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Practical chemotherapy in veterinary practice (Proceedings)
The majority of neoplastic disorders presenting to the practitioner are manageable in the practice setting and advances in cancer chemotherapeutics are realized virtually every year.
The majority of neoplastic disorders presenting to the practitioner are manageable in the practice setting and advances in cancer chemotherapeutics are realized virtually every year. More and more clients are searching (often on the internet) for high quality care for their companions with cancer. These points in combination with the high incidence rate of neoplasia in our companion animal population make an understanding of the principles of chemotherapy a benefit to the practitioner and the client alike.
Most chemotherapy drugs target rapidly dividing cells; this is both an opportunity (i.e., tumor cells are rapidly dividing) and an obstacle, since some normal cell populations are rapidly dividing (e.g., bone marrow and gastrointestinal stem cells, growing hair follicles). These two competing interests lead to the concept of "fractionating" our drug treatments, that is, chemotherapy is given in several fractions (e.g., once every 3 weeks) and since normal cells generally heal better and faster than cancer cells, the time between fractions allows for normal host recovery. Each fraction and treatment break in between is termed a cycle.
Basic Cell kinetics
Figure 1: Gompertz Growth Curve
Tumor growth is best described by the Gompertz growth curve: Note that our diagnostic abilities are such that clinical and radiographic diagnosis occurs near the end of the logarithmic growth phase of the cancer (i.e. the point where chemotherapy is most effective), often necessitating combined modalities of therapy (e.g. adjuvant surgical or radiotherapeutic cytoreduction). As well, the larger the tumor volume, the more likely tumor clones capable of drug resistance and metastasis will have arisen.
Drug Choice and Dosage
Certain chemotherapeutics act only on specific portions of the cell cycle and are termed 'cell cycle specific agents' (e.g. vincristine acts during the formation of the mitotic spindle). Others affect the cell cycle in a variety of locations and are known as 'cell cycle nonspecific' (e.g. alkylating agents like cyclophosphamide). Combination drug protocols are theoretically most effective when the drugs used in combination act at different stages of the cell cycle. When choosing a combination protocol, several key elements should be considered. Only chose drugs proven to have efficacy when used alone; select each drug on the basis of toxicity (i.e. avoid drugs with overlapping toxicities), and ideally, combine drugs that have different mechanisms of action. The determination of chemotherapeutic drug dosages should be based on several generalities. The ultimate objective is to elicit maximal antitumor effect concomitant with minimal host toxicity. The phenomenon of tumor drug resistance is the leading cause of drug failure. Tumor cells have an unstable genetic makeup, which allows resistant mutations to occur at a relatively regular rate; the larger the tumor volume, the more likely such a mutations is present in one of the tumor clones. In general, when a tumor gains resistance to a drug, it gains resistance to other drugs in the same class, which act by similar mechanisms. Also, multiple drug resistance (MDR, pleotrophic drug resistance) may develop that allow a tumor to be resistant to a wide variety of drug classes.
Most cytotoxic chemotherapeutics are dosed on surface area (meter squared [m2 ]) cue to a better approximation of organ clearance mechanisms. This dosing method tends to result in small dogs (<15kg) receiving a greater dose-density and can result in a higher degree of adverse events; it is recommended that small dogs be dose-reduced (< by 20%) or dosed based on body weight. Melphalan is an exception and is dosed based on body weight.
The Goal of Cancer Therapy
The first and foremost goal of cancer therapy is to sustain or improve the animal's quality of life. The secondary goal is to stabilize, decrease, or eliminate the neoplastic process. A therapeutic strategy should be clearly defined for each patient based on the identified histology and clinical stage of the disease. The full cooperation of the owner is essential: all aspects of the plan must be clearly explained, ideally through the use of handouts which the owners can read and consult as needed. Each client may have a different 'comfort level' with adverse events; some take a 'go out with guns blazing' approach while others may feel that one mild adverse event is too many and the clients personal expectations should be factored into the choice of palliative versus aggressive chemotherapy protocols after educating them on the balance between efficacy and toxicity.
There exist five potential roles for chemotherapy: 1) induction therapy for advanced disease (i.e., measurable tumor with known sensitivity like lymphoma); 2) as an adjunct to local therapy (e.g., to eradicate occult micrometastatic disease as in the case of osteosarcoma following primary amputation); 3) primary or neo adjuvant therapy (i.e. chemotherapy used to downstage disease prior to surgical excision as in the example of unresectable mast cell tumors); 4) palliation, where return to or maintenance of quality of life takes precedence over cure or extension of survival.
Once a patient is started on chemotherapy, there must be a clear method of evaluating the tumor response so that future treatment decisions can be made. When dealing with macroscopic (measurable) disease, tumors should be measured prior to treatment. The common 'RECIST' criteria are usually applied which involves comparing the longest diameter of a lesion (or sum of the longest diameters when multiple tumors are present). A complete response (CR) is defined as disappearance of all measurable tumors; a partial response (PR) is at least a 30% reduction in the longest diameter; progressive disease (PD) as at least a 20% increase in longest diameter; and stable disease (SD), which can itself be a significant response, is a change in diameter that is neither a PR nor PD.
When dealing with disease that is not measurable (e.g., micrometastatic disease following amputation for osteosarcoma), temporal endpoints are used and can include time to metastasis (TTM), disease-free interval (DFI), or disease-free survival (DFS). Alternatively, rates can be applied such as progression-free rate (PFR).
Finally and of significant importance, quality of life (QOL) measures can be applied. These can be client-reported, using standard simple QOL questionnaires that owners fill out at each visit or following each treatment that query them as to attitude, appetite, playfulness, etc. Alternatively more objective measures can be applied such as body weight, body score, etc.
Drug Handling and Safety
Most chemotherapeutics are known to be potentially carcinogenic, mutagenic and teratogenic in their own right. While the risk is low when appropriate precautions are applied, it is prudent that the clinician, caregiver, and any technical staff who may come in contact with these agents be forewarned as to their potential toxicity both verbally and through the use of handouts in the case of clients and in-service educational methods for staff. In the practice setting, common sense and regionally mandated guidelines should be the rule.
Drug mixing and Reconstitution
In an ideal situation, all solutions would be prepared in a registered fume hood by a clinical pharmacist or technician. Small, cost-effective units are now commercially available for specialty practices. In the absence of a fume hood, commercially available closed mixing and delivery systems (e.g., PhaSeal? system) can be used. Staff and clients who are pregnant or are trying to become so should avoid handling these agents. Approved chemotherapy gloves, and goggles should be worn during the preparation and handling of all solutions. Masks should be worn during solution preparations and spill sheets (e.g. disposal diapers) should be used in the area of preparation.
It is recommended that jugular phlebotomy be used for sampling while saving the use of peripheral veins for chemotherapy. Luer-locks should be used to protect against inadvertent spray. Chemotherapy should be transported in clearly marked plastic zip-lock style bags. Prior to giving any patient chemotherapy, the recitation and confirmation of the "4 R's" should be performed (i.e., the right drug, the right dose, the right route and the right patient). After drug handling and delivery, the preparation area as well as the operator's hands should be washed thoroughly. Cage labels clearly indicating that a patient has been given chemotherapy should be used such that cleaning staff and other health-care professionals are aware to handle excretions and soiled linens with appropriate care. Check local ordinances with regard to disposal of contaminated items. Appropriately stocked chemotherapy 'spill kits' should be present and kept in a designated area and all staff should be fully versed in their use.
If sending home oral chemotherapy for a client to give, all drugs should be placed in a clearly marked plastic zip-lock style bag along with an appropriate supply of chemotherapy gloves and handouts that explain clearly the handling and disposal of such agents. These handouts should provide information on handling spills and excreta in the home, and methods of disposing of bowel movements for the 36 – 48 hours that they may contain small amounts of chemotherapy. Clients should be educated as to methods of pilling and to observe their companion for a period after pilling to ensure the pills are swallowed and not spit out. Contact with family members and other companion animals should be minimized for 48 hours after dosing by confining the pet to designated areas and ensuring the yard or litter box is cleared frequently and safely. Drugs should be stored away from food, and hands should be washed thoroughly after drugs are handled, and potentially contaminated laundry should be washed separately.
Recently, the concept of low-dose, continuous delivery of cytotoxic agents, sometimes called "metronomic" chemotherapy has been introduced. With this delivery method treatments are spaced such that the normal tissues have sufficient time to recover, rather than administering the cytotoxic agent at the MTD. With metronomic delivery a more frequent (e.g., daily) low dose (well below the MTD) of the drug is given continuously. There is significant in vitro and in vivo (in rodent tumor models) evidence to suggest that cytotoxic agents applied in this fashion affect the endothelium of growing tumor vasculature and exert their affects through an anti-angiogenic mechanism rather than through tumor cell cytotoxicity. The theorized outcome of metronomic chemotherapy is stabilization rather than regression of disease. Administration of chemotherapeutics in this fashion also has the possible advantage of being less toxic because doses well below the MTD are used.
It appears that combining metronomic chemotherapy with drugs known to possess some inherent anti-angiogenic activity (e.g., doxycycline) and cyclooxygenase-2 (COX-2) inhibitors (e.g., piroxicam) may increase the likelihood of an anti-tumor response. At present, several trials of metronomic therapy are underway in humans and animals. It must be stressed that these studies have not been subjected to rigorous evaluation and therefore, the use of metronomic chemotherapy awaits validation through appropriate clinical trials.
Adverse Events Following Chemotherapy
The next lecture in this series will deal specifically with adverse events and their prevention and management.