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?