Chemotherapy of Chemotherapy of MedulloblastomaMedulloblastoma

By: Minh TrinhBy: Minh Trinh

ObjectivesObjectives

Briefly describe chemotherapy of Briefly describe chemotherapy of medulloblastomamedulloblastoma

Discuss different regimens used for Discuss different regimens used for therapy and their mechanisms, therapy and their mechanisms, administrations, how they are supplied, administrations, how they are supplied, dosages for certain drugs, and side effectsdosages for certain drugs, and side effects

Relate therapy to Jorge P.Relate therapy to Jorge P.

ConclusionConclusion

Overview of chemotherapy of Overview of chemotherapy of medulloblastomamedulloblastoma

At this time, the role of chemotherapy in At this time, the role of chemotherapy in medulloblastoma is primarily an additional medulloblastoma is primarily an additional treatment following surgery and radiationtreatment following surgery and radiation

For average-risk disease, children from 3-For average-risk disease, children from 3-10 who received chemotherapy and 10 who received chemotherapy and radiation had a superior survival rate radiation had a superior survival rate

3 year progression free survival rate 80%3 year progression free survival rate 80%

Regiments used in chemotherapyRegiments used in chemotherapy

Methotrexate – tablets, powder/solution for injection; Methotrexate – tablets, powder/solution for injection; folate antimetabolitefolate antimetaboliteLomustine (CCNU) - capsule; an oral nitrosurea alkylating Lomustine (CCNU) - capsule; an oral nitrosurea alkylating agent agent Etoposide – solution for injection; cell cycle-phase specific Etoposide – solution for injection; cell cycle-phase specific antineoplastic agentantineoplastic agentVincristine – solution for injection; plant-derived vinca Vincristine – solution for injection; plant-derived vinca alkaloid which is extracted from alkaloid which is extracted from Catharanthus roseaCatharanthus roseaCyclophosphamide – tablets or powder for injection; Cyclophosphamide – tablets or powder for injection; bifunctional alkylating agent related to nitrogen mustardbifunctional alkylating agent related to nitrogen mustardCisplatin – solution for injection; planar platinum Cisplatin – solution for injection; planar platinum bifunctional alkylating agentbifunctional alkylating agentCarboplatin – powder/solution for injection; platinum Carboplatin – powder/solution for injection; platinum compound related to cisplatin, less cytotoxiccompound related to cisplatin, less cytotoxic

Details of methotrexateDetails of methotrexate

Mechanism of actionMechanism of action- Competitively inhibits dihydrofolate Competitively inhibits dihydrofolate

reductasereductase- Interferes with DNA/RNA synthesisInterferes with DNA/RNA synthesis- Cell cycle-specific (S-phase or G1 into Cell cycle-specific (S-phase or G1 into

S-phase)S-phase)AdministrationAdministration

-- Intravenously, orally, intraventricularly Intravenously, orally, intraventricularly (Jorge P.), intrathecally, (Jorge P.), intrathecally, intramuscularlyintramuscularlyDosingDosing

- Intraventricular dosing guidelines do Intraventricular dosing guidelines do not exist, however in children 2mg/day not exist, however in children 2mg/day is commonly used (Jorge P.)is commonly used (Jorge P.)Side EffectsSide Effects

-- Severe:Severe: changes in vision, diarrhea, changes in vision, diarrhea, confusionconfusion

-- Mild: Hair loss, nausea, eye irritationMild: Hair loss, nausea, eye irritationhttp://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00353_ZOOM.gif

Details of lomustine (CCNU)Details of lomustine (CCNU)

Mechanism of actionMechanism of action- Inhibits DNA replication, RNA Inhibits DNA replication, RNA

transcription, and nucleic acid transcription, and nucleic acid functionfunction

- The chloroethyl group alkylates The chloroethyl group alkylates nucleic acids and cell proteins to nucleic acids and cell proteins to form DNA-DNA or DNA-protein form DNA-DNA or DNA-protein crosslinkscrosslinks

• Administration Administration - OrallyOrally• Side effectsSide effects-- Severe: difficulty breathing, low Severe: difficulty breathing, low

blood count, signs of infectionblood count, signs of infection-- Mild: confusion, hair loss, loss of Mild: confusion, hair loss, loss of

appetiteappetitehttp://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00292_ZOOM.gif

Details of etoposideDetails of etoposide

Mechanism of actionMechanism of action

-- Active during G2Active during G2

-- Binds to a complex of DNA and Binds to a complex of DNA and topoisomerase IItopoisomerase II

-- ApoptosisApoptosis

AdministrationAdministration

-- Orally or intravenouslyOrally or intravenously

Side EffectsSide Effects

-- Severe: tarry stools, blood in urine, Severe: tarry stools, blood in urine, difficulty breathingdifficulty breathing

-- Mild: diarrhea, hair loss, headacheMild: diarrhea, hair loss, headachehttp://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00239_ZOOM.gif

Details of vincristineDetails of vincristineMechanism of actionMechanism of action

-- Binds to the alpha, beta sites of tubulinBinds to the alpha, beta sites of tubulin- Interferes with microtubules which Interferes with microtubules which

compose mitotic spindle fibers compose mitotic spindle fibers - Cell cycle arrest in metaphaseCell cycle arrest in metaphase• AdministrationAdministration

-- IntravenouslyIntravenously• DosingDosing

-- 1.5 mg/m^2 BSA1.5 mg/m^2 BSA

-- For Jorge P, his BSA is 0.61 m^2 so For Jorge P, his BSA is 0.61 m^2 so he would get (0.61 m^2 * 1.5mg/m^2 = he would get (0.61 m^2 * 1.5mg/m^2 = 0.915 mg/day0.915 mg/day

• Side effectsSide effects

-- Severe: constipation, fever, rashSevere: constipation, fever, rash

-- Mild: hair loss, loss of appetite, feeling Mild: hair loss, loss of appetite, feeling tiredtired http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/

PC_IMAGE/APRD00495_ZOOM.gif

Details of cyclophosphamideDetails of cyclophosphamideMechanism of actionMechanism of action

- Prodrug that requires hepatic activation in order to be Prodrug that requires hepatic activation in order to be cytotoxiccytotoxic

- Activated in liver by cytochrone P450 enzymesActivated in liver by cytochrone P450 enzymes- Phosphoramide mustard is the active moietyPhosphoramide mustard is the active moiety- Forms intrastrand and interstrand DNA-DNA Forms intrastrand and interstrand DNA-DNA

crosslinks.crosslinks.

AdministrationAdministration

-- Orally or intravenouslyOrally or intravenously

DosingDosing

-- 800 mg/m^2 BSA800 mg/m^2 BSA

-- For Jorge P. (0.61 m^2 * 800 mg/m^2 = 488 For Jorge P. (0.61 m^2 * 800 mg/m^2 = 488 mg/dose)mg/dose)

Side effectsSide effects

-- Severe: blood in urine, signs of infection, confusionSevere: blood in urine, signs of infection, confusion

-- Mild: decreased appetite, hair loss, muscle painsMild: decreased appetite, hair loss, muscle painshttp://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00408_ZOOM.gif

Details of cisplatinDetails of cisplatin

Mechanism of actionMechanism of action

- Intracellularly, loses its chloride Intracellularly, loses its chloride groups making it electrophilic.groups making it electrophilic.

- Forms interstrand/intrastrand DNA & Forms interstrand/intrastrand DNA & RNA crosslinksRNA crosslinks

AdministrationAdministration

-- Intravenously or intraarteriallyIntravenously or intraarterially

Side effectsSide effects

-- Severe: difficulty breathing, hearing Severe: difficulty breathing, hearing loss, nausea and vomitingloss, nausea and vomiting

-- Mild: blurred vision, changes in Mild: blurred vision, changes in taste, loss of appetitetaste, loss of appetite

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

Details of carboplatinDetails of carboplatin

Mechanism of actionMechanism of action- Hydroxylated by water to form the Hydroxylated by water to form the

active compound, slower than active compound, slower than cisplatin.cisplatin.

- Works like other bifunctional alkylating Works like other bifunctional alkylating agentsagents

AdministrationAdministration

-- IntravenouslyIntravenously

Side effectsSide effects

-- Severe: changes in eyesight, hearing Severe: changes in eyesight, hearing loss, difficulty breathingloss, difficulty breathing

-- Mild: fatigue, loss of appetite, loss of Mild: fatigue, loss of appetite, loss of hair, metallic tastehair, metallic taste

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

Jorge P.Jorge P.

Methotrexate Methotrexate

-- 2mg/day2mg/day

CyclophosphamideCyclophosphamide

-- 488 mg/dose488 mg/dose

VincristineVincristine

-- 0.915 mg/dose0.915 mg/dose

ConclusionConclusion

Chemotherapy usually used after radiation Chemotherapy usually used after radiation or surgical therapyor surgical therapy

Wide variety of different regimens used Wide variety of different regimens used each with different dosages, each with different dosages, administrations, and side effectsadministrations, and side effects

Jorge P was administered methotrexate, Jorge P was administered methotrexate, vincristine, and cyclophosphamidevincristine, and cyclophosphamide

ReferencesReferences

Oncolink. 1994. Abraham Cancer Center of the University of Oncolink. 1994. Abraham Cancer Center of the University of Pennsylvania. 1 March 2007 Pennsylvania. 1 March 2007 http://www.oncolink.org/types/article.cfm?c=14&s=78&ss=783&id=9http://www.oncolink.org/types/article.cfm?c=14&s=78&ss=783&id=9484484

Mcdonald T., MD. Emedicine. 21 July 2006. Web MD. 1 March Mcdonald T., MD. Emedicine. 21 July 2006. Web MD. 1 March 2007. 2007. http://www.emedicine.com/ped/topic1396.htmhttp://www.emedicine.com/ped/topic1396.htm

Clinical Pharmacology. CD-ROM. Tampa: Gold Standard, 1994-Clinical Pharmacology. CD-ROM. Tampa: Gold Standard, 1994-20052005

DrugBank. February 1, 2006. Genome Alberta & Genome Canada DrugBank. February 1, 2006. Genome Alberta & Genome Canada and Departments of Computing Science & Biological Sciences at and Departments of Computing Science & Biological Sciences at the University of Alberta. 1 March 2006. the University of Alberta. 1 March 2006. http://redpoll.pharmacy.ualberta.ca/drugbank/http://redpoll.pharmacy.ualberta.ca/drugbank/