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Brain Tumor Update

Brain Tumor Update. 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

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Brain Tumor Update

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  1. Brain Tumor Update

  2. 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.

  3. 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

  4. Epidemiology new casesdeaths (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 55:10-30, 2005. * Does not include benign brain tumors or metastatic tumors

  5. Malignant Glioma - Statistics • 5-8 / 100,000 malignant gliomas • 35,000 primary CNS neoplasms / year • 15-20% of all primary intracranial tumors (1/2 of gliomas). Occurs in 40’s - 50’s with a M:F of about 2:1 • Disproportionate disability and mortality • 3rd leading cause of cancer related death among men 15-54 years • 4th leading cause in women 15-34 years

  6. Generalizations • In adults, 2/3 tumors occur supratentorially • In children, 2/3 tumors are infratentorial • The most common neoplasms along the spinal cord are schwannomas and meningiomas • The most common glioma found in the spinal cord is the ependymoma • The brain and its coverings are primarily or secondarily involved by neoplasm in about 30% of all cases of systemic cancer

  7. Risk Factors • Hereditary syndromes*: tuberous sclerosis, neurofibromatosis types 1 and 2, nevoid basal cell carcinoma syndrome, and adenomatous polyposis syndromes, Li-Fraumeni cancer family syndrome (inherited p53 mutations). • Family history of brain tumors • Constitutive polymorphisms in glutathione transferases, cytochrome p450 2D6 and 1A1, N-acetyltransferase, ERCC1 and ERCC2, other carcinogen metabolizing, DNA repair, and immune function genes.Lymphocyte mutagen sensitivity to gamma radiation • Prior cancers • Infectious agents or immunologic response: • Allergies • Head traumaEpilepsy, seizures, or convulsionsDrugs and medications • Diet and vitamins: nitrosamine/nitrosamide/nitrate/nitrite consumption, cured foods, calcium, food frequency • Tobacco smoke exposures • Alcohol • Hair dyes and hairsprays • Occupations and industries: synthetic rubber manufacturing, vinyl chloride, petroleum refining/production work, licensed pesticide applicators, agricultural work, others (see text), parental workplace exposures • Ionizing radiation: therapeutic*; diagnostic and other sources • Cellular telephones • Other radiofrequency exposures • Lower frequency electromagnetic field

  8. Clinical Presentation • Headache 40 50 36 35 • Seizure65-95 15-25 40 17 • Hemiparesis 5-15 30-50 22 24 • Mental status changes 10 40-60 21 61 Symptom low-grade high-grade meningioma PCNSL glioma glioma percent with symptom ref: DeAngelis NEJM 344:114-123, 2001.

  9. Tumors of neuro-epithelial tissue Astrocytic 55% Oligodendroglial 3%* Mixed gliomas (oligoastrocytoma) Ependymal Choroid plexus Neuronal (and mixed neuronal-glial) Pineal embryonal 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 Pathologic classification *Likely to be higher (~20%) Neurosurgery 45:1279, 1999 ref: National Cancer Data Base (1985-92) 63,252 cases of primary CNS tumors J Neurooncology 40:151, 1998

  10. 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 tumors2.7%

  11. Histology

  12. Grade II: 5 yr (3-10y) Nuclear atypia Grade III: 3 yr Nuclear atypia + mitosis Grade IV: 1 yr (GBM) Nuclear atypia + mitosis + either endothelial proliferation and/or necrosis Grade II: 15 yr (8-20y) Grade III: 3 yr Glioma Grading and Natural history AstrocytomaOligodendroglioma mixed Median survival (range)

  13. Glioblastoma Multiforme • Grossly, spherical to irregular or ‘butterfly’ shaped in larger centrally located tumors. • More superficial tumors penetrate cortex and invade adjacent leptomeninges to attach to dura. • Mottled appearance with frequent hemorrhage and necrosis. • Multiplicity in 10% of cases • Microscopically, features of anaplastic astrocytoma with key presence of endothelial proliferation and necrosis

  14. (1986-1997) Sept 17, 2005

  15. 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 impairment—eg, moderate dysphasia, moderate paresis, or visual disturbances such as field defect 4 Deficit causing major functional impairment—eg, inability to use limb, gross speech impairment, or visual disturbances 5 Inability to make conscious responses

  16. 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)

  17. 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.

  18. 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.

  19. RTOG 94-02Does chemotherapy given prior to radiation improve survival in patients with anaplastic oligodendroglioma? 88% pts had surgical resection 70% pure oligo (30% mixed) ASCO 2004

  20. Ino et al CCR 2001

  21. 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)

  22. Malignant Glioma - Survival • Surgery : 20 weeks • Surgery + RT : 36 weeks • Surgery + RT + chemotherapy : 40-50 weeks

  23. Benefits of Surgery • Removes heterogeneously resistant cells • Tumor burden diminished - increase in ratio of immune to neoplastic cells • Increases proliferative fraction suscept (decr G0) • Improves oxygenation and vulnerability to RT • Reduces tumor cell density / paracrine factors • Diminishes pool of potential mutants • Diagnostic (sampling) • Neurologic (improved QOL, relief of neurologic deficit / ICP, reduction of steroid requirement) • Oncologic (extension of survival, reduce tumor burden, allow or enhance adjuvant therapy) • More complete surgical resection tends to result in longer survival

  24. Radiation Therapy - Principles • Many techniques for delivering RT - linac, proton beam, gamma knife, interstitial brachytherapy, etc • Usual total dose is 60 Gy in 2 Gy Fx’s. • Treatment area by MRI includes contrast enh. + T2 + 2 cm (46 Gy) with cone down to contrast enh. + 2cm (14 Gy) • 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)

  25. Chemotherapy in GBM (pre-2005) • Meta-analysisLancet 359:1011, 2002 • MRC 2001 J Clin Onc 19:509, 2001 • Large randomized trial (n=674) 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

  26. Temozolomide (TMZ) development for glioma • Novel oral cytotoxic agent (imidazotetrazine-related 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 17:2762, 1999 • 2005 FDA approval for GBM (first line) • Stupp et al. Phase III trial NEJM 352:987, 2005 • Athanassiou et al Phase III trial ASCO 2005 • Stupp et al. Phase II trial J Clin Onc 20:1375, 2002 • Lanzetta et al. Phase II trial Anticancer Res 23:5159, 2003 FDA approval summary: Clin Cancer Res 11:6767, 2005

  27. March 10, 2005

  28. Phase III randomized trial of newly diagnosed patients with GBM The two groups are well-balanced Stupp et al. NEJM 352: 987, 2005

  29. Addition of TMZ to radiotherapy prolongs survival • 78% of patients in RT+TMZ 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

  30. Primary end point

  31. 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

  32. 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.

  33. 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 (p=0.27).

  34. 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 systemsmall molecules targeting Pl-3 kinase and Akt • mTOR inhibitorsrapamycin • p53 gene therapy • Ras pathway antisense oligonucleotides, farnesyl transferase inhibitors • Angiogenesis antibodies to VEGF, VEGF receptors, tyrosine kinase • inhibitors of VEGF

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