1. General Applications of Chemotherapy

• Goals of anticancer chemotherapy - inducing and maintaining clinical remission, delaying metastatic disease, prolonging survival and maintaining quality of life. Occasionally chemotherapy may be used to decrease the size and control localized tumors.
• General strategies for Application of Chemotherapy - sole modality vs. Adjuvant vs. Neoadjuvant chemotherapy.

2. General Principles of Chemotherapy

• Cell cycle effects.
• The primary goal for most chemotherapy agents is to injure the DNA or prevent RNA production and proteins coded by DNA. This may lead to a decreased tumor ability to replicate and ideally cell death. Many chemotherapy agents result in apoptosis of cancer cells.
• Normal cell populations that are actively proliferating may also be affected by chemotherapy.
• Renewing populations.
• Bone marrow, gastrointestinal mucosa, hair follicles (anagen phase), germ cells.
• Typically affected.
• Slowly proliferating aka expanding populations.
• Renal, hepatic, lung, vascular, endocrine cells.
• Occasionally affected by chemotherapy agents.
• Static population.
• Muscle, bone, cartilage, nerve.
• Rarely affected.
• Chemotherapy agents can be classified depending on their effect on a particular phase of the cell cycle.
• Dose-response effect.
• Slope of the curve - for many drugs, curve is fairly steep. A minor increase in doses may have a significant impact on anticancer activity. For this reason, drugs should be given using the recommended clinical dosages.
• Therapeutic ratio - a measure of the relative efficacy against a tumor as compared with normal tissue damage.
• Increasing doses of chemotherapy may improve antitumor efficacy but may result in increasing normal tissue toxicity; goal: give dose that can be administered without producing unacceptable normal tissue toxicity.
• Therapeutic index is often very narrow.

Figure 1

• Maximum tumor response - despite success in the treatment of many tumor types using chemotherapy, most fail to be cured. Maximum tumor response is often limited by many factors, including drug resistance.

3. Gompertzian Growth

• Model that describes tumor growth. Initially a tumor grows exponentially.
• At 1 cm diameter or 10^9 cells, growth fraction decreases and tumor doubling time increases.
• Microscopic or small tumors are more likely to be rapidly dividing and therefore more sensitive to chemotherapy.

Figure 2

• Clinical implication - treat early, when the smallest amount of disease is present and growth fraction is highest!

4. Goldie-Coldman Hypothesis

• Cancer cells are genetically unstable so as they divide, they accumulate more mutations. As a tumor grows, cells can develop mutations that confer drug resistance, even without exposure to chemotherapy.
• Goldie-Coldman hypothesis also suggests that a tumor may initially respond to a drug, but then resistant clones will expand, and the tumor will become resistant to a drug that was initially effective.
• Clinical implications: → Treat early, when the tumor burden is small and potentially has few resistant clones. → Use combinations of effective drugs to kill cells before resistance develops.

5. Cell Kill Hypothesis

• A dose of chemotherapy kills a constant fraction (proportion) of cells - not a constant number. Remaining cells have the ability to proliferate in between treatments. This suggests that cure is unlikely and eventually resistant populations will emerge.
• Clinical implications: → Start treatment early when tumor burden is small. → Use appropriate dosages of chemotherapy drugs that are known to be effective as frequently as is safe for the patient.

Figure 3

6. MTD vs. Metronomic Chemotherapy

• MTD chemotherapy: highest dose of chemotherapy is given alternated with long drug-free period to allow the patient to recover from adverse drug reactions.
• Metronomic chemotherapy = repeated administration of anti-neoplastic drugs at comparatively low doses frequently and without long drug-free period. → inhibit tumor angiogenesis, stimulate anticancer immune response and induces tumor dormancy.

Figure 4

7. Body Surface Area Dosing

• Most chemotherapy drugs doses are calculated on the basis of estimated body surface area (BSA).
• BSA supposedly correlates with basal metabolic rate and physiologic processes that determine drug exposure. Max tolerated doses of drug among species are supposedly normalized when doses are expressed in mg/m². Evidence suggests that BSA dosing may not be appropriate for all drugs.

8. Chemotherapy Toxicity

• Myelosuppression.
• → Neutrophils are most affected. Platelets can also be affected. The drop in the neutrophil count (aka nadir) is usually 5–7 days after treatment. Generally, the neutrophil count will return to normal 2–3 days after the nadir of most drugs.
• → Risk for secondary infections if neutrophil count <750–1000/uL (variable # based on literature).
• → Myelosuppressive chemotherapy should not be administered if neutrophil count <1500–2000 cells/uL.

This number is variable as well.

• → 10–25% dose reduction next time drug is given if it caused moderate to severe myelosuppression or hospitalization of the patient, respectively.

Gastrointestinal (GI) toxicity

• → Acute GI toxicity involves stimulation of the chemoreceptor trigger zone.
• → Delayed GI toxicity is due to damage to the rapidly dividing cells of the intestinal crypts. This results in vomiting, diarrhea, loss of appetite usually 2–5 days after administration of chemotherapy.
• Other tox possible–see below.

9. Chemotherapy Drugs

• Vincristine
• Plant alkaloid, Extracted from periwinkle plant (Cantharanthus roseus).
• Metabolism: hepatic and biliary excretion, small amount in urine.
• Toxicities → Extravasation.
• → GI: * paralytic ileus/constipation/pain/emesis - autonomic nervous system dysfunction due to effect on peripheral nerves.
• Delayed GI toxicity due to mucosal epithelial damage.
• → Myelosuppression.
• Minimal at usual doses. However, when combined with L-asparaginase, neutropenia may occur. If hepatic insufficiency, more myelosuppression.
• → Peripheral neuropathy (rarely documented in veterinary patients).
• Clinical applications: * IV bolus, * Used for LSA, Leukemias, TVT, sarcoma (VAC protocol) and refractory ITP.
• Vinblastine
• Plant alkaloid,
• Metabolism: hepatic and biliary excretion, small amount in urine.
• Toxicities → Extravasation.
• → GI: * Delayed GI toxicity possible.
• * Paralytic ileus/constipation/pain/emesis.
• → Myelosuppression.
• * More severe than vincristine.
• → Peripheral neuropathy (rarely documented in veterinary patients).
• Clinical applications: * IV bolus, * Used for MCT, LSA (high dose).
• Doxorubicin
• Natural antitumor antibiotic isolated from soil fungi in the genus Streptomyces.
• Metabolism: hepatic.
• Toxicities → Acute/during administration: Direct mast cells degranulation and histamine release, cutaneous hyperemia, pruritus, head shaking, emesis.
• → Short-term toxicity (1–2 weeks post administration).
• * Myelosuppression, nadir 7–10 days, always check CBC 1 week post administration.
• * Delayed GI toxicity with emesis and possible colitis (hemorrhagic, dog, can be severe).
• * Extravasation (severe).
• → Long-term (cumulative): *Renal toxicity - primarily in cats, *Alopecia, *Cardiac toxicity, dose dependent. In dog, cumulative doses >180 mg/m² associated with irreversible cardiomyopathy and arrhythmias. This can occur at lower doses as well.
• Clinical applications: * IV slow over at least 20 min, * No heparin flushes * Pretreatment with maropitant.
• * Dogs with breed predisposition to DVM/cardiomyopathy/heart murmur → cardiology screening.
• * Used for LSA, HSA, ALL, OSA, some carcinomas.
• L-Asparaginase
• Enzyme, sources are E. Coli and Erwinia carotovora.
• Toxicities → Anaphylactic reaction (rare).
• * Antibody production against foreign protein, usually requires prior sensitization.
• → Other (rare) pancreatitis, hepatotoxicity, coagulation abnormalities, hyperammonemia.
• Clinical applications: * IM or SQ injection, Pre-medicate with diphenhydramine IM.
• * Used for LSA, ALL, CLL.
• Cyclophosphamide
• Alkylating agent.
• Metabolism: Metabolized (activated) by the liver, acrolein is the major non-active metabolite that causes sterile hemorrhagic cystitis.
• Toxicities: → Myelosuppression–potential for moderate, always evaluate CBC 1 week after administration → GI–acute and delayed are possible but uncommon.
• → Sterile Hemorrhagic Cystitis (SHC): Caused by acrolein.
• * Give Furosemide or split dose over several days.
• Clinical applications: * IV bolus or PO, *metronomic chemotherapy, LSA, Leukemias, Sarcomas, carcinoma, IMHA.
• Lomustine (CCNU)
• Alkylating agent, nitrosurea subclass.
• Metabolism: Orally available, Metabolized by the liver.
• Toxicities: → Myelosuppression - Expect severe, provide broad spectrum antibiotics as prophylaxis; cats’ nadir is highly variable occurring day 7–28 (check CBC weekly).
• → Hepatotoxicity. always check ALP and ALT prior to next dose. Give Denamarin.
• → Thrombocytopenia - cumulative side effect, if PLT # decreases, discontinue drug.
• → Pulmonary fibrosis - cumulated, rare in dogs.
• Clinical applications: * Oral, Use for LSA, MCT, Brain tumors, histiocytic sarcoma.
• Carboplatin
• Platinum class.
• Metabolism: Renally excreted, unchanged.
• Toxicities: → Myelosuppression: Neutropenia - potential for moderate to severe, in dogs & cats nadir occurs most often on day 10–14. A double nadir may occur at day 21. Thrombocytopenia - may be moderate to severe.
• → GI toxicity - not common.
• → Irritant during IV injection.
• Clinical applications: * IV, over 10–15 min, Intralesional, * Use in cats and dogs for OSA, OMM, Sarcomas, carcinomas.
• Rabacfosadine (Tanovea)
• Guanine analogue.
• FDA approved for canine lymphoma.
• Toxicity.
• Self-limiting GI toxicity and myelosuppression.
• Cumulative dermatologic changes.
• Occasional liver value elevation.
• Rare delayed pulmonary fibrosis.
• Clinical applications: * IV, over 30 min, every 3 weeks * Use in dogs for treatment of LSA.