Glioblastoma Multiforme

1
Glioblastoma Multiforme

• Grand Rounds 2/2005
• Caron Rigden

2
Case Presentation

• 49 y/o presents to ED with 2 episodes of loss of
  consciousness over the preceeding month.
• Symptoms associated with lightheadedness, nausea,
  generalized weakness, and confusion upon arousal.
  Episodes not witnessed.
• Dull frontal headache for a month.
• 30 pound weight loss over past 3 months.

3
Case cont.

• PMHx Two prior brain tumor resections, and
  patient describes similar symptoms prior to these
  resections.
• Social lives with his mother, past hx of etoh
  abuse and ivda
• Meds none
• NKDA
• FHX n/c
• ROS no nightsweats, fevers/chills, rest ros (-)

4
Case cont.

• PE AF VSS
• Thin, NAD
• Oriented x 4, no papilledema, perrl
• CN grossly intact, strength 5/5, sensation
  intact, reflexes symmetric, finger to nose
  intact, unsteady gait
• Rest of exam unremarkable
• Labs chemistries and blood counts unremarkable

5
Case cont.-Head CT

• evidence of prior left frontal craniotomy
• suggestion of large mass in the frontal region
  near the midline
• left temporal vasogenic edema
• mass effect on the intrahemispheric fissure and
  the frontal horns of the lateral ventricles.

6
Case cont.-MRI

• 5 x 4 x 4 cm homogeneously enhancing left frontal
  mass with midline shift to the right of 1 cm
• 2 x 2 x 2 cm enhancing lesion in left temporal
  lobe
• 1.2 cm lesion in right cerebellar medullary angle

7
Old records obtained

• 1994 left frontal lobe mass resection with
  pathology low grade astrocytoma.
• 1999 recurrent resection of left frontal lobe
  mass with pathology malignant astrocytic cells
  with enlarged pleomorphic hyperchromatic nuclei
  and focal areas of necrosis c/w glioblastoma
  multiforme.
• Underwent adjuvant tx with EBRT (6300Gy) and BCNU
  in 1999

8
Epidemiology of Primary Brain Tumors

• ACS 2005 estimated 18,500 new cases
• estimated 12,760 deaths
• CBTRUS 14.1/100,000/yr
• 7.3/100,000/yr are
  malignant
• Worldwide 3.6/100,000 males/yr
• 2.5/100,000 females/yr
• Overall the incidence is higher in developed
  countries

9
Histologic Subtypes of Primary Brain Cancer

• Glioblastoma Multiforme
  21.7
• Malignant Astrocytomas
  16.6
• All oligodendroglioma
  3.1
• All ependymomas
  2.3
• Low grade astrocytomas
  1.8
• Meningiomas
  26.7
• Pituitary
  9.7
• Nerve Sheath tumors
  7.3
• CNS Lymphoma
  3.5
• Neuron and neuron/glial tumors 1.0
• Craniopharyngiomas
  1.0
• Germ Cell Tumors
  0.5
• Choroid plexus
  0.3
• Other tumors
  2.7

10
Histologic Classification of Glial Tumors
(World Health Organization 2000)

• Astrocytic Tumors
• Pilocytic (grade 1)
• Diffuse/Fibrillary (Grade 2)
• Anaplastic (grade 3)
• Glioblastoma Multiforme (grade 4)
• Oligodendroglial tumors and mixed variants
• Oligodendroglioma, well differentiated
  (grade 2)
• Anaplastic oligodendroglioma (grade 3)
• Mixed oligodendroglioma/astrocytoma (grade
  2)
• Mixed anaplastic oligodendroglioma/astrocyto
  ma (grade 2)
• Ependymal Tumors
• Myxopapillary ependymoma (grade 1)
• Ependymoma (grade 2)
• Anaplastic (grade 3)

11
Histology
12
More Histology

• Necrosis surrounded by pallisading cells
• Hypercellular
• Hyperchromatism
• Pleomorphism

13
Clinical Presentation(Varies depending upon size
and location of tumor)

• Most common symptoms
• Headache (80)
• Seizure (30)
• Focal neurologic deficits
• Change in mental status
• Time from initial symptoms to diagnosis usually lt
  6 months (70 of patients)

14
Imaging
15
Prognosis

• Median Survival at time of diagnosis is
• 4-12 months depending upon degree of tx
• 5 year survival rate lt5
• Good prognostic indicators
• Young age
• Good performance status

16
Treatment

• Surgery
• Radiation
• Chemotherapy

17
Surgical Resection

• Incurable secondary to the infiltrative nature
• Rationale behind resection
• -to obtain definitive histologic diagnosis
• -to palliate symptoms from local tumor effect
• -to potentially provide better tumor control
  
• with radiation/chemotherapy
• -to provide tissue for molecular/genetic
  analysis for
• prognostication and research
• -to provide improved survival

18
Surgery cont.

• Controversy exists behind the correlation between
  the extend of resection and survival
• Goal is to remove as much tumor without causing
  neurologic dysfunction
• Those that cannot be removed will need a
  stereotactic/open needle bx

19
Radiation Therapy

• Most effective therapy postoperatively
• Improves local control and survival
• 80-90 of recurrence are within 2 cm of original
  tumor, thus EBRT is directed at the
• T2 weighted tumor with an additional 1.5-2.0
  cm margin (total dose 60Gy)

20
Radiation Therapy cont.

• Alternative strategies
• -Hyperfractionated/Accelerated
  therapy
• -Conformational radiotherapy
• -Interstitial brachytherapy
• -Stereotactic radiosurgery
• -Heavy particle therapy
• -Radiosensitizers
• have been investigated alone and in conjuction
  with EBRT
• without any additional improvement in survival

21
Chemotherapy

• Two meta-analyses showed survival benefit with
  adjuvant chemoradiation vs. radiation alone.
• Traditional Choices
• Nitrosoureas (BCNU/CCNU) vs.
• PCV (procarbazine, CCNU, vincristine)
• Neither regimen has been proven to be more
  effective.

22
Chemotherapy cont.

• Temozolomide
• -oral alkylating agent
• -FDA approval in 1999 for recurrent/progressi
  ve anaplastic astrocytoma that had failed
  nitrosoureas/procarbazine
• -Phase II study, 2002, by Stupp et. al
  showed potential survival advantage by adding TMZ
  concomitantly and adjuvantly to RT.

23
Phase III of concomitant and adjuvant TMZ with RT
in newly dx GBMStupp et al, JCO 2004 (22)14S 2

• 573 patients 85 centers
• Histology proven to be grade 4 at a central
  location
• Randomized to
• 1. Standard RT (60 Gy in 30 daily
  fractions)
• VS.
• 2. Standard RT (60 Gy in 30 daily
  fractions)
• concomitant (TMZ 75 mg/m2/d daily
  x 42 days
• followed by 6 cycles of adjuvant TMZ
  (150-200
• mg/m2, daily x 5 days, q28d).

24
Results
25
Results cont.

• Toxicities
• Grade 3/4 myelosuppression in
• 7 during concomitant TMZ/RT
• 16 of adjuvant TMZ
• Overall showed improved PFS/OS in GBM

26

• BCNU embedded in a biocompatible, biodegradable
  wafer which is deposited within the resected
  cavity
• FDA approved in 1996 as an adjunct to surgery for
  recurrent GBM
• 2003 approval extended to include the use as
  adjunct to surgery and RT for newly dx GBM

27
Phase III study comparing adjuvant BCNUwafer vs
placeboWestphal et al. Neuro-oncol 2003 (2) 79

• international, multicenter, double-blind,
  placebo-controlled trial of 240 patients with
  primary high grade gliomas
• randomized to resection and RT /- Gliadel wafer
  vs. placebo
• BCNU
  Placebo
• Median survival 13.9 months
  11.6 months (p0.3)
• Median Survival GBM subset 13.5 months
  11.4 months (p0.1)
• Adverse events CSF leak (5 bcnu vs 0.8
  placebo)
• Intracranial
  HTN (9.1 bcnu vs 1.7 placebo)
  

28
Molecular Pathways in Gliomas(UpToDate 2005)
29
Targets and Potential Novel Therapeutic Agents

• EGFR antibodies (including
  tagged to toxins/radioactive isotopes)
• tyrosine
  kinase inhibitors of EGFR (ie. gefitinib,
  erlotinib)
• PDGF inhibitors of tyrosine
  kinase activity of PDGFR (imatinib)
• Pl-3 kinase system small molecules targeting Pl-3
  kinase and Akt
• mTOR inhibitors rapamycin
• p53 gene therapy
• Ras pathway antisense oligonucleotides,
  farnesyl transferase inhibitors
• Angiogenesis antibodies to VEGF, VEGF
  receptors, tyrosine kinase
• inhibitors
  of VEGF

30
Recurrent Astrocytoma-Treatment

• Surgical Resection if possible
• Further EBRT usually not feasible, but possible
  role for brachytherapy or stereotactic
  radiosurgery
• Chemotherapy-
• Gliadel wafer
• Temezolemide
• Nitrosoureas (but limited by previous use
  secondary to resistance and cumulative toxicities
  ie. myelosuppresion/pulmonary fibrosis)
• Clinical trial

31
Phase II study of 225 patients with first relapse
GBM randomized to temozolomide or
procarbazineYung et al., BJC 2000 (5) 588

• TMZ 150-200mg/m2/day x 5 days repeated q28 days
• vs.
• PCB 125-150mg/m2/day x 5 days repeated q28
  days
• Primary objectives PFS, Safety Secondary
  objectives OS, HRQL
• 
  TMZ PCB
• 6 month PFS 21
  8 (p0.0008)
• Median PFS 12.4
  wks 8.32 wks (p0.0063)
• 6 month OS 60
  44 (p0.019)
• QOL favored TMZ over PCB

32
Systemic review of the effectiveness of
temozolomide for the tx of recurrent malignant
glioma Dinnes, BJC 2002 (86) 501

• Temozolomide may increase PFS, but has no
  significant impact on overall length of survival.
• Appears to have few serious side effects
• Positive impact upon quality of life
• Overall, evidence is not strong and more
  controlled randomized studies are needed.

33
Conclusions

• Most common primary brain malignancy in adults
  with very poor prognosis
• Incurable, but current therapy can prolong
  survival surgery RT chemotherapy
• Novel agents targeting molecule mechanisms may
  provide improvements in therapy or may eventual
  be used for prognostic implications.