for medical oncologist

1. Brain Tumors
By
Dr Abeer Elsayed Ali
Associate professor of medical oncology and
hematological maligancies
South Egypt cancer Institute
Assiut Egypt
12-3-2017

2. • The overall annual incidence of primary brain tumors in the
US is 14 cases per 100,000 population.
• The most common primary brain tumors are meningiomas
27% of all primary brain tumors, and glioblastomas, 23% of all
primary brain tumors
• Brain metastases occur in approximately 15% of cancer
patients as a result of hematogenous dissemination of
systemic cancer, and the incidence may be rising due to
better control of systemic disease. Lung and breast cancers
Incidence

3. Etiology and risk factors
• Genetic factors; <5% of patients with glioma , tuberous
sclerosis, neurofibromatosis type I, Turcot syndrome, and
Li-Fraumeni cancer syndrome, Loss of heterozygosity (LOH) on
chromosomes 9p and 10q and p16 deletions are frequently
observed in high-grade gliomas,. In oligodendrogliomas, 1p and
19q LOH is associated with significantly improved survival.
• Molecular markers IDS, MGMT of brain tumors can
predict survival and will become increasingly important in the
diagnosis and treatment of glioma.
• Environmental factors Prior cranial irradiation
• Lifestyle characteristics cigarette smoking, alcohol
intake, or cellular phone use. No relation

5. Sites of origin
• Neuroepithelial Tissue
• Cranial and Spinal Nerves
• Meninges
• Malignant Lymphomas
• Germ Cell Tumours
• Sellar Region
• Local Extension of Regional Tumours
• Metastatic Tumours

6. Astrocyte (Astroglia): Star-shaped cells
that provide physical and nutritional support for
neurons:
1) clean up brain "debris"; 2) transport nutrients
to neurons; 3) hold neurons in place; 4) digest
parts of dead neurons; 5) regulate content of
extracellular space
Microglia: Like astrocytes, microglia digest
parts of dead neurons.
Ependymal :Form epithelial membrane lining
cerebral cavities & central canal • Produce
cerebrospinal fluid (CSF)
Oligodendroglia: Provide the insulation
(myelin) to neurons in the central nervous
system.
CNS Cells

7. 2 cell types in PNS
• Satellite Cells: Physical support to neurons in
the peripheral nervous system.
• Schwann Cells: Provide the insulation (myelin)
to neurons in the peripheral nervous system.
•PNS Cells

8. Histological
Classification

9. • Neuroepithelial tumors.
– Glial tumors.
• Astrocytic tumors.
– Pilocytic astrocytoma.
– Diffuse astrocytoma
– Anaplastic astrocytoma.
– Glioblastoma
– (Pleomorphic xanthoastrocytoma.
– Subependymal giant cell astrocytoma.
• Oligodendroglial tumors.
– Oligodendroglioma.
– Anaplastic oligodendroglioma.
• Mixed gliomas.
– Oligoastrocytoma.
– Anaplastic oligoastrocytoma.
• Ependymal tumors.
– Myxopapillary ependymoma.
– Subependymoma.
– Ependymoma (
Anaplastic ependymoma.
• Neuroepithelial tumors of uncertain origin.
– Astroblastoma.
– Chordoid glioma of the third ventricle.
– Gliomatosis cerebri.
– Neuronal and mixed glial
Gangliocytoma.
• Ganglioglioma.
• Desmoplastic infantile as
.
• Dysembryoplastic neuroe
.
• Central neurocytoma.
• Cerebellar liponeurocytom
.
• Paraganglioma.

10. .
• Meningeal tumors.
– Meningioma.
– Hemangiopericytoma.
– Melanocytic lesion.
• Germ cell tumors.
– Germinoma.
– Embryonal carcinoma.
– Yolk-sac tumor (endodermal-sinus
tumor).
– Choriocarcinoma.
– Teratoma.
– Mixed germ cell tumor.
• Tumors of the sellar region.
– Pituitary adenoma. (Pituitary
carcinoma.
– Craniopharyngioma.
• Tumors of uncertain histogenesis.
– Capillary hemangioblastoma.
• Primary CNS lymphoma.
•
Tumors of peripheral nerves that affect the
.
– Schwannoma.
• Metastatic tumors.
• Nonglial tumors.
Embryonal tumors.
• Ependymoblastoma.
Medulloblastoma.
• Supratentorial primitive
• neuroectodermal tumor (PNET).
Choroid plexus tumors.
• Choroid plexus papilloma.
• Choroid plexus carcinoma.
Pineal parenchymal tumors.
Pineoblastoma.
Pineocytoma.
Pineal parenchymal tumor of
intermediate differentiation

11. Staging and Grades
• WHO grade I includes lesions with low proliferative potential,
a frequently discrete nature, and the possibility of cure
following surgical resection alone.
• WHO grade II includes lesions that are generally infiltrating
and low in mitotic activity but recur. Some tumor types tend to
progress to higher grades of malignancy.
• WHO grade III includes lesions with histologic evidence of
malignancy, generally in the form of mitotic activity, clearly
expressed infiltrative capabilities, and anaplasia.
• WHO grade IV includes lesions that are mitotically active,
necrosis-prone, and generally associated with a rapid
preoperative and postoperative evolution of disease.

12. WHO Classification of CNS tumors
WHO grade I
• Pilocytic astrocytoma . Meningioma
• Mayxopapillary ependymoma
• Craniopharyngioma .Subependymoma
WHO grade II
• Diffuse astrocytoma .Ependymmoma
• Pleomorphic Xanthoastrocytoma
• Pineocytoma .Oligodendroglioma
• Atypical meningioma .Oligoastrocytoma
WHO grade III
• Anaplastic astrocytoma
• Anaplastic oligastrocytoma
• Anaplastic oligodendroglioma Anaplastic ependymoma
• Anaplastic (Malignant) meningioma
WHO grad IV
• Glioblastoma Pineoblastoma

13. Isocitrate dehydrogenase gene
(IDH)
Methyl- guanine methyle transfererase
(MGMT) gene

14. Diagnosis
• MRI is best , For primary brain tumors, the MRI
scan should always be obtained both with and
without contrast material (gadolinium).
• High-grade or malignant primary brain tumors
appear as contrast-enhancing mass lesions that
arise in white matter and are surrounded by
edema Multifocal malignant gliomas are seen in
~5% of patients.
• Low-grade gliomas typically are nonenhancing
lesions that diffusely infiltrate and tend to involve a
large region of the brain. Low-grade gliomas are
usually best appreciated on T2-weighted or fluid-
attenuated inversion recovery (FLAIR)MRI scans

16. Diagnosis
Magnetic resonance spectroscopy and
diffusion imaging
• can help differentiate low-grade from high-grade brain tumors
but cannot distinguish different tumor types of the same grade
CT
• A contrast-enhanced CT scan may be used if MRI is
unavailable or the patient cannot undergo MRI (eg, because
of a pacemaker).
• CT is adequate to exclude brain metastases in most patients,
but it can miss low-grade tumors or small lesions located in
the posterior fossa. Tumor calcification is often better
appreciated on CT than on MRI.
PET
have a sensitivity of only 75% and a specificity of 83% for

18. Treatment
ChemotherapySurgeryRadiotherapy
Carmustine Wafer
Stereostatic
radiosurgery

19. Surgery
GUIDING PRINCIPLES
• Maximal tumor removal
• Minimal surgical morbidity
• Accurate diagnosis
FACTORS
• Age .Performance status (PS)
• Feasibility of decreasing the mass effect with surgery
• Resectability, including number of lesions, location of lesions,
time since last surgery (recurrent patients)
• New versus recurrent tumor
OPTIONS
• Gross total resection where feasible
• Stereotactic biopsy
• Open biopsy/debulking
NB
• Postoperative MRI should be performed within 24-72 hours to
determine the extent of resection

20. Chemotherapy
• Temozolomide
• Carmustine
• PCV (procarbazine + CCNU + vincristine)
• Nitrosourea (Lomustine [CCNU] )
• Etoposide
• Platinum-based regimens: Single agent or combination
• Bevacizumab

21. Radiotherapy
• Tumor volumes are best defined using pre- and postoperative
imaging, usually FLAIR and or T2 signal abnormality on MRI
for GTV. CTV (GTV plus 1-2 cm margin) should receive 45-54
Gy in1.8-2.0 Gy fractions. Or 54-59.4 Gy in 1.8 to 2.0 or Gy54-60
Gy in 1.8 to 2.0 Gy fractions
• Limited Fields
• Craniospinal
• Whole brain radiotherapy (WBRT): Doses of 30-45 Gy in
1.8 to 3.0 Gy fractions are recommended depending on
patient's
performance status.
• Stereotactic radiosurgery: Recommend maximum
marginal doses of 24, 18, or 15 Gy for targets 2 cm, 2.1-3 cm or
3.1-4 cm, respectively (RTOG 90-05).

22. Stereotactic radiosurgery

23. Primary vs Secondary
GBM
• Primary GBM
– Develops de novo from
glial cells
– Accounts for > 90% of
biopsied or resected cases
– Clinical history of 6 months
– Occurs in older patients
(median age: 60 years)
• Secondary GBM
– Develops from low-grade
or anaplastic astrocytoma
• ~ 70% of lower grade
gliomas develop into
advanced disease
within 5-10 years of
diagnosis
– Comprises < 5% of GBM
cases
– Occurs in younger patients
(median age: 45 years)

24. Presentation
• Headache
• Seizure
• Motor weakness/speech deficit
• Altered personality
• Loss of memory/cognition
• Dizziness

25. Investigations
• MRI
• Biopsy

26. Features of Glioblastoma
Multiforme
• Rapid progression
• Enhancing tumor
• Surrounding edema
– Contains tumour
• ~ 5% multifocal

27. Treatment
• Surgery
• Radiotherapy
• Chemotherapy

28. Temozolomide
(Temodal)
• Methylating agent
• Principal mechanism is causing damage to DNA of
tumour cell, leading to cell death
• Taken orally, rapidly absorbed
• Penetrates the blood-brain barrier
• Dose according to ‘body surface area’
(height/weight)

29. Temozolomide – Side Effects
• Tiredness / fatigue
• Nausea
• Constipation (from anti-emetics)
• Low blood counts – red/white/platelets
– Particularly lymphocytes (risk of
Pneumocystis carinii pneumonia)
• Rash

30. Standard Treatment for GBM
• Radiotherapy concurrently with
Temozolomide followed by 6 months of
Temozolomide

31. Focal RT daily—30 x 200 cGy;
total dose: 60 Gy
TMZ 75 mg/m2
PO QD for 6 weeks,
then 150-200 mg/m2
PO QD on Days 1-5 every 28 days for 6 cycles
Concomitant
TMZ + RT*
Adjuvant TMZ
Wks6 10 14 18 22 26 30
RT Alone
R
0
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Phase III Study: New GBM
Radiation ± Temozolomide
Stupp R, et al. N Engl J Med. 2005;352:987-996.

32. Temozolomide - indications
• Recurrence of anaplastic astrocytoma
and glioblastoma multiforme

33. Surgical Implantation of
Chemotherapy Wafers:
Gliadel®
Gliadel®
is a trademark of Guilford Pharmaceuticals.
• BCNU-infused wafers
• implanted to tumour
bed at time of surgery
• chemotherapy released
to surrounding brain
tissue over a period of
2 to 3 weeks
• Clinical trials showed
survival benefit
• PBS difficulties

34. Further Treatment for
Progression
• Surgery
• Radiation (stereotactic radio-surgery)
• 2nd
line chemotherapy

35. 2nd
line Chemotherapy
• No consensus
• Low dose temozolomide (+/-
procarbazine)
• Carboplatin
• BCNU/CCNU
• Bevacizumab (+/- Irinotecan)
• Clinical trials if possible

36. Glioblastoma: A Highly Vascular
Tumour
• The vascular network formed in GBM is
abnormal
– vessels are dilated, tortuous, disorganised,
highly leaky

37. Angiogenesis

38. Avastin (Bevacizumab) –
mechanism of action

39. Bevacizumab: Anti-VEGF
Antibody
1. Vredenburgh JJ, et al. J Clin Oncol. 2007;25:4722-4729.
2. National Comprehensive Cancer Network guideline: CNS cancers (V.1.2008)
Recurrent GBM
at baseline
After 4 cycles
bev/irinotecan

40. Bevacizumab for recurrent
glioblastoma
• Unanswered questions
• Phase II results only
• ?changes on MRI reflect tumour
shrinkage, or reduced swelling from
stopping leaking blood vessels
• Concerns about rapid progression upon
stopping treatment
• Phase III trials underway

42. Adult Intracranial Ependymoma
Ependymoma or Anaplastic ependymoma
status post maximal resection or stereotactic or
open biopsy or subtotal resection
CSF -veCSF +ve
Limited-field fractionated
external beam RTf
Craniospinal RTh observe

43. METASTASES
• 20-25% of CNS Tumours in Adults
• Diverse origins
• Dural / Meningeal / Parenchymal
• Single or Multiple
• Well circumscribed
• Lung, Breast, Melanoma, Renal, GIT
• Direct extension neighbouring tissues

44. Metastatic Lesions
Limited (1-3) Metastatic Lesions>3 Metastatic Lesions
Known history
of cancer
WBRT ± stereotactic
Radiosurgery (SRS)
Not Known history
of cancer
Stereotactic or Open
biopsy/resection
DisseminatedStable systemic
WBRT
Surgical resection ,(SRS)
followed by WBRT
WBRT and/or
radiosurgery
MRI every 3 mo for 1 y then as
Clinically indicated

45. PITUITARY ADENOMA
• 10 - 15 % intracranial
• neoplasms
• Presentation
• Mass effect
• Apoplexy,
• haemorrhage
• Peptide production
• (GH, ACTH, Prolactin,
• TSH etc)
• Pituitary deficiencies
• Treatment, Bromocriptin , surgery if compersion , No RTH

46. LYMPHOMA
• Secondary involvement common late in
course
• (meningeal, nerve roots, epidural)
• Primary: uncommon
• Hodgkin’s - exceptional
• Majority B-cell, high grade
• cerebral hemispheres, multifocal,
paraventricular, perivascular distribution
• (AIDS) Poor prognosis

47. Primary CNS Lymphoma
Hold steroids, if possible prior to
diagnostic procedure
CT/MRI suggestive of lymphoma
+ve diagnosis of primary CNS
lymphoma
CSF sampling , eye exam with biopsy and/or
Brain biopsy
-ve diagnosis of primary CNS
lymphoma
High-dose methotrexate-
based regimen
± WBRT after
completion
of chemotherapy
LP positive
Intratheca
l chemotherapy
Discontinue steroids
and rebiopsy
when disease
progresses
If eye exam positive,
IO CTH
) or RT to globe

48. Thank you