Practical chemotherapy in veterinary practice (Proceedings)


Practical chemotherapy in veterinary practice (Proceedings)

Apr 01, 2009

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.

General Principles

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.

Clinical Endpoints

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.