All you need to know about Chemotherapy.

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All you need to know about Chemotherapy.

• Lynne Cormode

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What is Chemotherapy?

• Systemic treatment against malignant cells to try
  and prevent growth, invasion, metastasis and
  eventual death of patients.
• Initially discovered after WW1 when soldiers
  exposed to nitrogen mustard were observed to have
  had a improvement in solid tumour size.

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Chemotherapy Intent / Terms

• Adjuvant
• To reduce cancer recurrence
• Neo-Adjuvant
• To down stage tumour prior to surgery or radical
  treatment
• Palliative
• To reduce cancer load thereby improving symptoms
  and prognosis
• Radical
• Curative treatment
• Concomitant
• Combined modality treatment (Chemo/radiotherapy)

• Regime
• Single / Combination Drugs
• Cycle
• Varies from weekly to 12 weekly
• Dose
• Body surface area i.e. mg/m2 (Dubois Dubois)
• Renal excretion i.e. AUC (Area under the curve)

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Chemotherapy Forms / Types

• Oral
• Intravenous
• Bolus / Infusional
• Central / Peripheral
• Locally
• Intratheccal
• Intraperitoneal / Intravesical
• Topical
• Intra-arterial (limb perfusion)
• Subcutaneous or Intramuscular

• Classic chemotherapy
• Immunotherapy
• Biological / Molecular targeted therapy

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Modes of Action - General

• Inhibition of cell multiplication via
• Macromolecular synthesis and function i.e. DNA /
  RNA / Proteins
• Cytoplasmic signalling
• Cell membrane receptor synthesis, expression and
  function
• Cellular environment

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The Cell Cycle

• Interphase
• G1 (presysnthesis gap)
• S (synthesis of DNA)
• G2 (postsynthesis gap)

• Mitosis
• M (cell division)
• Prophase
• Sister chromatids condense
• Mitotic spindle assembles
• Nuclear envelope breaks down
• Metaphase
• Microtubles align chromosomes
• Centromeres halfway between spindle poles
• Anaphase
• Separation of sister chromatids at centromere
  moving towards poles
• Cytokinesis (cell division) starts
• Telophase
• Nuclear membranes reforms
• Chromosomes become extended
• Cytokinesis completes

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Traditional Chemotherapy Classes
ANTIMETABOLITES
PODOFYLOTOXINS
TAXANES
ANTITUMOUR ANTIBIOTICS
ANTIMICROTUBULE AGENTS
ANTRACYCLINES
CHEMOTHERAPY
CAMPTOTHECINES
VINCA ALKALOIDS
ALKYLATING AGENTS
PLATINUM DRUGS
NITROSOUREAS
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Antimetabolites nucleoside analogues /
antagonists
FOLIC ACID
Methotrexate inhibits DHFR
PURINES Guanine Adenine
PYRIMIDINES Cytosine Thymine Uracil
TETRAHYDROFOLIC ACID
5FU Capecitabine Cytarabine Mercaptopurine Azathio
prine Fludarabine inhibit Thymidylate synthase
NUCLEOTIDES
DNA REPLICATION
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Antitumour Antibiotics

• Topoisomerases are essential enzymes that
  maintain the topology of DNA. Inhibtion
  interferes with both transcription and
  replication of DNA by upsetting proper DNA
  supercoiling.
• Cell cycle specfic G1 and S phase
• Type I topoisomerase inhibitors,
  Camptothecins (Irinotecan, Topotecan)
• Type II topoisomerase inhibitors,
  Epipodopyllinotoxins (Etoposide)
  Antracyclines (Doxorubicin, Daunorubicin)
  also induce O2 free radicals that break DNA
  strands inhibiting replication
• Others include Actinomycin D, Mitomycin C,
  Bleomycin

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Antimicrotubule Agents

• Prevent microtubule function therefore preventing
  the separation of chromatids.
• Cell cycle dependant M (anaphase)
• Taxanes (Paclitaxel Docetaxel) causes
  hyperstabilisation of microtubules
• Vinca Alkaloids (Vincristine, Vinblastine,
  Vinorelbine) inhibits the assembly of tubulin
  into microtubules

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Alkylating agents

• Ability to alkylate many nucleophilic function
  groups causing the formation of covalent bonds
  (cross linking of DNA)
• Non cell cycle specific
• Platinum drugs (Oxaliplatin, Cisplatin,
  Carboplatin) renally excreted
• Nitroureas (Carmustine, Lomustine, Semustine)
  highly lipid soluble i.e. cross BBB
• Others Cyclophosphamide, Dacarbazine,
  Procarbazine, Melphalan, Busulphan, Chlorambucil.

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Hormones / Cytokines

• Prednisolone / Dexamethasone
• Tamoxifen
• Aromatase Inhibitors (Letrozole, Anastrozole)
• Gonadotropin releasing hormone agonists (Zoladex)
• Interferon alpha

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Monoclonal Antibodies

• Designed to target highly expressed tumour
  specific antigens thereby increasing the immune
  response to the tumour cell.
• Rituximab (CD20)
• Cetuximab (Epidermal Growth Factor Receptor 1)
• Transtuzumab (Human Epidermal growth factor
  Receptor 2)
• Bevacizumab (Vascular Endothelial Growth Factor)
• Tyrosine Kinase Inhibitors
• Imatinib (Philadelphia chromosome, Bcr-Abl TKI)
• Erlotinib (EGFR inhibitor)
• Sunitinib (multiple receptor inhibitors inc
  VEGFR, PDGFR)

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Chemotherapy Toxicities 1

• Bone Marrow Suppression
• Neutropenia
• Anaemia
• Thrombocytopenia
• GI
• Nausea / Vomiting
• Mucositis
• Reproductive

• Skin / Hair
• Palmar plantar erythodysthesia
• Sun sensitivity
• Extravasation
• Rashes
• Alopecia (scalp cooling)
• Nephrotoxicity
• Hepatic toxicity

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Chemotherapy Toxicities 2

• Neurotoxicity
• Peripheral neuropathy
• Ototoxicity
• Constipation
• Cardiac toxicity
• Coronary vasospasm
• Reduced LVEF
• Bladder toxicity
• Haemorrhagic cystitis

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Practical Issues

• Ward admissions
• Neutropenic sepsis
• Symptomatic myelosupression
• Dehydration
• Cardiac events
• Extravasations
• Anaphylactoid reactions

• Chemotherapy spillage policy