Chemotherapy of Medulloblastoma By: Minh Trinh

Objectives Briefly describe chemotherapy of medulloblastoma Discuss different regimens used for therapy and their mechanisms, administrations, how they are supplied, dosages for certain drugs, and side effects Relate therapy to Jorge P. Conclusion

Overview of chemotherapy of medulloblastoma At this time, the role of chemotherapy in medulloblastoma is primarily an additional treatment following surgery and radiation For average-risk disease, children from who received chemotherapy and radiation had a superior survival rate 3 year progression free survival rate 80%

Regiments used in chemotherapy Methotrexate – tablets, powder/solution for injection; folate antimetabolite Lomustine (CCNU) - capsule; an oral nitrosurea alkylating agent Etoposide – solution for injection; cell cycle-phase specific antineoplastic agent Vincristine – solution for injection; plant-derived vinca alkaloid which is extracted from Catharanthus rosea Cyclophosphamide – tablets or powder for injection; bifunctional alkylating agent related to nitrogen mustard Cisplatin – solution for injection; planar platinum bifunctional alkylating agent Carboplatin – powder/solution for injection; platinum compound related to cisplatin, less cytotoxic

Details of methotrexate Mechanism of action -Competitively inhibits dihydrofolate reductase -Interferes with DNA/RNA synthesis -Cell cycle-specific (S-phase or G1 into S-phase) Administration -Intravenously, orally, intraventricularly (Jorge P.), intrathecally, intramuscularly Dosing -Intraventricular dosing guidelines do not exist, however in children 2mg/day is commonly used (Jorge P.) Side Effects -Severe: changes in vision, diarrhea, confusion -Mild: Hair loss, nausea, eye irritation AGE/APRD00353_ZOOM.gif

Details of lomustine (CCNU) Mechanism of action -Inhibits DNA replication, RNA transcription, and nucleic acid function -The chloroethyl group alkylates nucleic acids and cell proteins to form DNA-DNA or DNA-protein crosslinks AdministrationAdministration -Orally Side effectsSide effects -Severe: difficulty breathing, low blood count, signs of infection -Mild: confusion, hair loss, loss of appetite GE/APRD00292_ZOOM.gif

Details of etoposide Mechanism of action Mechanism of action -Active during G2 -Binds to a complex of DNA and topoisomerase II -Apoptosis Administration -Orally or intravenously Side Effects -Severe: tarry stools, blood in urine, difficulty breathing -Mild: diarrhea, hair loss, headache GE/APRD00239_ZOOM.gif

Details of vincristine Mechanism of action -Binds to the alpha, beta sites of tubulin -Interferes with microtubules which compose mitotic spindle fibers -Cell cycle arrest in metaphase AdministrationAdministration -Intravenously DosingDosing -1.5 mg/m^2 BSA -For Jorge P, his BSA is 0.61 m^2 so he would get (0.61 m^2 * 1.5mg/m^2 = mg/day Side effectsSide effects -Severe: constipation, fever, rash -Mild: hair loss, loss of appetite, feeling tired E/APRD00495_ZOOM.gif

Details of cyclophosphamide Mechanism of action -Prodrug that requires hepatic activation in order to be cytotoxic -Activated in liver by cytochrone P450 enzymes -Phosphoramide mustard is the active moiety -Forms intrastrand and interstrand DNA-DNA crosslinks. Administration -Orally or intravenously Dosing -800 mg/m^2 BSA -For Jorge P. (0.61 m^2 * 800 mg/m^2 = 488 mg/dose) Side effects -Severe: blood in urine, signs of infection, confusion -Mild: decreased appetite, hair loss, muscle pains MAGE/APRD00408_ZOOM.gif

Details of cisplatin Mechanism of action -Intracellularly, loses its chloride groups making it electrophilic. -Forms interstrand/intrastrand DNA & RNA crosslinks Administration -Intravenously or intraarterially Side effects -Severe: difficulty breathing, hearing loss, nausea and vomiting -Mild: blurred vision, changes in taste, loss of appetite nk/PC_IMAGE/APRD00359_ZOOM.gif

Details of carboplatin Mechanism of action -Hydroxylated by water to form the active compound, slower than cisplatin. -Works like other bifunctional alkylating agents Administration -Intravenously Side effects -Severe: changes in eyesight, hearing loss, difficulty breathing -Mild: fatigue, loss of appetite, loss of hair, metallic taste RD00466_ZOOM.gif

Jorge P. Methotrexate -2mg/day Cyclophosphamide -488 mg/dose Vincristine mg/dose

Conclusion Chemotherapy usually used after radiation or surgical therapy Wide variety of different regimens used each with different dosages, administrations, and side effects Jorge P was administered methotrexate, vincristine, and cyclophosphamide

References Oncolink Abraham Cancer Center of the University of Pennsylvania. 1 March Mcdonald T., MD. Emedicine. 21 July Web MD. 1 March Clinical Pharmacology. CD-ROM. Tampa: Gold Standard, DrugBank. February 1, Genome Alberta & Genome Canada and Departments of Computing Science & Biological Sciences at the University of Alberta. 1 March