Chemotherapy of Medulloblastoma

1. Chemotherapy of Medulloblastoma By: Minh Trinh

2. 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

3. 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 3-10 who received chemotherapy and radiation had a superior survival rate • 3 year progression free survival rate 80%

4. 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

5. 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 http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00353_ZOOM.gif

6. 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 • Administration • Orally • Side effects - Severe: difficulty breathing, low blood count, signs of infection - Mild: confusion, hair loss, loss of appetite http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00292_ZOOM.gif

7. Details of etoposide • 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 http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00239_ZOOM.gif

8. 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 • Administration - Intravenously • Dosing - 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 = 0.915 mg/day • Side effects - Severe: constipation, fever, rash - Mild: hair loss, loss of appetite, feeling tired http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00495_ZOOM.gif

9. 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 http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00408_ZOOM.gif

10. 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 http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00359_ZOOM.gif

11. 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 http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00466_ZOOM.gif

12. Jorge P. • Methotrexate - 2mg/day • Cyclophosphamide - 488 mg/dose • Vincristine - 0.915 mg/dose

13. 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

14. References • Oncolink. 1994. Abraham Cancer Center of the University of Pennsylvania. 1 March 2007 http://www.oncolink.org/types/article.cfm?c=14&s=78&ss=783&id=9484 • Mcdonald T., MD. Emedicine. 21 July 2006. Web MD. 1 March 2007. http://www.emedicine.com/ped/topic1396.htm • Clinical Pharmacology. CD-ROM. Tampa: Gold Standard, 1994-2005 • DrugBank. February 1, 2006. Genome Alberta & Genome Canada and Departments of Computing Science & Biological Sciences at the University of Alberta. 1 March 2006. http://redpoll.pharmacy.ualberta.ca/drugbank/