It s s Always Something! New Approaches in Brain Tumor Treatment Virginia Stark-Vance, M.D.
When Something Is a Brain Tumor Brain tumors aren t rare: there are over 100,000/yr Most originate as other cancers Even the benign ones are bad Some are curable Some are preventable
The Most Common Brain Tumor Lung cancer: responsible for the most cancer deaths in women Types: Small cell (70% CNS) Adenocarcinoma (40% CNS) Average survival 4-8 mo.
Primary vs. Metastatic Over 100 types Usually don t spread outside the CNS Can be benign Incidence is increasing Glioma is the most common subtype Can be single or multiple Most commonly originate in lung, breast, kidney, melanoma Almost always in other sites Never benign Incidence is increasing Can be single or multiple
Primary Brain Tumors: Who Cares? Brain tumors are among the most deadly of all malignancies Comprise only 2% of all cancers Few risk factors known No prevention strategies identified Early detection does not prolong survival
Doctor, I think I have a brain tumor Headaches: common but not universal Seizures: often in slowgrowing tumors Memory loss, speech disturbance, loss of balance common Almost impossible to detect early by symptoms alone Symptoms may continue less than 1 mo or more than 10 yrs
What Happens Next
Primary Brain Tumors Benign: take it out! Malignant: take out what you can (usually) Radiation (sometimes) Chemotherapy (sometimes) As a rule, there are no rules!
Current Treatment Strategies in Malignant Glioma After surgical resection, pts complete 6 wks of RT and Temodar Maintenance: Temodar for 6-12 mo. Median survival 17 mo., most relapse Very well tolerated; some long term survivors
Radiation Therapy & Knives Whole brain radiation Metastases CNS lymphoma Local RT Most solitary tumors Typically 6 weeks Gamma Knife and Cyberknife Very precise Very small tumors For some non-tumor conditions
Cytotoxic Therapy in Malignant Glioma Gliadel wafer, placed into tumor cavity Temodar, at diagnosis or relapse Other options: Carboplatin BCNU/CCNU CPT-11 Procarbazine Etoposide (VP-16) Combinations
Gliadel: Chemotherapy Even a Neurosurgeon Could Love Gliadel is a BCNU wafer Gliadel is implanted after surgical resection Gliadel releases BCNU 2-3 weeks Gliadel Takes 15 minutes Adds about 2-3 mo. survival
The New Standard of Care Temodar is an oral chemotherapy drug developed in Europe and approved by the FDA in 1999 Most brain tumor pts receive Temodar as their first (and only) chemotherapy Cost: $25004000/mo.
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
Targeted Therapeutics These agents modify the behavior of the malignant state by modulating abnormal signals Example: agents that block angiogenesis, the proliferation of blood vessels allowing tumor growth At least 600 distinct agents have been clinically evaluated
Targets of Approved Drugs CD 20 Her-2/neu Cyclooxygenase-2 DNA polymerase Platelet-derived growth factor Adenosine deaminase Epidermal growth factor receptor P-glycoprotein Vascular endothelial growth factor Estrogen receptor IL-2 receptor Retinoic acid receptor
Is There a Brain Tumor Gene? There are over 3,000 genes that have been reported as possible factors in the development of malignant brain tumors Few have been examined as potential targets for therapy
A New Definition of What Works Cancers may respond by disappearing completely (CR) or by at least 50% of the original size (PR) Because of the aggressiveness of many brain tumors, stable disease (SD) is considered a response Margins of some tumors are difficult to measure, so survival (OS) and 6 mo. progression free survival (PFS) are used
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 has been approved for colon cancer, lung cancer, and breast cancer Genentech initially did not sponsor clinical trials in MG because of the risk of intracranial hemorrhage
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; >1% of patients develop intracranial hemorrhage; 2% develop bowel perforation
Avastin: A Breakthrough?
Avastin s Effect on Cerebral Edema 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, typically within 1 month Avastin was FDA approved for recurrent malignant glioma in May 09
News from ASCO 2009 American Society of Clinical Oncology Avastin trials in Glioblastoma: Avastin + oral VP-16: 6 mo. PFS 44% Avastin + fotemustine: 33% CR and PR Avastin + CPT-11: 6 mo. PFS 37% Avastin q 3 wks: 6 mo. PFS 32% By comparison: Tarceva + Torisel: 6 mo. PFS 12.5%; no objective responses
Cilengitide: the next Avastin? Cilengitide is an integrin inhibitor that has anti-angiogenic and anti-invastive properties Combined with Temodar and RT, showed a 6 mo. PFS of 69% However, when used alone in patients who had failed standard therapy, 6 mo. PFS was 16% Mild side effects: Fatigue, joint aches
Brain Tumor Vaccines Dendritic cell vaccines have shown promise when combined with standard therapy Pt s dendritic cells are cultured with pt s tumor cells Dendritic cells are injected SQ over a period of weeks In some studies, survival has doubled
The Future of Targeted Therapy Avastin will likely move into first line treatment, in combination with Temodar Cilengitide, AZD2171, Talampanel, all show activity in glioma Vaccines that target EGFR are also proving effective
Daria s Case: Primary CNS Lymphoma 42 yo voice teacher, stuttered and stumbled over words Tumor in left temporal area diagnosed 12/05 Surgically removed 6 months of chemotherapy Chance of cure: 70%
Gwen s Case: Anaplastic Oligodendroglioma 35 yo marketing VP, had seizure 6/2000 Diagnosis: anaplastic oligodendroglioma Treatment: Surgical resection Radiation to left frontal area Stereotactic radiation boost 2 years of oral chemotherapy Survival: 9 yrs so far
Julie s Case: Recurrent Anaplastic Astrocytoma For several years, 30 yo medical transcriptionist, had severe headaches, seizures Surgery 4/2002: anaplastic astrocytoma Had radiation and chemo; tumor returned in 8/2003 Had 4 mo of intra-arterial chemotherapy Has been in remission since 1/2004
Dorothy s Case: Refractory Glioblastoma 34 yo diagnosed with glioblastoma 4/2001 Had 3 surgeries, radiation, 6 types of chemotherapy Started Avastin 3/2004 The first person in the world to receive Avastin for a malignant brain tumor
Say Yes to Drugs! TO DIE BECAUSE YOUR CARE COSTS The newer drugs are all expensive Insurance won t pay for experimental therapy Medicare and Medicaid also deny payment for many drugs for brain tumors
The Ethical Dilemma Is it ever ethical to withhold treatment because of the pt s inability to pay? How much should physicians tell their pts about cost? Can pts truly give informed consent without knowing how $$ affects treatment?
On the Road to a Cure Treatment early in the course of the disease may limit spread Approved drugs + drugs in development= 100 s; combinations = 10000 s? Agents risk abandonment before thorough study Clinical trials must keep pace with drug discovery