Chemotherapy

Aka: Chemotherapy, Chemotherapy Extravasation, Antineoplastic Agent, Chemotherapeutic Drug

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II. Medications: Traditional Chemotherapy

  1. Background
    1. Traditional Chemotherapy targets cells that divide frequently
      1. Cancer cells typically divide more rapidly than normal cells
      2. Limits cell proliferation
      3. However, normal cells (e.g. gastrointestinal mucosa) also divide frequently, resulting in adverse effects
    2. Mechanisms of traditional Chemotherapy activity
      1. DNA cross-linking
      2. Alkylating DNA bases
      3. DNA or RNA base analog mimics
      4. Intercalation between DNA base pairs
  2. Traditional Chemotherapy Drug Classes
    1. Alkylating Agent
      1. Replicating cells and rapidly growing cells are most susceptible to agents (rbc, GI cells, hair cells)
      2. Exert cytotoxic effects via transfer of unstable alkyl group
        1. DNA alkylation (key to cellular lethality, esp. DNA cross linking)
        2. Chemically react with other cellular constituents (e.g. Proteins)
        3. Not Cell Cycle specific
      3. Alkylating Agent sub-classes
        1. Nitrogen Mustard Antineoplastic Compounds (e.g. Bendamustine, Chlorambucil, Cyclophosphamide)
        2. Nitrosourea Compounds (e.g. Carmustine, Lomustine, Semustine, Streptozocin)
        3. Aziridines (e.g. Thiotepa, Triethylenemelamine)
        4. Mesylate (e.g. Busulfan)
        5. Triazene Antineoplastic (e.g. Procarbazine, Dacarbazine, Temozolamide)
        6. Platinum Analogs (e.g. Carboplatin, Cisplatin, Oxaliplatin)
        7. Miscellaneous Alkylating Agents (e.g. Hexamethylmelamine, Trabectedin)
    2. Antimetabolite Chemotherapy
      1. Analogs block DNA, RNA or Protein synthesis, suppressing cancer cell expression, growth and replication
      2. Purine Analogs (e.g. Azathioprine, Cladribine, Fludarabine, Mercaptopurine, Pentostatin, Thioguanine)
        1. Purine Analogs, resembling adenine or guanine, and incorporate into DNA
        2. Result in DNA cross-linking and inhibition of synthesis and repair of DNA
      3. Pyrimidine Analogs (e.g. Capecitabine, Floxuridine, Fluorouracil, Trifluridine)
        1. Pyrimidine Analogs, resembling cytosine, uracil or thymine, and incorporate into DNA and RNA
        2. Inhibits DNA and RNA synthesis
      4. Cytidine Analogs (e.g. Azacitidine, Cytarabine, Decitabine, Gemcitabine)
        1. Antineoplastic, PyrimidineNucleoside analogs of cytidine
        2. By binding DNA at cytidine binding sites, these analogs block DNA methylation
      5. Folic Acid Antagonist (e.g. Methotrexate, Pemetrexed, Pralatrexate)
        1. Folic Acid analogs that resemble its structure, binding Folate-dependent enzymes, and block their activity
        2. As an example, inhibition of dihydrofolate reductase results in a failed synthesis of Tetrahydrofolate (FH4)
        3. Result in decreased DNA, RNA and Protein synthesis
      6. Histone Deacetylase Inhibitor (e.g. Belinostat, Romidepsin, Panobinostat, Vorinostat)
        1. Histones are the spools around which DNA are wrapped, and which play a role in gene expression
          1. Cancers may be facilitated by abnormally expressed genes in specific histone regions
        2. HDAC Inhibitors block histone deacetylase
          1. Histone deacetylase is an enzyme that catalyzes removal of acetyl groups from core histones
          2. Results in hyperacetylation of histones, suppressing gene expression and cell differentiation
    3. Hormonally Active Chemotherapy
      1. Hormone Analogs (naturally occurring or derivatives)
        1. Corticosteroids
          1. Indicated in lymphoid malignancy
        2. Somatostatin Analogs (e.g. Octreotide, Lanreotide)
          1. Indicated in GI neuroendocrine tumors, Carcinoid Syndrome, Merkel Cell carcinoma
        3. Progestins (e.g. Megestrol acetate, Medroxyprogesterone acetate)
        4. Conjugates (novel, hormonal agents conjugated to a cytotoxic agent, e.g. Estramustine)
      2. Hormone Synthesis Inhibitors
        1. Used in Prostate Cancer or Breast Cancer
        2. Gonadotropin-Releasing Hormone Agonists (e.g. Leuprolide, Goserelin, Histrelin)
        3. Gonadotropin-Releasing Hormone Antagonists (e.g. Degarelix, Relugolix)
        4. Androgen Synthesis Inhibitor (e.g. Abiraterone)
        5. Aromatase Inhibitors (e.g. Letrozole, Anastrozole, Exemestane, Aminoglutethimide)
      3. Hormone Receptor Inhibitors
        1. Used in Prostate Cancer or Breast Cancer
        2. Selective Estrogen Receptor Modulators (e.g. Tamoxifen, Raloxifene, Toremifene, Fulvestrant)
        3. Antiandrogens - Non-Steroidal Testosterone Receptor Antagonists (for Prostate Cancer)
          1. First Generation (e.g. Flutamide, Bicalutamide, Nilutamide)
          2. Second Generation (e.g. Apalutamide, Darolutamide, Enzalutamide, Proxalutamide)
    4. Mitotic Inhibitor Chemotherapy (block Mitosis)
      1. Includes Plant Alkaloid Chemotherapy (e.g. Vinca Alkaloids, Podophyllotoxins)
      2. Vinca Alkaloids (e.g. Vinblastine, Vincristine, Vinorelbine)
      3. Taxanes (Paclitaxel, Taxotere, Cabazitaxel)
      4. Topoisomerase 1 Inhibitors (e.g. Topotecan, Irinotecan)
      5. Topoisomerase 2 Inhibitors (e.g. Anthracyclines, Etoposide, Teniposide)
    5. Antibiotic Chemotherapy
      1. S-Phase Specific (Synthesis Phase)
        1. Dactinomycin (Actinomycin D, Cosmegen)
        2. Anthracyclines (e.g. Daunorubicin, Doxorubicin, Idarubicin, Epirubicin, Valrubicin)
      2. G2 Cell Phase and M-Phase (Mitosis Phase) Specific
        1. Bleomycin
      3. Not Cell Phase Specific
        1. Plicamycin (Mithramycin)
        2. Mitomycin (Mitomycin C, Mitocin-C, Mutamycin)
        3. Mitoxantrone (Novantrone)
  3. Miscellaneous Traditional Chemotherapy
    1. Amsacrine
    2. Arsenic Trioxide
    3. Asparaginase
    4. Hydoxyurea
    5. Mitoxantrone
    6. Mitotane (Lysodren)
    7. Quinacrine
    8. Tretinoin

III. Medications: Targeted Cancer Therapy

  1. See Targeted Cancer Therapy
  2. See Immuno-Chemotherapy
  3. See Monoclonal Antibody-Mediated Chemotherapy
  4. See Immune Checkpoint Inhibitor
  5. See CAR T-Cell Therapy
  6. See Small Molecule Inhibitor-Mediated Chemotherapy
  7. Monoclonal Antibody-Mediated Chemotherapy
    1. Example: Rituximab (Rituxan), used in Non-Hodgkin's Lymphoma and Rheumatoid Arthritis
    2. Monoclonal antibodies act at targeted cells via oncogene downregulation or tumor cell flagging for destruction
    3. Initially targeted to CD20 on immune cells to treat Lymphoma and Leukemia, later for Autoimmune Disease
    4. Targeted to solid tumors (e.g. Breast Cancer, Lung Cancer, Colon Cancer) , binding extracellular Ligands and receptors
      1. xHER2 (e.g. Trastuzumab) have been very effective in HER2 positive Breast Cancer
      2. xEGFR (e.g. Cetuximab) have been effective in metastatic Colorectal Cancer (without RAS mutation)
  8. Small Molecule Inhibitor-Mediated Chemotherapy
    1. Example: Imatinib (Gleevec)
    2. Primarily oral agents (contrast with other Chemotherapy which is primarily intravenous)
    3. Targeted to Protein kinases (esp. Tyrosine Kinase), interfering with EGFR, HER2-neu and VEGF
    4. Small molecules that principally act intracellularly, with less Specificity than monoclonal antibodies
    5. Small molecules also effect healthy tissue, and therefore have systemic effects
    6. Widely variable efficacy depending on tumor type
  9. Antibody-Drug Conjugates (ADC)
    1. Example: Trastuzumab emtansine (T-DM1, trade name: Kadcyla) for refractory, advanced HER2+ Breast Cancer
    2. Monoclonal Antibody bound to cytotoxic Chemotherapy is specifically directed at tumor cells
    3. Local destruction of normal cells in vicinity of tageted tumor cells
    4. Systemic effects include Fatigue, Nausea, Peripheral Neuropathy and Thrombocytopenia
  10. Active Immunotherapy (tumor cell specific targeting)
    1. Monoclonal Antibody-Mediated Chemotherapy
    2. CAR T-Cell Therapy
    3. Oncologic Vaccines (e.g. sipuleucel-T, Prostate Cancer)
  11. Passive Immunotherapy (Immuno-modulators)
    1. Cytokines
    2. Immune Checkpoint Inhibitors
      1. Counter tumor cell generated Immune Suppression by blocking their activity on T-Cells
      2. Immune Checkpoint Inhibitors are very effective in mestatatic Non-Small Cell Lung Cancer
      3. Example: Pembrolizumab (Keytruda) targets Programmed Cell Death Protein 1 (PD-1)
      4. Example: Atezolizumab (Tecentriq) targets Programmed Death Ligand-1 (PDL-1)
      5. Example: Ipilimumab (Yervoy) targets Cytotoxic T Lymphocyte Associated-4 (CTLA-4)

IV. Adverse Effects

  1. See specific drugs and their classes
  2. See Cancer Symptom (includes Oncologic Emergencies)
  3. See Cytokine Release Syndrome
  4. See Tumor Lysis Syndrome
  5. See Neutropenic Fever

V. Management: General

  1. See Cancer Symptom
  2. Exercise encouraged following high dose Chemotherapy
    1. Safe
    2. Prevents deconditioning
    3. Decreases toxic side effects of Chemotherapy
    4. Dimeo (1997) Blood 90:3390-4 [PubMed]

VI. Management: Extravasation of agents from IV

  1. Practice vigilent prevention
  2. Findings: Onset with hours of Chemotherapy
    1. Early: Pain, local erythema and swelling
    2. Later: Blanching, Blistering, discoloration and tissue necrosis
  3. Management: Early recognition and treatment is critical
    1. Immediately stop any infusion
    2. Leave cannula in place until management plan is established
    3. Apply ice to area
    4. Do not compress area
    5. Use antidotes if available
    6. Urgent Consultations with Oncology and Surgery
      1. Debridement with skin grafting may be needed
  4. Complications
    1. Scarring
    2. Contractures
    3. Amputation
  5. References
    1. Higdon (2006) Am Fam Physician 74:1873-80 [PubMed]
    2. Higdon (2018) Am Fam Physician 97(11):741-8 [PubMed]

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