Chemotherapy Resident Educational Objectives 42105

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ChemotherapyResident Educational
Objectives4-21-05

• Todd D. Tillmanns MD
• Assistant Professor
• Division of Gynecologic Oncology
• University of Tennessee / West Clinic

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TREATMENT PRINCIPLES AND APPROACHES

• Chemotherapy has a narrow therapeutic window.
  Potential complications from chemotherapy range
  from drug reaction to death. Consequently,
  administration of chemotherapy requires more
  intensive preparation than other drug
  prescriptions.
• Before giving chemotherapy, we recommend going
  over a checklist
• 1. The cancer diagnosis must be confirmed
  histologically
• 2. The chemotherapy agents must be appropriate
  for the diagnosis
• 3. Patient must be healthy enough to stand up
  to the rigors of
• chemotherapy (GOG performance status of 0,
  1, or 2 and an
• estimated survival of ?3 months)
• Laboratory results should be adequate (WBC ? 3000
  ANC gt 1500), platelets ? 100,000. AST, ALT,
  GGT, LDH, and alkaline phosphatase ? 3 x normal.
  Bilirubin must be ?1.5 x normal. Creatinine ? 2
  mg or creatinine clearance ³ 50 mL/min)
• If the patients body surface area is more than
  2, the chemotherapy dose is usually limited to
  BSA of 2.

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Differing Roles of Chemotherapy

• Induction given when no alternative treatment is
  available
• Adjuvant used after initial surgical or
  radiation therapy to minimize recurrence
• Salvage used after recurrence of refractory
  tumor after previous chemotherapy
• Chemosensitive given concurrently with radiation
  to increase radiosensitivity
• Neoadjuvant given prior to definitive treatment
  (surgery or radiation) to reduce tumor burden

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RESPONSE TO CHEMOTHERAPY

• Complete response (CR) A complete disappearance
  of all clinical evidence of tumor, including
  normalization of the CA-125 value, determined by
  two observations at least 4 weeks apart. There
  should be no evidence of disease by CT, PET scan
  or MRI if these radiologic modalities are used.
• Partial response (PR) A gt50 decrease in the sum
  of the product of measured lesions, determined by
  two observations not less than 4 weeks apart. No
  simultaneous increase in the size of any lesion
  or the appearance of new lesions may occur.
  Nonmeasurable lesions must remain stable or
  regress to be included in this category.
• Stable disease (SD) A steady state of response
  less than PR, or progression less than PD,
  lasting at least 4 weeks. No new lesions.
• Progressive disease (PD) An unequivocal increase
  of at least 50 in the product of the measured
  lesion. New lesions also constitute PD.

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MEASURABLE DISEASE

• Measurable disease - the presence of at least one
  measurable lesion. If the measurable disease is
  restricted to a solitary lesion, its neoplastic
  nature should be confirmed by cytology/histology.
  
• Measurable lesions - lesions that can be
  accurately measured in at least one dimension
  with longest diameter ?20 mm using conventional
  techniques or ?10 mm with spiral CT scan.
• Non-measurable lesions - all other lesions,
  including small lesions (longest diameter lt20 mm
  with conventional techniques or lt10 mm with
  spiral CT scan), i.e., bone lesions,
  leptomeningeal disease, ascites,
  pleural/pericardial effusion, inflammatory breast
  disease, lymphangitis cutis/pulmonis, cystic
  lesions, and also abdominal masses that are not
  confirmed and followed by imaging techniques
  and.

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General Mechanism

• Cytotoxic
• Apoptosis

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Indications

• Neoadjuvant Chemo-radiation
• Primary Treatment
• Chemoradiation
• Adjuvant
• Recurrent Treatment
• Palliative

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TYPES OF CHEMOTHERAPY

• ALKYLATING AGENTS
• ANTIMETABOLITES
• VINCA ALKALOIDS
• ANTIBIOTICS
• HORMONES
• HEAVY METALS
• IMMUNOTHERAPY

1.
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ALKYLATING AGENTS

• All possess positively charged alkyl groups
  that are able to bind to negatively charged sites
  on DNA. They form DNA adducts, leading to single
  and double strand breaks or cross links. Most
  commonly occurs at N-7 position of guanine.
• Altretamine (Hexamethylamine, Hexalen, HMM
• Carboplatin (Paraplatin)
• Chlorambucil (Leukeran)
• Cisplatin (Platinol, CDDP)
• Cyclophosphamide (Cytoxan, Neosar, Endoxan)
• Etoposide (Vepesid, VP-16)
• Ifosfamide (Ifex)
• Melphalan (Alkeran)
• Mitomycin (Mitomycin-C, Mutamycin)
• Mitoxantrone (Novantrone, DHAD, DHAQ)
• Thiotepa (Tespa, TSPA)

SGO Chemotherapy of Gynecologic Cancers 2nd edit.
Stephen C. Rubin 2004. Lippincott Williams
Wilkins
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ANTIMETABOLITE

• Structural and chemical analogs of naturally
  occuring substances in the metabollic pathways
  leading to synthesis of purines, pyrimidines, and
  nucleic acids. Usually S-phase specific. Most
  effective in rapidly growing tumors. Long
  exposure is often most effective.
• Fluorouracil (5FU, Effudex, Adrucil)
• Gemcitabine (Gemzar)
• Methotrexate (Mexate, Folex, Abitrexate,
  Rheumatrex)

SGO Chemotherapy of Gynecologic Cancers 2nd edit.
Stephen C. Rubin 2004. Lippincott Williams
Wilkins
12
VINKA-ALKALOIDS

• Derived from the common periwinkle plant known
  as Catharanthus roseus. Inhibit microtubular
  polymerization by binding to the tubulin subunit
  at a site distinct from the taxane-binding site.
  This causes mitotic arrest by inhibiting the
  mitotic spindle.
• Vinblastine (Velban, VLB, Velsar, Alkaban)
• Vincristine (Oncovin, Vincasar PFS, VCR,
  Leurocristine)

SGO Chemotherapy of Gynecologic Cancers 2nd edit.
Stephen C. Rubin 2004. Lippincott Williams
Wilkins
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ANTIBIOTICS

• Bleomycin (Blenoxane) Single strand breaks in
  the DNA, dependent on a metal ion cofactor
  (copper or iron) forming superoxide ions.
• Dactinomycin (Cosmogen, Actinomycin-D) DNA
  intercalation inhibiting DNA transcription and
  RNA translation.
• Doxorubicin (Adriamycin, Rubex) Topoisomerase II
  inhibition, DNA intercalation and free radical
  formation
• DoxorubicinLiposomal (Doxil)

SGO Chemotherapy of Gynecologic Cancers 2nd edit.
Stephen C. Rubin 2004. Lippincott Williams
Wilkins
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HORMONES AND SERMS

• Medroxyprogesterone acetate (Provera,
  Depo-Provera)
• Megestrol acetate (Megace, Megestrol)
• Tamoxifen (Novaldex)

SGO Chemotherapy of Gynecologic Cancers 2nd edit.
Stephen C. Rubin 2004. Lippincott Williams
Wilkins
15
MICROTUBULE INHIBITION

• Paclitaxel (Taxol) Binds to and stabilizes
  intracellular microtubules? abnormal spindle
  formation, which leads to cytotoxic effect.
• Taxotere (Docetaxel) Similar to paclitaxel
  though promotes assembly and inhibits
  depolymerization of intracellular microtubules

SGO Chemotherapy of Gynecologic Cancers 2nd edit.
Stephen C. Rubin 2004. Lippincott Williams
Wilkins
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TOPOISOMERASE-I INHIBITOR

• Topotecan (Hycamtin) Inhibitionn of
  topoisomerase I. DNA breaks occurdue to
  stabilized covalent bonds between genomic DNA and
  the topo I enzyme.

SGO Chemotherapy of Gynecologic Cancers 2nd edit.
Stephen C. Rubin 2004. Lippincott Williams
Wilkins
17
OTHER MECHANISMS

• Vinorelbine (Navelbine, NVB)
• nucleoside analog, mechanism not exactly known

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IMMUNOTHERAPY

• ANOTHER LECTURE ANOTHER TIME

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Endometrial Cancer
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Response to Chemotherapy in Endometrial Cancer
Phase II Studies
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Response to Chemotherapy in Endometrial Cancer
Phase III Studies
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Response to Hormones for Endometrial Cancer
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Chemotherapy treatment for Leiomyosarcomas of the
uterus
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Chemotherapy for Carcinosarcoma of the Uterus

• GOG Trial Response Rates
• Adriamycin 10
• Cisplatin 18
• Etoposide 7
• Ifosfamide 35
• Taxol 19
• Ifos/Cisplatin 54
• PFI increased (4 v 6 months)
• Increased toxicity
• No increase in survival
• Ifos/Taxol ?---GOG 161
• Thalidomide ?---GOG 230B

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Chemotherapy for Gestational Trophoblastic Disease
May substitute cyclophosphamide 3 mg/kg IV x
5d same as EMA-CO except substitute
etoposide/cisplatin for vincristine
cyclophosphamide
SGO Chemotherapy of Gynecologic Cancers 2nd edit.
Stephen C. Rubin 2004. Lippincott Williams
Wilkins
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Ovarian Cancer
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Expected Response by Stage to Chemotherapy for
Ovarian Cancer