Chemotherapy in Neuro-oncology

1. 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

2. 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

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

4. 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

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

6. Carmustine and Lomustine • Highly lipophilic nitrosureas • Hydrolysis in vivo to form reactive metabolites • 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

7. Nitrosurea Toxicities • Dose limiting toxicity is myelosuppression • Nadir 25-60 days, recovery 35-85 days • Nausea and vomiting • Dizziness, ataxia, lethargy, disorientation • Pulmonary fibrosis (dose dependent) • Infertility and mutagenesis • Carmustine is a vesicant

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

9. Procarbazine Toxicities • DLT = myelosuppression, nadir 14-21 days, recovery 28 days • Nausea and vomiting • CNS depression, lethargy, peripheral neuropathy • Hypersensitivity pneumonitis • Infertility, mutagenesis • Radiation enhancer

10. 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 O6 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

11. Temolozomide Toxicites • DLT is myelosuppression, nadir 21-28 days, recovery within 14 days of nadir • Immunosuppression (lymphopenia) • Nausea and vomiting • Infertility and mutagenesis

12. 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

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

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

15. 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

16. 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)

17. Adjuvant Temozolomide in GBM • Sixty-four patients with GBM 28 days post biopsy or resection • TMZ 75 mg/m2 x 6 wks concomitant with 6000 cGy in 30 fractions, followed by • TMZ montherapy (200 mg/m2 x 5d/28d x 6 cycles

18. 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%

19. 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

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

21. Phase II Randomized Trial of Temozolomide versus Procabazine • 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

22. 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

23. Chemotherapy for Low Grade Gliomas • 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

24. 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

25. Active Chemotherapy Clinical Trials at