Brain Tumors

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Brain Tumors

• Deepa Subramaniam, M.D.
• Director, Brain Tumor Center
• Lombardi Comprehensive Cancer Center
• Georgetown University Hospital
• Apr 20, 2009

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Classification 1o CNS Tumors

• Glial tumors
• Astrocytic
• I pilocytic
• II fibrillary, gemistocytic
• III anaplastic
• IV glioblastoma (var. gliosarcoma, GC GBM)
• Oligodendroglial
• II oligodendroglioma, III anaplastic
• Ependymal
• I subependymoma, II ependymoma, III anaplastic

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Classification of CNS tumors

• Neuronal tumors
• Gangliocytoma, ganglioglioma, esthesioneuroblastom
  a
• Neuroblastic/glioblastic origin
• Neuroblastoma, medulloblastoma (PNET), RB
• Pineal parenchymal origin
• Pineocytoma, pineoblastoma
• Meningeal origin
• Meningioma, atypical meningioma, malignant
  meningioma
• Germ cell origin
• Pure germinoma, dysgerminoma
• MPNST
• Chordoma

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WHO Grading System
High cellularity/Nuclear atypia
Geographic necrosis/ Pseudopalisading
Vascular proliferation
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WHO Grading System
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Molecular Progression
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Predisposing Factors

• Cranial irradiation
• NCI Case-control Study
• GST polymorphisms
• Cyt P450 isoenzymes
• Inverse relationship to allergic and AI dz
• No relationship to cell phones or transmission
  lines

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Diagnosis MRI in HGG
T1 weighted post-gadolinium T2 weighted image
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High grade gliomas Surgery

• Maximal surgical resection (GTR vs NTR)
• rapid symptom resolution, decreased mass effect
• adequate tissue for accurate histologic grading,
• reduces tumor burden prior to chemoradiation
• Reoperation for recurrent disease
• MS with reoperation for recurrent GBM 14-36
  weeks
• MS with reoperation for recurrent AA 56-88 weeks

Harsh GR et al. Neurosurgery 1987
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HGG Radiation

• Brain Tumor Study Group Addition of adjuvant
  WBRT increased MS from 14 to 36 weeks
• Shift from WBRT to focal EBRT
• Dose-response relationship

Walker MD et al. J Neurosurg 1978 Liang BC, et
al. J Neurosurg 1991 Walker MD, Int J Radiat
Oncol Biol Phys 1979
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HGG Radiation

• Phase II studies of high-dose boost added to
  standard XRT OS benefit
• Randomized Phase III trial of SRS boost No added
  benefit

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HGG Single Agent Chemo

• 1978 BTSG (Protocol 69-01)
• Walker, MD. J Neurosurg 1978
• 18-month survival
• WBRT carmustine (19) WBRT (4)
• 1983 BTSG (Protocol 75-01)
• Green, SB. Cancer Treat Rep 1983
• WBRT procarbazine WBRT carmustine

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HGG Combination chemo

• Northern California Oncology Group protocol 6G61
• Randomized trial comparing PCV to BCNU after
  adjuvant radiotherapy

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Adjuvant Chemo Combination

• Fine et al. Cancer, 1993
• Meta-analysis of 16 randomized trials, 17-year
  period, 3000 patients (GBM and AA), assigned to
  WBRT nitrosoureas
• Absolute increase in survival with addition of
  chemo was 10.1 at 1 year, 8.6 at 2 years
• Median survival increased from 9.4 to 12 months
• Medical Research Council. JCO, 2001
• Randomized study where 674 patients (GBM and AA)
  were treated with surgery RT PCV
• MS of GBM 9.5 months v 10 months MS of AA 13
  months
• Stewart, LA. Lancet, 2002
• Meta-analysis of 12 RCTs, 3004 patients, compared
  RT alone to RT chemo
• Absolute increase in survival with addition of
  chemo was 6 at 1 year
• Median survival increased by 2 months

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Newer agents
O

• Temozolomide
• Novel alklyating agent
• Orally active, 100 bioavailable
• Pro drug with good CSF penetration converted to
  an active metabolite (MTIC) in CNS
• Well tolerated/immune suppression
• MGMT silencing molecular marker

N
H
N
N
H2N
N
H
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HRQOL TMZ vs PCB for recurrent GBM
Osoba et al. JCO 2000
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TMZ in Newly Diagnosed GBM
Stupp NEJM 2005
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PFS Benefit
OS Benefit
Stupp NEJM 2005
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MGMT gene methylation
Hegi ME et al. NEJM 2005
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Glioblastoma Research
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Overcoming Resistance
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Individualized therapy
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Targeting angiogenesis

• Bevacizumab
• AZD2171
• Vatalanib (PTK 787)
• Vandetanib (ZD6474)

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Bevacizumab/Irinotecan

• Phase II study (Vredenburgh et al, JCO 2007)
• 63 radiographic response rates in AAGBM study
  (CCR, Feb 2007)
• 6-month PFS 46, 6-month OS 77 in GBM (n35 1
  CNS bleed, 4 DVT/PE JCO, Oct 2007)

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AZD2171 (Cediranib)

• Phase II multicenter trial
• 56 radiographic partial responses
• 25 APFS
• PFS 117 days
• OS 221 days
• Phase III RCT lomustine, vs AZD2171 vs combination

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Novel agents

• EGFR inhibitors (erlotinib)
• PKC inhibitors (enzastaurin)
• Integrin inhibitors (cilengitide)
• mTOR inhibitors (everolimus, temsirolimus)

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Metastatic Brain Disease

• 150,000 annual cases in the US
• 10-20 of all cancers will metastasize
• Most common to brain
• Lung cancer
• Breast
• Melanoma
• Kidney

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Metastatic Brain Disease

• Standard therapy
• Whole brain radiation
• Stereotactic radiosurgery
• Surgical resection
• Combination of the above
• NO SYSTEMIC THERAPIES
• The Basic premise BBB is intact

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The Blood-Brain Barrier
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BBB Drug transporters
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CNS Metastases Novel Approaches

• Nanoparticles
• Immunoliposomes
• Peptide vectors
• Endogenous-carrier mediated transport
• Small molecule TKIs