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Diagnosis and early treatment of brain tumors
Lynne Taylor, MDNeuro-OncologyTufts Medical CenterBoston, MAAugust, 2013
Primary brain tumors
Median age at diagnosis
Schwartzbaum JA et al. (2006) Epidemiology and molecular pathology of glioma
Nat Clin Pract Neurol 2: 494–503 10.1038/ncpneuro0289
Intra-axial vs Extra-axial tumors
Brain tumor types and location
Astrocytoma 5-year survival
Space occupying lesions•Skull prevents expansion and forces “brain
shift” with increasing pressure• Increasing pressure especially a problem
with rapidly growing tumors•Signs of increased intra-cranial pressure
(ICP): HA, N/V, double vision
The Blood-brain barrier
Infiltrating growth patterns - glioma
Low grade astrocytomas•15% of intra-cranial tumors in adults
•Diffuse, slow growing
•“Benign” but lack a capsule and infiltrate surrounding brain tissue
•Potential for change into a more aggressive type of tumor
Clinical•Younger patients 20-40 years of age
•Typically present with seizures only or with “accidental” discovery of tumor on a scan performed for headache or trauma
•Generally neurological examination is normal
Eskandar, E. N. et al. N Engl J Med 2004;351:1875-1882
MRI Scans of the Brain Obtained at the Time of Diagnosis and after Treatment
•Young, previously healthy patient with a
new onset of seizures. The clinical presentation and overall appearance of the lesion are consistent with a primary brain tumor, most likely astrocytoma or oligodendroglioma.
Homunculus
Low grade glioma•35 year old male
with a 2 year history of loss of initiative
•2 month history of increasing loss of energy and HA
•Day of scan developed twitching right arm and face
Axial T-2 weighted image
•Diffuse lesion•Same signal
content as spinal fluid
•Well-demarcated boundaries
•No growth over the corpus callosum to the other side
Coronal Gd-enhanced scan
•Generally no contrast enhancement
•Reflects lack of blood vessel formation and break-down of the BBB
Differential Diagnosis• Oligodendroglioma
• Astrocytoma
• Radiographically very little other than a low grade glioma possible, given location and appearance
Treatment?• Partial resection of the
tumor• Radiation therapy can
be initiated• However, no evidence
that this will change outcome
• 50% 5 year survival even without treatment
Conservative approach•Neurologic and radiographic follow-up
•3-6 month intervals
•Treatment only initiated with change in symptoms or signs for the patient AND change in radiographic studies
•Or, begun with growth noted on x-rays
Symptomatic treatment•Anti-convulsants for seizures•Keppra vs. Dilantin and Tegretol re:
subsequent change in chemotherapy effectiveness
•Dexamethasone for increased intra-cranial pressure
•Education re: symptoms to report immediately
Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors
2000;54;1886-1893 Neurology
•Recommendations.
•1. In patients with newly diagnosed brain tumors, anticonvulsant medications are not effective in preventing first seizures. Because of their lack of efficacy and their potential side effects, prophylactic anticonvulsants should not be used routinely in patients with newly diagnosed brain tumors (standard).
Juvenile pilocytic astrocytoma
JPA
JPA-gross histology
Oligodendroglioma
•Generally calcified
•Cystic component common
•Young boy with HA and visual loss to the right
Histopathology
•Generally round, uniform cells
•“Fried egg” appearance
Chromosomal analysis•Can be done on biopsy or surgical tissue
•Evaluation of loss of chromosomes 1P and 19Q
•Predicts longer survival and potential sensitivity of the tumor to chemotherapy
Eskandar, E. N. et al. N Engl J Med 2004;351:1875-1882
Loss of Heterozygosity
High grade tumors•Anaplastic astrocytomas•Anaplastic oligodendrogliomas•Anaplastic mixed oligo-astrocytoma•Glioblastoma multiforme•Gliosarcoma
MRI appearance GBM
Rim of contrast enhancement•Typically represents the break down of the
“blood-brain barrier”•Thought to be the actual tumor cells
actively expanding faster than the tumor blood supply can keep up which produces dead or necrotic tumor in the interior
Defining features GBM•Necrosis (dead tissue which corresponds
to the dark area on the MRI scan within the rim of white contrast enhancement)
•New tumor blood vessels•Mitotic figures (dividing cells) or a high Ki-
67 index
Two pathways to GBM. (Left panel) Astrocytoma, WHO grade II from a young woman whose tumor recurred 5 yr later as GBM (not shown).
Maher E A et al. Genes Dev. 2001;15:1311-1333
©2001 by Cold Spring Harbor Laboratory Press
Two pathways to GBM. GBM can develop over 5–10 yr from a low-grade astrocytoma (secondary GBM), or it can be the initial pathology at diagnosis (primary GBM).
Maher E A et al. Genes Dev. 2001;15:1311-1333
©2001 by Cold Spring Harbor Laboratory Press
Common symptoms•Headache
•Personality change
•Seizures
•Hemiparesis (less common)
Prognostic factors GBM•1,578 pts on 3 consecutive RTOG
studies/defined six prognostic subsets•Age•Histology•Mental status•Symptom duration•Extent of surgical resection•Neurologic deficit post-op (Karnofsky
score)
Temozolomide (Temodar)•Accelerated approval in 1999 for the
treatment of RECURRENT AA in the USA but both recurrent AA and GBM in Europe
•Rapidly adopted as first line therapy given efficacy and low toxicity profile
•Drug company underestimated the power of a low toxicity oral, highly bioavailable drug for GBM patients.
Temozolomide- a new standard of care
•Second generation imidazotetrazine•Methylates specific DNA site, most
critically O6 position of guanine (AGT)•Nucleotide mismatch leads to apoptosis•Readily crosses the BBB, CSF
concentrations 40% of plasma•100% bioavailable after oral dosing•Mild and predictable toxicity
Mason WP and Cairncross JG (2005) Drug Insight: temozolomide as a treatment for malignant glioma—impact of a recent trial Nat Clin Pract Neurol 1: 88–95 doi:10.1038/ncpneuro0045
Figure 2 Kaplan–Meier estimates of progression-free survival in patients with glioblastoma, according to treatment group
Tumor angiogenesis
Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma
JamesJ. Vredenburgh, Annick Desjardins, James E. Herndon II,
Jeannette M. Dowell, David A. Reardon, Jennifer A. Quinn, Jeremy N. Rich, Sith Sathornsumetee, Sridharan
Gururangan, MelissaWagner, Darell D. Bigner, Allan H. Friedman,and Henry S. Friedman
Clin Cancer Res 2007;1253 13(4) February 15, 2007
6 month survival 72%6 month PFS 38%
Avastin•Bevacizumab•Anti-angiogenic•Anti-Vascular endothelial growth factor
(anti-VEGF) monoclonal anti-body•Significantly improved survival for
metastatic colon cancer patients
Treatment response high grade glioma
2005 Enhanced scan 2010 Enhanced scan
Before treatment with bevacizumab
After treatment with bevacizumab
Diagnosis?
Diagnosis?
Diagnosis?
Diagnosis?
Diagnosis?