All you need to know about Chemotherapy.

Lynne Cormode

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.

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)

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

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

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

Traditional Chemotherapy Classes

TAXANES ANTIMICROTUBULE AGENTS VINCA ALKALOIDS ANTIMETABOLITES CHEMOTHERAPY PODOFYLOTOXINS ANTITUMOUR ANTIBIOTICS ANTRACYCLINES CAMPTOTHECINES ALKYLATING AGENTS NITROSOUREAS PLATINUM DRUGS

PURINES Guanine Adenine

Antimetabolites

nucleoside analogues / antagonists

FOLIC ACID Methotrexate inhibits DHFR PYRIMIDINES TETRAHYDROFOLIC ACID Cytosine Thymine Uracil 5FU Capecitabine Cytarabine Mercaptopurine Azathioprine NUCLEOTIDES Fludarabine inhibit Thymidylate synthase DNA REPLICATION

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

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

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.

Hormones / Cytokines

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

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)

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

Chemotherapy Toxicities 2

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

Practical Issues

Ward admissions   Neutropenic sepsis Symptomatic myelosupression     Dehydration Cardiac events Extravasations Anaphylactoid reactions Chemotherapy spillage policy