallel bundles
• Prognosis - poor
• Dead within 1 year of diagnosis.
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Optic pathway glioma
6/24/2018 71
AVM
6/24/2018 72
Acoustic Neuromas
6/24/2018 73
CHOROID PLEXUS TUMOR
6/24/2018 74
GEMISTOCYTIC ASTRO
6/24/2018 75
GANGLIOGLIOMA
• Temporal lobe
• Surgery main stay
• Adjuvant radiaton
6/24/2018 76
SPINAL EPENDYMOMAS
6/24/2018 77
ASTROCYTOMA
Poorly defined margins
Multiple vertebral levels inv.
Eccentrically located
Heterogenous enhancement
MRI findings of Astrocytoma
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EPENDYMOMA
T 1W-HYPO to ISO T 2W-HYPERINTENSE T 1W- CONTRAST
6/24/2018 79
L 1
L 2
L 3
L 4
MR PLAIN SAGITTAL T 1 W
Well defined hyperintense
mass from L4 to S1 vertebrae
engulfing cauda equina
measuring
8 X1.8 cm.
Ependymoma CASE -2….
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MRI CASE 3…Pre op MR IMAGE
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PILOCYTIC ASTROCYTOMA
• Common in paedriatic
group/posterior fossa
• Surgery alone if the tumor is
totally Resectable.
• Surgery followed by
radiation therapy to known
or suspected residual tumor
• Curative
• WHO grade 1
• Well defined, slow growing
cystic tumor
6/24/2018 83
Brain stem glioma
• 20% of childhood and 5% of adult CNS
tumours.
• Most frequently in children between 3 and
10 years
• Tissue confirmation is frequently not
feasible with infiltrating, except in
expansile tumors
• 60-80%of patients do not have a
histological diagnosis
• Universally associated with dismal
prognosis
• Historically, regarded as a single
entity
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Clinical presentation
• Insidious/sudden
onset
• Cranial nerve palsies
• Long tract signs
(hemiparesis)
• Cerebellar signs
(ataxia)
• Long history –
better prognosis
6/24/2018 86
Survival
Median 8.5
months for 54 Gy
8 months for 70.2
Gy
Mandell IJROBP 19996/24/2018 87
•Haemorrhage, calcification
•Cellular, with rosettes/pseudorosettes
•Anaplastic: 10-30%
•Spinal mets: 10-15%
•Ependymoblastoma (PNET)
•Spinal MRI/CSF for post
fossa/anaplastic tumours
Surgery treatment of choice and the most
important prognostic factor
Gross tumour resection (GTR) - 50-75%
long term control
Subtotal resection (STR) - 0-30% GTR
possible in only 50% cases, aggressive
debulking/2nd look
Ependymoma
6/24/2018 88
ATYPICAL TERATOID RHABDOID TUMOR
• Posterior fossa
• Below 2 year age
• High grade
• Highly malignant
6/24/2018 89
High-grade hemispheric gliomas
Relatively rare
Somewhat better outcome
than adults but long-term cure
still rare
Overexp of p53 strong
prognostic factor (NEJM 2002)
Surgery, conv RT std of care
as in adults
Role of chemo not fully
evolved
6/24/2018 90
High-grade hemispheric gliomas
• Randomised trial of RT + adj pCV Vs RT alone
(n=58): 5yr DFS of 46% Vs 18% (CCG 943)
• Results never duplicated (38 % slides reviewed were
not high-grade, Boyett 1998)
• Intensive/pre irradiation chemo: no major impact
• Currently several regimens being tested (TMZ,
thalidomide, carboplatin, topetecan, etc)
Sposto J NeuroOncol6/24/2018 91
MEDULLOBLASTOMA
926/24/2018
Immobilization
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CRANIO SPINAL RADIATION
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Conventional IMRT Protons
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MEDICAL DECOMPRESSIVE THERAPY
• Dexamethasone in tapered dose
• Mannitol
• Antiemetics
• Anticnvulsants/sos
986/24/2018
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Follow-up policies
Low grade Gliomas and other benign tumours: Post
Treatment baseline imaging at 3 months, then 6
monthly follow up for 5 years and then annually.
Subsequent imaging not routinely recommended
unless there is a neurological worsening or a specific
clinical concern
For children and those with tumours in and around
the sella or this region in the radiation field
(including cranio-spinal) monitor growth (height and
weight) and regular endocrine evaluation
1006/24/2018
Follow-up policies-contd.
High grade gliomas and brain metastasies: First
follow up and Post Treatment baseline imaging at 6
weeks and subsequent follow ups at 2 - 4 months
for2 years and then 6 monthly. Subsequent imaging
not routinely recommended unless there is a
neurological worsening or a specific clinical concern.
1016/24/2018
CONCLUSION
• Team Work
• Sx Is The Main Stay Treatment
• Maximal Safe Resection Should Be Attempted First
• Pathological review/IHC should be done
• Radiation Has Radical, adjuvant In All Most All Tumors
• Role Of Chemotherapy Is Minimal
• Timely Reference
• Even In Low grade tumors, when to observe team discussion
is helpful to prevent untoward effect
1026/24/2018
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Stage IV: Metastatic Cancer
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108
METASTASIS
-please do not watch crying
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METASTASIS- give a smiling death
110
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Palliative radiation
Skeletal X-Ray
Bone scan
MRI
PET-CT
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Spinal metastasis
112
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113
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Brain metastasis
114
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115
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Whole brain radiotherapy
116
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Choroidal metastasis
117
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Superscan-extensive bone mets
118
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Hemibody radiation
119
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Prophylactic radiation
120
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svco
121
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CAUTION
C - Change in bowel or bladder habits
A - A sore that does not heal
U - Unusual bleeding or discharge
T - Thickening or lump in the breast or any part of the body
I - Indigestion or difficulty swallowing
O - Obvious change in a wart or mole
N - Nagging cough or hoarseness
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Change in bowel habits
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Change in bladder habits
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A sore that does not heal
10/20/12 01:12 PM 125
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Unusual bleeding or discharge
10/20/12 01:12 PM 126
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Thickening or lump in the
breast or any part of the body
10/20/12 01:12 PM 127
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Indigestion or difficulty swallowing
10/20/12 01:12 PM 128
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Obvious change in a wart or mole
10/20/12 01:12 PM 129
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Nagging cough or hoarseness
10/20/12 01:12 PM 130
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138
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Prevention-passive smoking
6/24/2018 139
Liver cancer-
hepatitis B vaccine
6/24/2018 140
Cervix cancer vaccine
10/20/12 01:12 PM 141
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Promise-Stop drinking alcohol
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RELAX
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Meditation
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145
Dietary protective factors
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Breast feeding
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REGULAR CHECK-UP
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Physical activity
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LOTS OF BLOOD REQUIRE
6/24/2018 155
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TABLET FORMS
6/24/2018 157
All specialities under one roof
6/24/2018 158
10/20/12 01:12 PM 159
6/24/2018 159
10/20/12 01:12 PM 160
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Just “Doing It” is not good enough !
You must know “what” to do and “where” to do it !
10/20/12 01:12 PM 161
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10/20/12 01:12 PM 162
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10/20/12 01:12 PM 163
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Whenever not
possible,
make friends
6/24/2018 164
16510/20/12 01:12 PM
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16610/20/12 01:12 PM
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THANKS
6/24/2018 170
171
?
6/24/2018 171
6/24/2018 172
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Just “Doing It” is not good enough !
You must know “what” to do and “where” to do it !
6/24/2018 174
1756/24/2018
1766/24/2018
THANKS
1776/24/2018
1786/24/2018
179
?
1796/24/2018
Email-drkcpatro@gmail.com
M-09160470564
6/24/2018 180

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ROLE OF RADIATION IN BRAIN TUMORS FOR NEUROSURGEONS

  • 1. APPROACHING TOWARDS NEURO-ONCOLOGY & ROLE OF RADIOTHERAPY 6/24/2018 1
  • 2. DR KANHU CHARAN PATRO RADIATION ONCOLOGIST M.D,D.N.B[RT],FAROI[USA],MBA[ICFAI],PDCR,CEPC 6/24/2018 2
  • 3. O N O L Y O M G C H R I C G R S P E U S P E C I L T Y I VISAKHAPATNAM,1/7-MVP[AP] 36/24/2018
  • 5. Statistics • Near 10 million new cases are detected each year • Near 20 million people living with cancer in the world today • Near 7 million people will die from cancer • Every day, around 1700 Americans die of the disease • 1 in 3 people will be diagnosed with cancer in the UK and • 1 in 4 will die from their disease 56/24/2018
  • 6. Lung Breast Colon/Rectum Stomach Liver Prostate Cervix uteri Oesophagus Bladder Non-Hodgkin Lymphoma Leukaemia Oral cavity Pancreas Kidney Ovary 1000 800 600 400 200 0 200 400 600 8001000 Men Women From: D.M. Parkin The Lancet Oncology 2: 533-543 (2001) (Thousands) Incidence Mortality 337 293 105 0370 241 318 446 234 165 166 471 233 133 111 76 33 121 68 113 86 47 97 101 101 34 71 192 114 810 902 558 405 255 499 398 384 204 543 279 260 227 99 93 167 144 109 81 170 116 112 57 119 5.3 million cases 3.5 million deaths 4.7 million cases 2.7 million deaths The Global Burden of Cancer 2000 66/24/2018
  • 7. Levels of evidence  Level I=large double blind RCTs, or, meta-analysis of sma RCTs , with clinically relevant outcomes I a=evidence from meta-analysis of RCT I b=evidence from at least 1 RCT  Level II=small RCTs, non-blinded RCTs II a=evidence from one well designed non-RCT II b=evidence from one well-designed quasi- experimental study  Level III=observational [cohort ] studies , case- control studies , non-RCTs  Level IV=opinion of expert committees, or Rspected authorities  Level V=expert opinion 76/24/2018
  • 12. Neuro-oncology team • Neurosurgery • Radiation Oncology • Paediatric Medical Oncologist • Adult Medical Oncologist • Neurology • Neuro Radiology • Neuro-Pathology • Occupational Therapy • Physiotherapy • Clinical Psychology 126/24/2018
  • 13. Just a look 13 • Brain tumors account for 85% to 90% of all primary central nervous system (CNS) tumors • Anaplastic astrocytoma and glioblastoma account for approximately 38% of primary brain tumors • Meningiomas and other mesenchymal tumors account for approximately 27% • Other less common primary brain tumors include – PITUITARY TUMORS, – SCHWANNOMAS, – CNS LYMPHOMAS, – OLIGODENDROGLIOMAS, – EPENDYMOMAS, – LOW-GRADE ASTROCYTOMAS, – MEDULLOBLASTOMAS, IN DECREASING ORDER OF FREQUENCY. • Spinal tumors. – Schwannomas, – Meningiomas, and e6/24/2018
  • 14. WHY • Exposure to vinyl chloride may predispose to the development of glioma • Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma • Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma. • The familial tumor syndromes • Prior radiation • Mobile phones-? 146/24/2018
  • 15. The familial tumor syndromes • Neurofibromatosis type i (17q11) • Neurofibromatosis type ii (22q12) • Von hippel-lindau disease (3p25-26) • Tuberous sclerosis (9q34, 16p13) • Li-fraumeni syndrome (17p13) • Turcot syndrome type 1 (3p21, 7p22) • Turcot syndrome type 2 (5q21) • Nevoid basal cell carcinoma syndrome (9q22.3 • Multiple enchondromatosis (Maffucci/Ollier ) 156/24/2018
  • 16. Clinical behavior • Raised ICT • Pressure effect • Deficits • Other nonspecific symptoms • Seizures are a presenting symptom in approximately 20% of patients with supra-tentorial brain tumors • 70% with primary parenchymal tumors and 40% with metastatic brain tumors develop seizures at some time during the clinical course 166/24/2018
  • 18. Neuro-radiology • CT scan • MRI • MRS • Contrast scan • PERFUSION • DTI • PET scan 18 Anatomic assessment 1. Location 2. size 3. Contrast characterstics 4. Edema 5. Calcification 6. Hemorrhage 7. Extent of the mass effect of the tumor 8. Shift of midline structures 9. Intracranial herniation 10. CSF obstruction- hydrocephalu 6/24/2018
  • 20. MRS METABOLITE VALUE TUMOR CHOLINE INCREASED HIGH GRADE GLIOMAs CREATININE INCREASED HIGH GRADE GLIOMAs NAA INCREASED NEUROGENIC TUMORs LIPID INCREASED RADIONECROSIS LYMPHOMA METASTASIS LACTATE INCREASED RADIONECROSIS LYMPHOMA METASTASIS CH/CITRATE INCREASED HIGH GRADE GLIOMAs 206/24/2018
  • 23. What else • Histopathology • Immuno-histochemistry[IHC] • Genetic –chromosomal study • Intra-operative diagnosis Sampling done by -smear cytology, -imprint cytology -cryostat sections. Smear preparations -cytological & nuclear characteristics -vasculature (capillary endothelial hyperplasia) Cryostat sections-tumor architecture 236/24/2018
  • 24. IHC ANTIBODY USE GLIAL FIBRILLARY ACIDIC PROTEIN LABELS ALMOST ALLASTROCYTIC AND EPENDYMAL TUMOURS AND SOME OLIGODENDROGLIAL TUMOURS ALPHA INTERNEXIN LABELS SOME OLIGODENDROGLIALTUMOURS S100 PROTEIN LABELS MOST EPENDYMOMAS & SOME ASTROCYTIC AND OLIGODENDROGLIAL TUMOURS KI-67/MIB-1 LABELS PROLIFERATING CELL NUCLEI IN GLIOMAS GERMINOMA  PALP (PLACENTAL ALKALINE PHOSPHATASE)  C-KIT (CD117)  OCT4 CAPILLARY HEMANGIOBLASTOMA  INHIBIN (INHIBIN A)  D2-40 MENINGIOMA  PHOSPHOHISTONE-H3  MIB-1/KI-67  CLAUDIN- ASTROCYTOMA  PHH3,MIB-1/KI-67,P53,GFAP MEDULLOBLASTOMA  SYNAPTOPHYSIN,  MICROTUBULE-ASSOCIATED PROTEIN 2,  NEUROFILAMENT PROTEIN,  NEURONAL NUCLEI EPENDYMOMA  EMA (ATRT)  INI1 VASCULAR TUMOR  CD34 6/24/2018 24
  • 25. Neuro-axis imaging • Medulloblastoma • PNET – pineoblastoma, – ependymoblastomas, – unclassified • Germ Cell tumour with CSF and/or MRI positive for malignant cells. • Non Hodgkins Lymphoma with CSF positive for malignant cells. • Pure germinoma. 256/24/2018
  • 26. MEDULLOBLASTOMA WITH SPINAL TUMORS 6/24/2018 26
  • 27. Spine germinoma with mets 6/24/2018 27
  • 28. Surgery • Maximal safe resection with the aim of total excision whenever feasible. • Open or stereotactic biopsy for very extensive and diffuse tumours or those in eloquent areas where near total excision could result in significant deficit. • Histological proof may not be required in diffuse pontine gliomas or Neurofibromatosis type 1 associated optic pathway gliomas 286/24/2018
  • 29. Role of chemotherapy • Children < 3 years of age: Partially excised or only biopsied tumours in critical sites such as optic pathway, hypothalamus or thalamus, or presence of neurological deficit or mass effect: Initial chemotherapy (Packer’s regimen or ICE) for 6 – 12 months and to defer radiotherapy till the age of 3 years for minimising the late radiation sequelae. 296/24/2018
  • 30. WHO grading-Gliomas • Grade I – – Pilocytic Astrocytoma – SEGA • Grade II- – Fibrillary – Protoplasmic • Anaplastic astrocytoma (AA) grade III • Glioblastoma multiforme (GBM) grade IV • Gemistocytic astrocytoma equivalent to AA 306/24/2018
  • 31. Age factor • Paediatrics – Medullobalstoma – ATRT – Fourth vntricle ependymomas – Pilocytic astrocytomas – Brain stem Gliomas – PNETs – Young age • Oligodendrogliomas • Gangliogliomas • DNET 316/24/2018
  • 32. Age factor –contd. • Adults – Anaplstic oligos/astros/ – GBM – Primary CNS lymhoma – Metastatic 326/24/2018
  • 33. Sex factor • Meningiomas • Pituitaries • craniopharyngiomas 336/24/2018
  • 34. Mode of presentation • Small duration of headache – LOW GRADE GLIOMA • Long duration of headache AND acute presentation – Transformed Gliomas/Anaplastic Gliomas • Sudden onset of headache – HIGH GRADE GLIOMAS • Spinal pain – Spinal tumors – PNETs with spinal mets 346/24/2018
  • 35. Site factors • Posterior fossa – Pilocytic astrocytoma – Ependymomas – Medulloblastoma – PNET – ATRT Any site • Gliomas • Temporal lobe – DNET – Ganglioglioma – Ganglioneuroma 356/24/2018
  • 36. Surgery Maximal safe resection with the aim of total excision whenever feasible. Open or stereotactic biopsy for very extensive and diffuse tumours or those in eloquent areas where near total excision could result in significant deficit. Histological proof may not be required in diffuse pontine gliomas or Neurofibromatosis type 1 associated optic pathway gliomas 366/24/2018
  • 39. Surgery/MEDULLOBLASTOMA • Goal – Total or near total excision – Normalization of ICP – Ext ventricular drainage – VP shunt→ resection (not recommended)? 6/24/2018 39
  • 40. Surgical resection Albright et al Neurosurgery. 1996 Feb;38(2):265-71. • T 3b, T4,residual > 1.5 cm, M+ – PFS was 20% better at 5yr in pts with < 1.5cm residual disease – PFS was 20% better at 5yr in pts with M0 disease – Extent of residual tumor does correlate with prognosis in certain children especially those who are > 3 years old, with no tumor dissemination Jenkin et al IJROBP 1990 Aug;19(2):265-74 • Post-operative meningitis, a residual disease on PO scan, disseminated disease were unfavorable factors • Five-year DFS – Stage I (total resection, no adverse factor) 100% – Stage II (total resection with one or more adverse factor or less than total resection with no other adverse factor) 78% – Stage III (less than total resection with one or more adverse factor) 18%. 6/24/2018 40
  • 41. Extent of Surgery • Total – No visible tumour in operative bed and on post op scan • Near Total– post op scan reveals a nodular enhancement in the surgical bed • Sub total– 51%-90% resection done • Partial-11%-50% resection done • Biopsy-<10% 6/24/2018 41
  • 42. CHEMOTHERAPY • COMPARING TO SX/RT ,CHEMO HAS MINIMAL ROLE • TEMOZOLAMIDE SHOWED THE SURVIVAL 2YR AND 5YR BENEFIT IN GLIOBLASTOMA • NOW SOME NEW DRUGS LIKE AVASTIN APPROVED • PCV[PROCARBAZINE+CCNU+VINCA] IN OLIGOS AS ADJUVANT AND RECURRENT TUMORS • IN CHILDREN BELOW 3 YEAR OLD • METHOTREXATE IN CNS LYMPHOMAs 426/24/2018
  • 43. ROLE OF RADIOTHERAPY • IN HIGH GRADE GLIOMAs AS ADJUVANT • IN GRADE II GLIOMAs AS PER PIGNATTIS CRITERIA • UNRESECTABLE/RESIDUAL LOW GRADE GLIOMAS • ALL BRAIN STEM GLIOMAs • ALMOST PAEDIATRIC BRAIN TUMORS • SPINAL CORD TUMORS • METASTATIC BRAIN TUMORS • GERM CELL TUMORS 436/24/2018
  • 46. History - radiation 1896 – Becquerel - Radioactivity 1898 – Madam Curie / Pierre Curie - Radium 1903 – Nobel Prize for Curie’s & Becquerel 1903 – First successful case of malignancy basal cell carcinoma of face 6/24/2018 46
  • 47. GOALS  High dose to tumor tissue-Tumor control  Normal tissue sparing  Minimize long and short term toxicities  Better Quality of life 6/24/2018 47
  • 48. Treatment • Delivered 5 days per week over 6-8 weeks • Typical treatment takes around 5 minutes • Treatment is painless--like having an X-ray taken • No radioactive substances involved; beam goes on/off • Side effects usually temporary; controlled with medication/diet • Covered by Medicare and many other insurance companies • 6/24/2018 48
  • 49. Role of radiation S- Size >6cm A- ASTRO component D- Deficit A- Age >40 M- midline shift 49  S-MRS activity  W-Wish  MIB index>6%  P- perfusion  E-Enhancement •Pignatti’s criteria are used to assist in decision making for observation: •If more than 2 criteria are present then patients to be offered immediate radiotherapy 6/24/2018
  • 50. Evolution of Treatment Techniques CONVENTIONAL RT Collimator shapes Beam Rectangular Treatment Field Shaped Treatment Field 1970s and earlier 6/24/2018 50
  • 52. • CONVENTIONAL • 3DCRT • IMRT • IGRT • DART • SRS • SRT 526/24/2018
  • 57. Immobilization for Stereotactic Radiosurgery 6/24/2018 57
  • 59. WHO grading-Gliomas  Grade I –  Pilocytic Astrocytoma  SEGA  Grade II-  Fibrillary  Protoplasmic  Anaplastic astrocytoma (AA) grade III  Glioblastoma multiforme (GBM) grade IV  Gemistocytic astrocytoma equivalent to AA 596/24/2018
  • 60. MENINGIOMA • Grade -1 – Surgery – Surgery plus radiation therapy is used in selected cases, such as for patients with known or suspected residual disease or with recurrence after previous surgery. – Radiation therapy for patients with unresectable tumors 6/24/2018 60
  • 61. ATYPICAL MENINGIOMA • WHO grade II meningiomas (i.e., atypical, clear cell, and chordoid) • WHO grade III meningiomas (i.e., anaplastic/malignant, rhabdoid, and papillary), and hemangiopericytomas are • worse than for patients with low- grade meningiomas because complete resections are less common and the proliferative capacity is greater • Surgery plus radiation therapy. 6/24/2018 61
  • 62. GLIOBLASTOMA MULTIFORMAE • WHO grade 4 • Commonest glial tumor & most malignant form of diffuse astrocytic glioma • De-novo or tumor progression from diffuse / anaplastic astrocytoma (secondary) • Male predominance • Sixth decade • Cerebral hemispheres (temporal, parietal & frontal) • Radiology :-large irregular mass with a peripheral ring area of contrast enhancement & a dark hypodense centre representing necrosis 6/24/2018 62
  • 63. Sub categories 1. Giant cell glioblastoma- giant cells predominate 2. Epithelioid glioblastoma- - large sheet like collections of cells with large nuclei & prominent nucleoli, - mimic metastatic carcinoma, - IHC is necessary 3. Small cell glioblastoma:- - Predominantly small poorly differentiated cells - Diagnostic difficulty with anaplastic oligodendroglioma & metastatic small cell carcinoma Gliosarcoma :- - Evidence of mesenchymal differentiation in addition to typical features of glioblastoma - Generally sarcomatous - Often has features of malignant fibrous histiocytoma or angisarcom or fibrosarcoma 6/24/2018 63
  • 64. Oligodendroglioma • 4 - 5%, who grade 2. • Fourth and fifth decades of life, with a male predominance. • Cerebral hemispheres, cerebellum, brainstem and spinal cord. • Focal neurological signs and seizures accompanied by headaches. • MRI scans show poorly defined hypodense tumours in the subcortical white matter with calcification. • Older than those with oligodendroglioma grade 2 tumours, • There is no clear distinction between grade 2 and grade 3 tumours, because the criteria for differentiation are controversial and ill defined. • Similar clinical features 6/24/2018 64
  • 65. Ependymomas • Slow-growing tumours • Walls of the cerebral ventricles, or occasionally from the spinal canal. • Children and young adults, • Children-posterior fossa • Adults-lateral ventricles and the third ventricle • Present with signs and symptoms of raised intracranial pressure and hydrocephalus • MRI shows a well-circumscribed lesion protruding into the ventricle, often with areas of cyst formation and haemorrhage • Gross-soft grey-pink tissue with areas of cyst formation and occasional focal haemorrhage. 6/24/2018 65
  • 66. CRANIOPHARYNGIOMA • Surgery alone if the tumor is totally resectable. • Debulking surgery plus radiation therapy if the tumor is unresectable 6/24/2018 66
  • 67. PITUITARY ADENOMA • Surveillance after surgery – Completely excised non secretory adenoma-- • Radiation after surgery – Incompletely excised non secretry adenoma, – Hormone secretory tumours (Acromegaly, Cushings, Prolactinoma, Nelsons syndrome) not controlled with surgery and /or medical therapy – Suprasellar extension 6/24/2018 67
  • 69. BRAIN METASTASIS • Single lesion- Sx  RADIATION • Multiple lesion- RADIATION • Role of chemotherapy– • Temozolamide is questionable 6/24/2018 69
  • 70. Gliomatosis Cerebri • Diffuse glial tumour infiltrating the brain and extensively involving at least two cerebral lobes • Bilateral • Adults - fifth decade • GFAP-positive astrocytic cells with an elongated morphology that typically infiltrate the white matter in parallel bundles • Prognosis - poor • Dead within 1 year of diagnosis. 6/24/2018 70
  • 76. GANGLIOGLIOMA • Temporal lobe • Surgery main stay • Adjuvant radiaton 6/24/2018 76
  • 78. ASTROCYTOMA Poorly defined margins Multiple vertebral levels inv. Eccentrically located Heterogenous enhancement MRI findings of Astrocytoma 6/24/2018 78
  • 79. EPENDYMOMA T 1W-HYPO to ISO T 2W-HYPERINTENSE T 1W- CONTRAST 6/24/2018 79
  • 80. L 1 L 2 L 3 L 4 MR PLAIN SAGITTAL T 1 W Well defined hyperintense mass from L4 to S1 vertebrae engulfing cauda equina measuring 8 X1.8 cm. Ependymoma CASE -2…. 6/24/2018 80
  • 81. MRI CASE 3…Pre op MR IMAGE 6/24/2018 81
  • 83. PILOCYTIC ASTROCYTOMA • Common in paedriatic group/posterior fossa • Surgery alone if the tumor is totally Resectable. • Surgery followed by radiation therapy to known or suspected residual tumor • Curative • WHO grade 1 • Well defined, slow growing cystic tumor 6/24/2018 83
  • 84. Brain stem glioma • 20% of childhood and 5% of adult CNS tumours. • Most frequently in children between 3 and 10 years • Tissue confirmation is frequently not feasible with infiltrating, except in expansile tumors • 60-80%of patients do not have a histological diagnosis • Universally associated with dismal prognosis • Historically, regarded as a single entity 6/24/2018 84
  • 86. Clinical presentation • Insidious/sudden onset • Cranial nerve palsies • Long tract signs (hemiparesis) • Cerebellar signs (ataxia) • Long history – better prognosis 6/24/2018 86
  • 87. Survival Median 8.5 months for 54 Gy 8 months for 70.2 Gy Mandell IJROBP 19996/24/2018 87
  • 88. •Haemorrhage, calcification •Cellular, with rosettes/pseudorosettes •Anaplastic: 10-30% •Spinal mets: 10-15% •Ependymoblastoma (PNET) •Spinal MRI/CSF for post fossa/anaplastic tumours Surgery treatment of choice and the most important prognostic factor Gross tumour resection (GTR) - 50-75% long term control Subtotal resection (STR) - 0-30% GTR possible in only 50% cases, aggressive debulking/2nd look Ependymoma 6/24/2018 88
  • 89. ATYPICAL TERATOID RHABDOID TUMOR • Posterior fossa • Below 2 year age • High grade • Highly malignant 6/24/2018 89
  • 90. High-grade hemispheric gliomas Relatively rare Somewhat better outcome than adults but long-term cure still rare Overexp of p53 strong prognostic factor (NEJM 2002) Surgery, conv RT std of care as in adults Role of chemo not fully evolved 6/24/2018 90
  • 91. High-grade hemispheric gliomas • Randomised trial of RT + adj pCV Vs RT alone (n=58): 5yr DFS of 46% Vs 18% (CCG 943) • Results never duplicated (38 % slides reviewed were not high-grade, Boyett 1998) • Intensive/pre irradiation chemo: no major impact • Currently several regimens being tested (TMZ, thalidomide, carboplatin, topetecan, etc) Sposto J NeuroOncol6/24/2018 91
  • 98. MEDICAL DECOMPRESSIVE THERAPY • Dexamethasone in tapered dose • Mannitol • Antiemetics • Anticnvulsants/sos 986/24/2018
  • 100. Follow-up policies Low grade Gliomas and other benign tumours: Post Treatment baseline imaging at 3 months, then 6 monthly follow up for 5 years and then annually. Subsequent imaging not routinely recommended unless there is a neurological worsening or a specific clinical concern For children and those with tumours in and around the sella or this region in the radiation field (including cranio-spinal) monitor growth (height and weight) and regular endocrine evaluation 1006/24/2018
  • 101. Follow-up policies-contd. High grade gliomas and brain metastasies: First follow up and Post Treatment baseline imaging at 6 weeks and subsequent follow ups at 2 - 4 months for2 years and then 6 monthly. Subsequent imaging not routinely recommended unless there is a neurological worsening or a specific clinical concern. 1016/24/2018
  • 102. CONCLUSION • Team Work • Sx Is The Main Stay Treatment • Maximal Safe Resection Should Be Attempted First • Pathological review/IHC should be done • Radiation Has Radical, adjuvant In All Most All Tumors • Role Of Chemotherapy Is Minimal • Timely Reference • Even In Low grade tumors, when to observe team discussion is helpful to prevent untoward effect 1026/24/2018
  • 107. Stage IV: Metastatic Cancer 6/24/2018 107
  • 108. 108 METASTASIS -please do not watch crying 6/24/2018
  • 109. 10/20/12 01:12 PM 109 6/24/2018 109
  • 110. METASTASIS- give a smiling death 110 6/24/2018 110
  • 111. Palliative radiation Skeletal X-Ray Bone scan MRI PET-CT 6/24/2018 111
  • 122. CAUTION C - Change in bowel or bladder habits A - A sore that does not heal U - Unusual bleeding or discharge T - Thickening or lump in the breast or any part of the body I - Indigestion or difficulty swallowing O - Obvious change in a wart or mole N - Nagging cough or hoarseness 6/24/2018 122
  • 123. Change in bowel habits 10/20/12 01:12 PM 123 6/24/2018 123
  • 124. Change in bladder habits 10/20/12 01:12 PM 124 6/24/2018 124
  • 125. A sore that does not heal 10/20/12 01:12 PM 125 6/24/2018 125
  • 126. Unusual bleeding or discharge 10/20/12 01:12 PM 126 6/24/2018 126
  • 127. Thickening or lump in the breast or any part of the body 10/20/12 01:12 PM 127 6/24/2018 127
  • 128. Indigestion or difficulty swallowing 10/20/12 01:12 PM 128 6/24/2018 128
  • 129. Obvious change in a wart or mole 10/20/12 01:12 PM 129 6/24/2018 129
  • 130. Nagging cough or hoarseness 10/20/12 01:12 PM 130 6/24/2018 130
  • 136. 10/20/12 01:12 PM 136 6/24/2018 136
  • 140. Liver cancer- hepatitis B vaccine 6/24/2018 140
  • 141. Cervix cancer vaccine 10/20/12 01:12 PM 141 6/24/2018 141
  • 142. Promise-Stop drinking alcohol 10/20/12 01:12 PM 142 6/24/2018 142
  • 144. Meditation 10/20/12 01:12 PM 144 6/24/2018 144
  • 154. 6/24/2018 154 LOTS OF BLOOD REQUIRE
  • 159. 10/20/12 01:12 PM 159 6/24/2018 159
  • 160. 10/20/12 01:12 PM 160 6/24/2018 160
  • 161. Just “Doing It” is not good enough ! You must know “what” to do and “where” to do it ! 10/20/12 01:12 PM 161 6/24/2018 161
  • 162. 10/20/12 01:12 PM 162 6/24/2018 162
  • 163. 10/20/12 01:12 PM 163 6/24/2018 163
  • 164. 10/20/12 01:12 PM 164 Whenever not possible, make friends 6/24/2018 164
  • 174. Just “Doing It” is not good enough ! You must know “what” to do and “where” to do it ! 6/24/2018 174