Felis ISSN 2398-2950

Therapeutics: anti-neoplastic agent

Synonym(s): Chemotherapy, Cytotoxic agent

Contributor(s): Laura Garrett, Lauren Trepanier

Cytotoxic drugs

  • See also chemotherapy   Chemotherapy; general principles  .
  • Most act upon process of cell growth and division: potent and potentially dangerous.
    Do not use without consulting a specialist oncologist.
  • Uses: for lymphoproliferative   Lymphoma  and myeloproliferative disorders.
  • Not very useful alone in large solid tumors.
  • Possible palliative role as adjunct to surgery or radiotherapy   Radiotherapy  for metastatic conditions - combination protocols generally preferred, eg cyclophosphamide   Cyclophosphamide  + vincristine   Vincristine  + prednisolone   Prednisolone   + doxorubicin   Doxorubicin   for feline lymphoma   Lymphoma  .
  • Drug resistance can develop in tumor cells   →   may need to cycle drugs with different modes of action, may   →   multi-drug resistance.

Toxicity

  • Not selective in action and organs with populations of rapidly growing or dividing cells, eg bone marrow and gastrointestinal mucosa are susceptible.
  • Myelosuppression(usually reversible on withdrawal of treatment)   →   leukopenia (neutrophils are the WBC of interest) and risk of infection and sepsis.
    • Nadir 7-10 days post-treatment.
    • The most common source of infection in animal cancer patients is translocation of enteric bacteria.
    • Thrombocytopenia   Hematology: platelet count  and anemia   Hematology: packed cell volume  can also occur: monitor blood counts prior to every treatment.
    • Reduce drug dosage by 20% at the next treatment with the same drug if neutrophils   Hematology: neutrophil  <1000 cells/ul.
    • Give prophylactic broad-spectrum antibacterials   Therapeutics: antimicrobial drug  (potentiated sulfonamides or fluoroquinolones preferred) if neutrophils <1000 cells/ul.
    • If febrile, need IV antibiotics and intensive care.
  • Gastrointestinal toxicity  →   anorexia, vomiting, diarrhea.
    • 3-5 days after treatment.
    • Usually short-term, spontaneous recovery/regeneration.
    • Supportive care and fluid therapy may be required.
    • Anti-emetics.
  • Hypersensitivity reactionsappear to be rare.
  • Some very irritating, extravasation   →  local necrosis.
  • Severe vesicants will   →   sloughing of tissue down to bone.
  • Some have specific tissue toxicity.

Dosage

  • Low therapeutic index: dose protocols compromise between efficacy and toxicity.
  • Calculated as function of body surface area because blood supply to organs of detoxification (liver and kidney) more closely related to surface area than bodyweight.
    Not to be handled by pregnant women; extreme care required during handling.

Alkylating drugs

  • Most widely used chemotherapy   Chemotherapy; general principles  in veterinary medicine.
  • Interfere with DNA replication by alkylating bases in DNA template.
  • Side-effects: myelosuppression, inhibit gametogenesis, gastrointestinal upset, alopecia.
  • Busulfan  Busulfan  : selective action against granulocytes; indicated for chronic granulocytic leukemia and polycythemia vera; toxic effects include leukopenia, hyperpigmentation of skin, Addison-like wasting syndrome, persistent cough and progressive dyspnea (rare), ocular lens changes and occasionally cataract formation - rarely used in veterinary medicine.
  • Chlorambucil  Chlorambucil  : slowest acting, least toxic; used for lymphoproliferative and myelosuppressive diseases, eg small cell GI lymphoma in cats.
  • CCNU (lomustine)  Lomustine  : lymphoproliferative and mast cell tumors. Oral administration (capsule). Myelosuppressive: monitor neutrophils and platelets.
  • Cyclophosphamide  Cyclophosphamide  : lymphoproliferative and myelosuppressive diseases, especially feline lymphoma; carcinomas and sarcomas; a metabolite (arecolin) may cause necrotizing hemorrhagic cystitis.
  • Melphalan  Melphalan  : multiple myeloma, some carcinomas.

Antimetabolites

  • Interfere with DNA and RNA synthesis by inhibiting synthesis of purines and pyrimidines.
  • Cytarabine  Cytarabine  : used in lymphoproliferative or myeloproliferative diseases; CNS lymphoma; myelosuppressant.
  • Fluorouracil  Fluorouracil  .
    Contraindicated in cats because it causes fatal toxic effects (myelosuppression and neurotoxicity resulting in cerebellar ataxia and seizures).
  • Methotrexate  Methotrexate  : used to treat lymphoproliferative and myeloproliferative diseases, sarcomas and mycosis fungoides; side-effects include gastrointestinal ulceration, myelosuppression, and at high dosage, renal tubular necrosis.
  • Mercaptopurine: used in managing lymphoid leukemia in humans. Cats deficient in thiopurine methyltransferase, which, overall, detoxifies mercaptopurine and its prodrug, azathioprine   Azathioprine  .
    Not recommended in cats due to potential for severe neutropenia.
  • Thioguanine: limited information on its use in cats with neoplasia. Well tolerated by healthy cats at 25 mg/m2 for 5 days.

Antitumor antibiotics

  • Interfere with synthesis of nucleic acids.
  • Bleomycin: reported for local injection (with electrical pulse to increase tumor penetration) in cats with squamous cell carcinoma.
  • Dactinomycin: has not been widely used; only limited experience available of its use in dogs.
  • Doxorubicin hydrochloride  Doxorubicin  : anthracycline antibiotic, very effective cytotoxic drug; lympho- and myeloproliferative disorders; also palliative in soft tissue and osteogenic sarcomas and mammary, thyroid and prostate carcinomas.
    Severe vesicant - must give through cleanly placed IV catheter.

    Some oncologists pretreat with antihistamines as is may   →   release of histamines when administered.

    Can cause nephrotoxicity, monitor BUN and creatinine during therapy.

    Cardiotoxicity not a major concern in cats, although cardiac muscle will show changes with repeated doses. Rarely a clinical problem.
  • Doxil (Doxorubicin encapsulated in polyethylene glycol-coated liposomes): developed to increase the therapeutic index of doxorubicin and to try to overcome the most common and clinically important dose-limiting toxicities (gastrointestinal toxicity, especially anorexia in cats); encapsulated doxorubicin has reduced toxicity compared to native doxorubicin and selective tumor accumulation; still at research stage, but so far appears to be well tolerated in cats (minimal myelosuppression and reduced anorexia) compared with native doxorubicin; other side-effects include chin alopecia and whisker loss. More nephrotoxic than native doxorubicin.
  • Epirubicin hydrochloride  Epirubicin  : same indications as for doxorubicin; cardiotoxic, although less so than doxorubicin.
  • Idarubicin: relatively new synthetic anthracycline analogue of daunorubicin; advantageous since highly bioavailable after oral administration, hence invasive administration not required; may be useful to treat lymphoma and for maintenance therapy for lymphoma; toxicity similar to doxorubicin. Not currently available in oral form.
  • Mitoxantrone: may have a wide spectrum of activity against feline lymphomas, sarcomas and carcinomas. May cause myelosuppression, anorexia, nausea, vomiting and diarrhea; also cardiotoxic, but less so than doxorubicin. Nephrotoxic with repeated doses - monitor BUN and creatinine.

Vinca alkaloids

  • Plant alkaloids bind to mammalian tubulin and inhibit mitosis in metaphase.
  • Cause severe extravascular reactions (less severe than doxorubicin).
  • Vinblastine sulfate  Vinblastine  : used for lymphoproliferative diseases; mast cell tumors; limited efficacy for solid carcinomas; causes myelosuppression.
  • Vincristine sulfate  Vincristine  : lymphoproliferative disorders; mast cell tumors; management of thrombocytopenia; may cause significant myelosuppression.

Other cytotoxic drugs

This article is available in full to registered subscribers

Sign up now to purchase a 30 day trial, or Login

Immunosuppressants

This article is available in full to registered subscribers

Sign up now to purchase a 30 day trial, or Login

Further Reading

Publications

Refereed papers
  • Recent references fromPubMed.
  • Rassnick K M, Gieger T L et al(2001)Phase I evaluation of CCNU (lomustine) in tumor-bearing cats. J Vet Intern Med15(3), 196-199.
  • Fox L E (2000)Carboplatin. JAAHA36(1), 13-14.
  • Salavaggione O E et al(2004)Cat red blood cell thiopurine S-methyltransferase: companion animal pharmacogenetics. J Pharmacol Exp Ther308(2), 617-626PubMed.
  • Hahn K A, McEntree  et al(1997)Hematologic and systemic toxicoses associated with carboplatin administration in cats. Am J Vet Res58(6), 677-679.
  • Hahn K A, Fletcher C M et al(1996)Marked neutropenia in five tumor-bearing cats one week following single-agent vincristine sulfate chemotherapy.  Vet Clin Pathol25(4), 121-123.

Other sources of information

  • Vail D M (1997)Advances in chemotherapy. In: Consultations in Feline Internal Medicine 3. Ed: J R August. Philadelphia: W B Saunders Co. pp 527-533. ISBN 0 7216 5814 8.
  • Bishop Y M (1996) EdThe Veterinary Formulary. Handbook of Medicines used in Veterinary Practice. 3rd edn. London: Royal Pharmaceutical Society of Great Britain and British Veterinary Association. pp 327-336. ISBN 0 85369 345 5.


ADDED