Chemotherapy in Neuro-oncology Rationale Barriers to effective use of chemotherapy Chemotherapeutic agents Chemotherapy for high grade gliomas Chemotherapy for low grade gliomas Chemotherapy for meningiomas Active chemotherapy clinical trials at JCC

Rationale For The Use Of Chemotherapy in Neuro-Oncology 1 gram of tumor = one billion cells GTR = removal of 99% (990,000,000 cells) Still have 10,000,000 tumor cells Radiation may remove 99% (9,900,000 cells), leaving 100,000 cells

Barriers to Use of Chemotherapy Uncommon (2% of all malignancies) Blood-brain barrier Interaction of chemotherapeutic agents with EIAC

Solutions to Barriers to Use of Chemotherapy Lipophilic molecules (Nitrosureas) Small molecules (Iressa) Osmotic Blood Brain Barrier Disruption Design drugs that do not interfere with EIAC medications Make chemotherapy drugs very expensive

Chemotherapeutic Agents Carmustine (BCNU) Lomustine (CCNU) Procarbazine (Natulan) Temozolomide (Temodal) Vincristine (Oncovin) Camptothecans (irinotecan, edotecarin) gefitinib (Iressa) gefitinib (Iressa)

Carmustine and Lomustine Highly lipophilic nitrosureas Hydrolysis in vivo to form reactive metabolites metabolites cause alkylation and cross- linking of DNA metabolites cause alkylation and cross- linking of DNA CSF equilibrates within one hour to > 50% of plasma levels Metabolism = hepatic microsomal enzyme Excretion = predominantly renal

Nitrosurea Toxicities Dose limiting toxicity is myelosuppression Dose limiting toxicity is myelosuppression Nadir days, recovery days Nausea and vomiting Dizziness, ataxia, lethargy, disorientation Pulmonary fibrosis (dose dependent) Infertility and mutagenesis Carmustine is a vesicant

Procarbazine ? Classification ? Classification Multiple sites of action (inhibits DNA, RNA and protein synthesis) Rapid equilibration with CSF Metabolism = microsomal enzymes Excretion = predominately renal

Procarbazine Toxicities DLT = myelosuppression, nadir days, recovery 28 days Nausea and vomiting CNS depression, lethargy, peripheral neuropathy Hypersensitivity pneumonitis Infertility, mutagenesis Radiation enhancer

Temozolomide Classification = alkylating agent Rapid conversion at physiologic pH to MTIC, CSF concentration is 30% of serum MTIC cytotoxicity due to methylation of DNA at the O 6 position of guanine Antitumor activity is schedule dependent Cytotoxicity influenced by levels of MGMT Levels not infuenced by cytochrome p450 Renal and hepatic clearance minor

Temolozomide Toxicites DLT is myelosuppression, nadir days, recovery within 14 days of nadir DLT is myelosuppression, nadir days, recovery within 14 days of nadir Immunosuppression (lymphopenia) Nausea and vomiting Infertility and mutagenesis Infertility and mutagenesis

Gefitinib (Iressa) Potent and selective inhibitor of EGFR tyrosine kinase EGFR expression and over-expression in GBM other brain cancers Over-expression correlated with poor prognosis in many cancers Once-daily, oral dosing Lipophilic compound but CNS levels are low

Iressa Toxicities DLT is diarrhea Skin rash Elevation in liver transaminases Interaction with EIAC with potential decrease in levels of Iressa

Iressa Efficacy in NSCLC In NSCLC phase III trials, no significant advantage over chemotherapy alone

Iressa Efficacy in GBMs Phase II single centre study, 53 relapsed GBM patients (Riche et al, 2004) No objective tumor responses Six-month EFS = 13% (7/53) Median OS = 39.4 weeks Presence of diarrhea predicted + OS

Adjuvant Chemotherapy for High Grade Astrocytomas Meta-analyses of randomized trials shown small to no improvent using older alkylating agents (Fine, 1993; Stewart 2002) Phase II trial of temozolomide concurrent with radiation followed by six cycles of temozolomide monotherapy (Stupp, 2001)

Adjuvant Temozolomide in GBM Sixty-four patients with GBM 28 days post biopsy or resection TMZ 75 mg/m 2 x 6 wks concomitant with 6000 cGy in 30 fractions, followed by TMZ montherapy (200 mg/m 2 x 5d/28d x 6 cycles

Adjuvant Temozolomide in GBM Safe and well tolerated Two cases of pneumocystis carinii during concomitant phase Median survival was 16 months (historical median survival = 10 months) One-year survival 58% Two-year survival 31%

Adjuvant Temozolomide in GBM EORTC/ NCIC Phase III randomized trial Efficacy results due in mid-2004 If significant, then surgery, plus radiation, plus TMZ may become standard-of-care for newly diagnosed GBM

Salvage Chemotherapy for Glioblastoma Multiforme (GBM) median survival for single agent or combination therapy is 6 to 8 months median survival for single agent or combination therapy is 6 to 8 months

Phase II Randomized Trial of Temozolomide versus Procabazine Response rates 5.4% for TMZ versus 5.3% for PCB Response rates 5.4% for TMZ versus 5.3% for PCB PFS 12.4 weeks for TMZ versus 8.32 weeks for PCB (P=.0063) No significant difference in median overall survival No difference in adverse events HRQL response higher in TMZ arm

Chemotherapy for Anaplastic Oligodendrogliomas and OAs Anaplastic oligodendrogliomas chemosensitive LOH for 1p and 19q confirm increased chemosensitivity and overall survival PCV Temozolomide (phase II trial evidence for first and second-line therapy) No randomized trial of PCV versus TMZ

Chemotherapy for Low Grade Gliomas Treatment of low-grade gliomas controversial Treatment of low-grade gliomas controversial Radiation may prolong TTP Prospective and retrospective show that deferred radiation does not compromise survival Primary chemotherapy as alternative to surgery or adjuvant radiation

Chemotherapy Treatment of Meningiomas Hydroxyurea for recurrent or unresectable meningiomas Case reports x 4 ( Schrell, 1997) Hydroxyurea well tolerated and inexpensive Temozolomide currently being studied in this setting

Active Chemotherapy Clinical Trials at