New Approaches in Brain Tumor Treatment Virginia Stark-Vance, M.D.
The Primary Brain Tumors es for PicturesMCD for 004.JPG 00 Meningioma 30% Glioblastoma 20% Astrocytoma 10% Nerve sheath 8% Pituitary 6% Oligodendroglioma 4% Lymphoma 3%
The Beast : Malignant Glioma Gliomas account for 78% of all malignant primary brain tumors Malignant gliomas are among the most deadly of all malignancies Comprise only 2% of all cancers Early detection does not prolong survival Few risk factors known
Current Treatment Strategies After surgical resection, pts complete 6 wks of RT and Temodar Median survival 17 mo., most relapse Very well tolerated; some long term survivors
Cytotoxic Therapy in Malignant Glioma Gliadel wafer, placed into tumor cavity Temodar, at diagnosis or relapse Other options: Carboplatin BCNU/CCNU CPT-11 Procarbazine Combinations
Convection Enhanced Delivery CED involves placing catheters around the tumor Several drugs or molecules have been delivered A European study of AP12009 showed 30+ mo. survival
Thalidomide, Accutane,, etc. Both have been used in numerous trials Thalidomide has anti-angiogenic properties with slight activity MDACC: 85% of pts stopped treatment due to death or toxicity
Cytotoxics vs. Targeted May be natural or synthetic May be administered as active agent or prodrug Affect: DNA of rapidly dividing cells Cell enzymes cytoskeleton Include monoclonal antibodies, peptides, cytokines, synthetic nucleic acid sequences May act as: Growth factors Cell-membrane targets Transmembrane targets Cytoplasmic targets Nuclear targets
Malignant Glioma and EGFR Epidermal growth factor receptor is amplified in 36% of malignant gliomas Appears to play a key role in progression Correlates with poor prognosis Associated with resistance to radiation and chemotherapy
Two Drugs, One Target Iressa and Tarceva were both developed as EGFR inhibitors Iressa showed no responses in glioma Tarceva showed responses in 8/49 pts Med. PFS 56 days EGFR amplification did not predict for response
VEGF: Why target vascular endothelium? Malignant gliomas are known to overexpress VEGF VEGF is upregulated in the transition from anaplastic astrocytoma to GBM VEGF can be induced by hypoxia
Avastin is a monoclonal antibody that binds to and inhibits VEGF Avastin was approved for treatment of colon cancer 2/2004 Genentech did not sponsor clinical trials in MG because of the risk of intracranial hemorrhage
The Trouble with Dorothy Dorothy, a 3 yr GBM survivor, read about Avastin on the internet and wanted to add it to her chemotherapy, CPT-11 After only 2 doses of Avastin, she had definite clinical and radiographic improvement
Avastin: A Ray of Hope? Avastin has been used as a single agent and in combination with CPT-11, Temodar, and other drugs Toxicities include hypertension and epistaxis; one patient developed intracranial hemorrhage; another developed bowel perforation
Avastin: Pathologic/Radiographic Responses Avastin blocks vascular proliferation, decreasing vasogenic edema as well as starving the tumor CT/MRI scans show reduction in enhancement and tumor volume
Avastin: Improving Survival? All pts initially treated with Avastin had failed RT and Temodar Pts who had disease progression during RT also responded 90% of patients receiving Avastin had clinical and/or radiographic improvement
The Future of Targeted Therapy Avastin will likely move into first line treatment, in combination with Temodar Nexavar and Sutent are other new drugs being evaluated for MG
Making Sense Out of the Choices Clinical trials may offer new therapies unavailable locally Some institutions may try to influence pts for/against drugs Statistically, only about 10% of pts benefit more from a trial than from standard therapy Pictures for MCD 006.jpg Pictures for MCD 006.jpg
The GBM Reality Show: Survivor or Lost?