Brain Tumor Update

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Brain Tumor Update

• Gerry Linette
• April 7, 2006

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Case presentation
67 year old woman presented with partial complex
seizures and headaches x1 mo. MRI shows a
non-enhancing T2 hyper-intense mass in the right
insula, temporal, and frontal areas. Dilantin was
started and the seizures improved. Stereotactic
bx showed a low grade glioma (grade 2
astrocytoma). The diffuse nature of the
glioma precluded surgical resection. PMH prior
radiotherapy for scalp ringworm infection as a
child. After hospital discharge, the patient
had a witnessed seizure (dilantin level 8.3) and
treatment recommendation was given for radiation
and temozolomide. Since starting treatment, the
patient has had no further seizure activity.
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Update on Randomized Clinical Trials
Malignant Glioma (WHO grade)

• 2 Low grade (diffuse) glioma EORTC 22845
• 3 Intermediate grade (anaplastic) glioma RTOG
  94-02
• 4 High grade glioma (glioblastoma multiforme)
  EORTC 22981

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Epidemiology
new cases deaths (estimated)

• 2005 (US) 18,500 12,760
• Incidence 11.47 per 100,000 (annual rate)
• Adjusted 5 yr survival rate (1995-2000)
• 33 adults
• 73 children
• 2nd leading cause of cancer deaths in persons 39 years (US in 2002)
• Jemal et al CA a cancer journal for clinicians
  5510-30, 2005.

Does not include benign brain tumors or
metastatic tumors
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Clinical Presentation
Symptom low-grade
high-grade meningioma PCNSL
glioma glioma
percent with symptom

• Headache 40 50 36 35
• Seizure 65-95 15-25 40 17
• Hemiparesis 5-15 30-50 22 24
• Mental status changes 10 40-60 21 61

ref DeAngelis NEJM 344114-123, 2001.
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Pathologic classification

• Meningeal Tumors
• Meningioma 15
• Hemangiopericytoma
• Melanocytic
• hemiangioblastoma
• Primary CNS lymphoma 4
• Germ Cell Tumors
• Tumors of the Sellar Region
• Pituitary ademoma
• Craniopharyngioma
• Metastatic Tumors
• Lung
• Breast
• Melanoma
• Renal

• Tumors of neuro-epithelial tissue
• Astrocytic 55
• Oligodendroglial 3
• Mixed gliomas (oligoastrocytoma)
• Ependymal
• Choroid plexus
• Neuronal (and mixed neuronal-glial)
• Pineal
• embryonal

Likely to be higher (20) Neurosurgery
451279, 1999
ref National Cancer Data Base (1985-92) 63,252
cases of primary CNS tumors J Neurooncology
40151, 1998
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Glioma Grading and Natural history
Astrocytoma Oligodendroglioma
mixed
Median survival (range)

• Grade II 5 yr (3-10y)
• Nuclear atypia
• Grade III 3 yr
• Nuclear atypia mitosis
• Grade IV 1 yr
• Nuclear atypia mitosis either endothelial
  proliferation and/or necrosis

• Grade II 15 yr (8-20y)
• Grade III 3 yr

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(1986-1997)
Sept 17, 2005
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Within 8 weeks post-op
MRC Neuro scale 1 No neurological deficit 2
Some deficit but adequate function for useful
work 3 Deficits causing moderate functional
impairmenteg, moderate dysphasia, moderate
paresis, or visual disturbances such as field
defect 4 Deficit causing major functional
impairmenteg, inability to use limb, gross
speech impairment, or visual disturbances 5
Inability to make conscious responses
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No survival benefit in patients receiving early
radiation
survival
Progression-free
Scans were obtained every 4 mo in yrs 1-2 then
every yr until progression (median follow up 7.8
yr)
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Study Conclusion
How should patients with a low-grade glioma be
treated? Because the time to clinical or
radiological progression is typically long, a
wait and see policy can be defended for younger
patients presenting with seizures only. In these
patients, treatment can be withheld until the
time of radiological or clinical progression.
In patients with focal deficits, signs of high
intracranial pressure, or cognitive deficits,
treatment should be initiated without delay.
Treatment should consist of a resection as
extensive as possible. If the site and extent of
the tumour prevents meaningful resection, a
biopsy is needed to obtain histological proof of
malignancy. Irradiation can then be recommended
for most patients.
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Case presentation
56 year old woman presented with focal seizures
in 1995. Imaging revealed a right frontal mass.
She had a gross total resection and the pathology
indicated an Intermediate grade glioma (grade 3
oligodendroglioma). She enrolled in a clinical
trial (RTOG 94-02) and received PCV
chemotherapy followed by radiation therapy. She
remained in remission until July 2005. She
experienced partial focal seizures. Brain MRI
revealed recurrence inferior to the surgical
cavity. Stereotactic biopsy revealed grade 3
oligodendroglioma with chromosome 1p and 19q
deletion. The anticonvulsants were adjusted and
the patient is currently receiving temozolomide.
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RTOG 94-02 does chemotherapy given prior to
radiation improve survival in patients with
anaplastic oligodendroglioma?
88 pts had surgical resection 70 pure oligo
(30 mixed)
ASCO 2004
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Ino et al CCR 2001
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astrocytoma, WHO grade IV (Glioblastoma
multiforme)

• Most common primary brain tumor (5 per 100,000
  cases per year)
• 2 of cancer deaths (adults)
• Older adults (65-74 yrs)
• Diffuse infiltrative tumors
• Median survival 12 months
• Optimal approach surgical resection followed by
  radiotherapy (plus temozolomide-2005)

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Chemotherapy in GBM (pre-2005)

• Meta-analysis Lancet 3591011, 2002
• MRC 2001 J Clin Onc 19509, 2001
• Large randomized trial (n674) in grade 3
  and 4 astrocytoma-first
  line comparing
  radiation alone versus radiation followed
  by PCV q 6 wk x up
  to 12 cycles.
  (1988-97)
• No differences in survival

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Temozolomide (TMZ) development for glioma

• Novel oral cytotoxic agent (imidazotetrazine-relat
  ed to dacarbazine).
• Rapid absorption with 100 bioavailability.
• Good CSF penetration (20-40)
• Well tolerated with good safety profile
• 1999 FDA approval for anaplastic astrocytoma
  (second line) refractory to nitrosourea and
  procarbazine. Ref J Clin Onc 172762, 1999
• 2005 FDA approval for GBM (first line)
• Stupp et al. Phase III trial NEJM 352987, 2005
• Athanassiou et al Phase III trial ASCO 2005
• Stupp et al. Phase II trial J Clin Onc 201375,
  2002
• Lanzetta et al. Phase II trial Anticancer Res
  235159, 2003

FDA approval summary Clin Cancer Res 116767,
2005
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March 10, 2005
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Phase III randomized trial of newly diagnosed
patients with GBM The two groups are
well-balanced
Stupp et al. NEJM 352 987, 2005
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Addition of TMZ to radiotherapy prolongs survival

• 78 of patients in RTTMZ arm started adjuvant
  TMZ
• median cycles was 3 (range 0-7)
• 47 patients completed 6 cycles
• 1 reason (39) for discontinuation of adjuvant
  TMZ was disease progression

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Primary end point
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TMZ is safe and well tolerated

• No grade 3 or 4 heme toxicities were seen in
  radiation only group
• Severe infections during the radiation period
• RT only 6 pts
• RT TMZ 9 pts

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Summary
WHO grade

• 2 Low grade (malignant) glioma early radiation
  does not confer a survival benefit. Pts with
  focal or cognitive deficits should be considered
  for radiotherapy.
• 3 Intermediate grade (anaplastic) glioma the
  optimal post-operative therapy has not been
  defined.
• 4 High grade glioma (glioblastoma multiforme)
  addition of TMZ with radiotherapy confers a
  survival benefit.

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Kaplan-Meier estimates of survival according to
MGMT status MGMT is a prognostic factor in GBM
median survival
45 methylated 18.2 mo 55 unmethylated
12.2 mo

• Tumor DNA was available from 307 patients and
  MGMT status could be determined from 206 pts (67
  success). Overall survival did not vary
  significantly according to whether the PCR was
  attempted or not (p0.27).

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