Chemotherapy of Medulloblastoma

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Chemotherapy of Medulloblastoma

• By Minh Trinh

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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

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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

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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

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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

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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

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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

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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/m2 BSA
• - For Jorge P, his BSA is 0.61 m2 so he would
  get (0.61 m2 1.5mg/m2 0.915 mg/day
• Side effects
• - Severe constipation, fever, rash
• - Mild hair loss, loss of appetite, feeling tired

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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/m2 BSA
• - For Jorge P. (0.61 m2 800 mg/m2 488
  mg/dose)
• Side effects
• - Severe blood in urine, signs of infection,
  confusion
• - Mild decreased appetite, hair loss, muscle
  pains

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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/drugB
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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/drugB
ank/PC_IMAGE/APRD00466_ZOOM.gif
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Jorge P.

• Methotrexate
• - 2mg/day
• Cyclophosphamide
• - 488 mg/dose
• Vincristine
• - 0.915 mg/dose

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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

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References

• Oncolink. 1994. Abraham Cancer Center of the
  University of Pennsylvania. 1 March 2007
  http//www.oncolink.org/types/article.cfm?c14s7
  8ss783id9484
• Mcdonald T., MD. Emedicine. 21 July 2006. Web
  MD. 1 March 2007. http//www.emedicine.com/ped/t
  opic1396.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/