Principles

Therapeutic goals

The most important change in cancer therapy (human) in the past 30 years has been to greatly increase the portion of patients that live with cancer as a chronic, well-managed chronic disease (rather than die of it in a short period of time).

Therapeutic targets

Drug toxicities

Resistance

Similar to antibiotic resistance

Regimens (protocols)

  • Most cancers are treated with multiple drug protocols
    • attack multiple targets
    • reduce adverse effects (of any ONE drug)
    • reduce or delay the onset of drug resistance
  • Protocols based on studying clinical outcomes (survival curves)
Survival curve

Lymphoma - L-CHOP, L-CHO (example)

Lasparaginase (L-asparaginase)Elspar®
CcyclophosphamideCytoxan®
Hhydroxydaunorubicin (doxorubicin)Adriamycin®
OvincristineOncovin®
Pprednisoloneprednisolone
methylprednisolone
prednisone

Individual agents

Chemotherapeutic class

Cyclophosphamide

  • prodrug, activated by the liver
  • can be given orally
  • extravasation (which should be still be avoided) may not cause a reaction.
  • myelosuppression almost always occurs
    • Neutropenia and thrombocytopenia
    • nadir at 7-10 days
  • Nausea and vomiting
    • high doses in cats - otherwise rare
  • High doses -> reversible neurotoxicity in cats
    • head bobbing, broad-based stance, falling
  • Alopecia, usually thinning
    • continuously growing hair coated dogs
  • Sterile necrotizing hemorrhagic cystitis
    • cyclophosphamide metabolites in urine
    • treatment / prevention:
      • dose in the morning
      • encourage water consumption
      • encourage frequent urination
      • Mesna (dimesna) orally -> mesna in urine (binds metabolites)

Alkylating Agent(s)

  • form covalent bonds with DNA (DNA is "alkylated")
  • DNA becomes uncopiable (generally non-functional)
  • multiple mechanisms of resistance
Nitrogen mustards
cyclophosphamide (Cytoxan®), mechlorethamine (Mustargen®), melphalan (Alkeran®), chlorambucil (Leukeran®)
  • especially toxic to lymphocytes and bone marrow
  • effect on susceptible tumors is rapid
  • myelosupression and immunosuppression are profound.
Nitrosureas
carmustine (BiCNU®), lomustine (CeeNU®), streptozotocin

Vincristine

  • dose dependent neutropenia, usually mild - nadir 5-10 days
  • thrombocytopenia, anemia are very rare
  • peripheral neuropathy - tingling, intermittent sharp pains, clumsiness
  • IV only - most list as vesicant, some as severe irritant

Microtubule binding agents

  • Bind to microtubules (mitotic-spindle)
  • Arrest mitosis, arrest cell-cycle, apoptosis (or necrosis)
Vinca alkaloids
vincristine (Oncovin®), vinblastine (Velban®), vinorelbine (Navelbine®)
Taxans
paclitaxel (Taxol®), docetaxel (Taxotere®)

Doxirubicin

  • Acute toxicity
    • EKG changes, cardiac arrest (usually brief)
    • IV only - a vesicant
      • liposomal form is less irritating
  • Short term
    • weight loss, anorexia, diarrhea, vomiting
    • myelotoxic
      • neutropenia, nadir 7-10 days and may last 3 weeks
      • bone marrow hypoplasia
      • poikilocytosis in cats
    • lymphoid atrophy
  • Chronic toxicity
    • Hair loss
    • Testicular atrophy
    • Dose dependent Cardiac toxicity
      • arrhythmias
      • cardiomyopathy
        • liposomal dose forms (reduce uptake by cardiac cells)
        • dexrazoxane (Zinecard®) is antidote for cardiotoxicity, extravasation

Antibiotics - topoisomerase inhibitors

  • inhibit topoisomerase I and II
  • create "nicks" in DNA strands
  • cause of death not entirely clear, several mechanisms suggested
Anthracyclines
(doxorubicin (Adriamycin®), daunorubicin (Cerubidine®)

L-asparaginase

  • anaphylaxis (immune/allergic - rare for first use)
  • pancreatitis
  • decrease clotting factors especially fibrinogen (decreased protein synthesis)

Enzymes

  • malignant lymphocytes have a reduced ability to synthesize l-asparagine
  • enzyme destroys exogenous supplies

Dosing

By Weight

Some dosing is standard body weight (e.g. mg/kg)

By Body surface area

Many cancer chemotherapeutics are dosed by body surface area or BSA (e.g. mg/M2)

Body Surface Area
BSA=Body weight (grams)2/3 x K / 104
Dogs
(k=10.1)
Body weight (kg)BSA (M2)
20.160
50.295
100.469
150.614
200.744
250.864
300.975
351.081
401.181
451.278
501.371
Cats
(k=10.0)
Body weight (kg)BSA (M2)
0.50.063
10.100
20.159
40.252
60.330
80.400
100.464

Chemotherapy Protocol Concerns

Patient

Extravasation
Neutral
  • little reaction potential
L-asparaginase
cyclophosphamide
Monoclonal antibodies
may not react at all
Inflammatory
  • irritating to tissue
  • tend not to cause significant damage
5-FU
methotrexate
you will likely notice
Irritants
  • Swelling, burning, redness
carboplatin
bleomycin
you should be concerned,
long term consequences rare
Exfoliants
  • inflammation
  • shedding of skin
  • may not cause necrosis
liposomal doxorubicin
cisplatin
taxanes
worrisome
patient will probably lose some skin
Vesicants
  • tissue necrosis
  • blister (vesicle) formation
doxorubicin
vincristine
EEEK! patient may lose a limb
Kreidieh, et al. Overview, prevention and management of chemotherapy extravasation. World Journal of Clinical Oncology 2016, February 10;7(1):87-97.
Catheter technique

Therapist and staff

Most antineoplastic drugs are mutagenic and carcinogenic. Great care should be taken while preparing, administering and even handling animal waste. This is especially important for individuals of child-bearing age. NIOSH (Workplace) Alert - Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health

Drug preparation
Figure 1. Chemotherapeutic drug being drawn into a syringe behind the protective glass of a laminar flow hood. The hood serves to contain any aerosols of drug product that might occur during transfer. Gloves and protective clothing are worn at all times. Eye protection is generally worn as well. Note, this person should be covering her nose with that mask. Note also that the hair covering is not "chemo-proof."
chemotherapeutic drug preparation, laminar flow hood
Administration
Figure 2. Administration of a chemotherapeutic drug to a canine patient. Gloves and spill-resistant gowns should be worn at all times. Eye protection is recommended. The face shield is a good idea though some patients may not react well to it. You should learn to keep your mouth closed while you catheterize in any case.
Disposal

Owner