Chemotherapy
From Felipedia
Contents |
Introduction
The fundamental biochemical and genetic differences between feline cancer cells and normal cells are not clearly understood. None of the empirically developed antineoplastic drugs appears to act on a process or component that is entirely unique to cancer cells. Clinically useful drugs achieve a degree of selectivity on the basis of certain characteristics of cancer cells that can be used as pharmacologic targets.
Cell cycle phases
Aspects of normal cell growth and the cell cycle provide the rationale for and are of major importance in the successful application of antineoplastic chemotherapy. In the S phase, DNA synthesis occurs; the M phase begins with mitosis and ends with cytokinesis; and the Go phase is a dormant or non-proliferative phase of the cell cycle. Tumour doubling time is related to the length of the cell cycle and the growth fraction (the proportion of a population of cells undergoing cell division). Antineoplastic agents can be classified according to a number of schemes relative to effects at different stages of the cell cycle. In the simplest sense, cycle-non-specific agents are considered to be lethal to cells in all phases of the cell cycle. Cells are killed exponentially with increasing drug levels, and the dose-response curves follow first-order kinetics. Phase-specific agents exert their lethal effects exclusively or primarily during one phase of the cell cycle, usually S or M; the greater the rate of cell division, the more effective the drug. The Go phase of the cell cycle is important, not as a target for chemotherapeutic agents, but as a time during which dormant tumour cells can escape the effects of drug therapy.
Principles of Antineoplastic Chemotherapy
The decision to use antineoplastic chemotherapy depends on the type of tumour to be treated, the stage of malignancy, the condition of the animal, and financial constraints. Chemotherapy can be used as an adjuvant to surgery and irradiation and can be administered immediately after or before the primary treatment. Neo-adjuvant therapy is administered before surgery or irradiation and is intended to improve the effectiveness of the primary therapy by possibly decreasing tumour size, stage of malignancy, or presence of micrometastatic lesions. Responses to cancer chemotherapy can range from palliation (remission of secondary signs, generally without increase in survival time) to complete remission (in which clinically detectable tumour cells and all signs of malignancy are absent). The percentage and duration of complete remissions are criteria for the success of a particular chemotherapeutic protocol.
Effective clinical use of antineoplastic drugs depends on the ability to balance the killing of tumour cells against the inherent toxicity of many of these drugs to host cells. Because of their narrow therapeutic indices, dosages for antineoplastics are frequently calculated based on body surface area (BSA) rather than body mass. However, evidence suggests that small dogs and cats may best be treated based on body weight to avoid overdosage. This is especially true if the primary toxicity is bone marrow suppression. Apparently, BSA does not correlate well with either stem cell number in the bone marrow or resulting hematopoietic toxicity. Correlation is better between body weight and these toxicities. Antineoplastic agents are administered by the PO, IV, SC, topical, intracavitary, intralesional, intravesicular, or arterial routes. The route chosen depends on the individual agent and is determined by drug toxicity; location, size, and type of tumour; and physical constraints.
Antineoplastic agents are commonly administered in various combinations of dosages and timing; the specific regimen is referred to as a protocol. A protocol may use 1 or as many as 5 or 6 different antineoplastic agents. Selection of an appropriate protocol should be based on type of tumour, grade or degree of malignancy, condition of the animal, and financial constraints. Preferences of individual clinicians for treatment of specific neoplastic conditions may also vary. Regardless of the protocol chosen, a thorough knowledge of the mechanism of action and toxicities of each individual therapeutic agent are essential.
Combination antineoplastic chemotherapy offers many advantages. Drugs with different target sites or mechanisms of action are used together to enhance destruction of tumour cells. If the side effects of the component agents are different, the combination may be no more toxic than the individual agents given separately. Combinations that include a cycle-nonspecific drug administered first, followed by a phase-specific drug, may offer the advantage that cells surviving treatment with the first drug are provoked into mitosis and, therefore, are more susceptible to the second drug. Another advantage of combination therapy is the decreased possibility of development of drug resistance.
Special considerations associated with administration of antineoplastic drugs include evaluation of the animal’s quality of life, medical and nutritional support, control of pain, and psychological comfort for the owner. Many owners who choose to treat neoplasia in their pets have experienced cancer themselves or have been involved with individuals or family members who have had cancer. Discussion of neoplasia in pets should provide the owners with appropriate information for decision-making.
Resistance to Antineoplastic Agents
Failure to respond, or resistance to antineoplastic agents, can be seen for several reasons. Pharmacokinetic resistance is seen when the concentration of a drug in the target cell is below that required to kill the cell. This may be due to altered rates of drug absorption, distribution, biotransformation, or excretion. In addition, marginal blood flow to a tumour may not provide sufficient drug, resulting in inadequate therapeutic drug concentrations and creation of a population of quiescent, less susceptible cells. Cytokinetic resistance is seen when the tumour cell population is not completely eradicated; this may be a result of dormant tumour cells, dose-limiting host toxicity associated with drug therapy, or the inability to achieve a 100% kill rate even at therapeutic drug dosages. Resistance can also develop via biochemical mechanisms within the tumour cell itself that block transport mechanisms for drug uptake, alter target receptors or enzymes critical to drug action, increase concentrations of normal metabolites antagonized by the antineoplastic drug, or cause genetic changes that result in protective gene amplification or altered patterns of DNA repair. Acquired multidrug resistance can result from amplification and over-expression of a multidrug resistance gene. This gene encodes a cell membrane protein that effectively pumps a variety of structurally unrelated antineoplastic agents out of the cell. As intracellular drug concentrations decline, tumour cell survival and resistance to therapy increase.
Patterns of Toxicity
Antineoplastic agents that act primarily on rapidly dividing and growing cells produce multiple side effects or toxicities, including bone marrow or myelosuppression, GI complications, and immune suppression. Patterns of toxicity may be either acute or delayed. Acute toxicities often include GI complications such as nausea, vomiting, anorexia, and diarrhoea. Allergic reactions and anaphylaxis may also be of immediate concern with selected drugs. Delayed toxicities may develop days to weeks after antineoplastic therapy. Myelosuppression, a common delayed toxicity, can be life-threatening due to the increased incidence of infection associated with leukopenia, increased risk of haemorrhage associated with thrombocytopenia, and anaemia. Other important delayed toxicities include tissue damage associated with extravasation of selected drugs, alopecia caused by hair follicle damage, and stomatitis or ulcerative enteritis. Adverse effects on spermatogenesis and teratogenesis may be of concern in breeding animals.
Prevention and management of toxicities is key to successful antineoplastic therapy. Collection of an adequate database before treatment can identify potential problems so that contraindicated drugs can be avoided. Several antineoplastic agents should not be used in the presence of specific organ impairment. For example, doxorubicin should not be used in animals with cardiac abnormalities, and cisplatin is contraindicated in animals with impaired renal function.
When a drug is chosen, supportive or preventive therapy aimed at ameliorating toxic side effects may be required. Concurrent administration of antiemetics may be indicated for acute GI toxicities. Active diuresis should accompany administration of nephrotoxic agents (eg, cisplatin). Administration or availability of appropriate antihistamines may be indicated with l-asparaginase and doxorubicin therapy.
The availability of recombinant products has added an additional resource for managing myelosuppression and immunosuppression induced by antineoplastic chemotherapy. Recombinant human erythropoietin (rhEPO) has been used in treatment of anaemia related to chronic malignancy. Recombinant human (rhG-CSF) and canine (rcG-CSF) granulocyte colony-stimulating factor have been used effectively in management of cytopenias induced by chemotherapy and radiation. Administration of rcG-CSF results in a rapid, significant increase in neutrophil numbers that is sustainable as long as the factor is administered. Neutrophil counts drop quickly when therapy is discontinued. Neutrophil phagocytosis, superoxide generation, and antibody-dependent cellular cytotoxicity all increase with G-CSF treatment. A related cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), has also shown promise for treatment of neutropenia induced by chemotherapy. Long-term (>2-3 wk) use of recombinant human products in dogs and cats results in anti-factor antibody formation and a decline in cell numbers.
Biologic Response Modifiers in Cancer Therapy
In recent years, a number of alternative modes of cancer therapy have been investigated. Foremost among these has been the development of biologic response modifiers aimed at enhancing innate anti-tumour defence mechanisms of the host. Nonspecific immunomodulators, including BCG, levamisole, and cimetidine, have been used to enhance immune responsiveness and improve outcomes after surgery or antineoplastic chemotherapy.
Development of lymphokines and cytokines (eg, interleukins, interferon, and tumour necrosis factor) for clinical use in cancer patients has long been an attractive goal. The clinical potential of these potent immunomodulators has not been fully realized, and they are not commonly used in veterinary medicine at this time. An exception to this is the use of selected cytokines (eg, G-CSF) to manage toxic side effects associated with antineoplastic chemotherapy (see above).
Anti-tumour antibody therapy has also been a cancer research focus for several years. Only one monoclonal antibody is approved and marketed for veterinary use—CL/MAb 231 recognizes canine lymphoma cells and is thought to mediate antibody-dependent cellular cytoxicity therapy has prolonged duration of remission when used in combination with chemotherapy.
Safe Handling of Antineoplastic Chemotherapeutic Agents
Most antineoplastic chemotherapeutic agents are potentially toxic as mutagens, teratogens, or carcinogens. Handling of these agents can result in unhealthy personal or environmental exposure in a number of different ways.
A common route of exposure is inhalation due to aerosolization during mixing or administration of cytotoxic drugs. This may occur when a needle is withdrawn from a pressurized drug container or upon expulsion of air from a drug-filled syringe. Transferring drugs between containers, opening drug-filled glass ampoules, or crushing or splitting oral medications may also aerosolize drug residues.
The best way to prepare cytotoxic drugs to avoid aerosolization is in a biologic safety cabinet or hood; a Class II, type A vertical laminar air flow hood exhausted outside the building is recommended. If a hood is not available, drugs should be prepared in a specified low-traffic area with proper ventilation where no food, drink, or tobacco products are allowed. This area should be equipped with supplies needed for drug reconstitution, including a disposable, plastic-backed liner for the working surface; latex gloves; gown; goggles; and mask with a filter. Disposal of contaminated vials, syringes, needles, and gloves in this area should be anticipated, and the proper containers provided. Aerosol exposures can be further decreased through the use of chemotherapy-dispensing pins (“chemo-pins”) or hydrophobic filters that limit escape of air from drug vials into the environment.
Another potential route of exposure to antineoplastic agents is by absorption of drug through the skin. This could occur during preparation or administration of drug, cleaning of the drug preparation area, or handling of excreta from animals that have received selected cytotoxic drugs. Most exposure of this type may be avoided by conscientious wearing of latex gloves and careful handling of drug-contaminated needles or catheters. Re-capping of needles containing drug residues is discouraged to avoid accidental self-inoculation.
Finally, antineoplastic agents can be inadvertently ingested if food, drink, or tobacco products are allowed in the vicinity of drug preparation areas, treatment areas, or kennels housing treated animals. Any ingestible materials should be restricted to a separate area that is far enough away to avoid any possible contamination with these agents. All personnel should handle antineoplastic agents with care. Women of child-bearing age should be particularly cautious, and pregnant women should not handle antineoplastic drugs.
Chemotherapy protocols in cats
Combination chemotherapy allows killing of tumour cells by several mechanisms. CBC assessment should be performed prior to and 1 week after each therapy until a pattern indicates that each agent is safe and well tolerated. If a serious side effect occurs, subsequent doses of that drug should be reduced by 10-15%. Feline Conversion of Body Weight in Kg to Body Surface Area
| Kg | Square metres (m2) |
| 0.5 | 0.06 |
| 1.0 | 0.10 |
| 2.0 | 0.15 |
| 3.0 | 0.20 |
| 4.0 | 0.25 |
| 5.0 | 0.29 |
| 6.0 | 0.33 |
| 7.0 | 0.36 |
| 8.0 | 0.40 |
| 9.0 | 0.43 |
| 10.0 | 0.46 |
| 11.0 | 0.49 |
| 12.0 | 0.52 |
The protocol with the highest first remission rate (69%) and highest remission duration (615 days) and survival time (510 days) is chlorambucil and prednisolone. This is followed by the protocol combination of COP (cyclophosphamide, oncovin, prednisolone) with a remission rate of 75% and remission duration of 150 days. The Modified Wisconsin protocol (Modified CHOP) includes L-asparaginase, vincristine, cyclophosphamide, chlorambucil, doxorubicin, prednisolone and methotrexate and purports a remission rate of 68% and survival time of 225 days1. Individual veterinarian preference appears to affect protocol choice.
| Drug | Dose for cats | Preparation | Administration |
| Doxorubicin | <10 kg:1 mg/kg | 10 mg vials | Diluted in saline over a minimum of 15 mins via an IV catheter |
| Carboplatin | 150-200 mg/m2 | 50 mg and 150 mg vials | Diluted in saline over a minimum of 15 mins via an IV catheter |
| Cyclophosphamide (Cytoxan) | 50 mg/m2 | 25 mg and 50 mg tablets | Give orally once daily for four days |
| Lomustine | 60 mg/m2 | 10 mg and 40 mg capsules | Give orally in one dose every 4 weeks |
| Vincristine (Oncovin) | 0.5-0.7 mg/m2 | 1 mg/mL vials | bolus IV via an IV catheter |
| Chlorambucil (Leukeran) | 15 mg/m2 | 2 mg tablets | 4 day pulse treatment repeated every 3 weeks |
| Prednisolone | 10 mg/day | 5 mg tablets | Give orally from Day 1 |
References
1. August, J.R. (2006). Consultations in feline internal medicine. Elsevier Saunders, Missouri
2. Merck Veterinary Manual http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/191700.htm
