In many veterinary patients the goal is to achieve a complete remission, typically in patients with lymphoma. It is important to realize that a complete remission means that there is no visible sign of the tumour, not that all the cancer cells have been eliminated. This means that at some point the cancer will recur and, when it does, drug resistance may have occurred. In some cases (e.g. osteosarcoma), the goal is to prolong median survival time whilst informing the client that eventually the cancer will return in the form of metastatic disease. When chemotherapy is used in this fashion it is known as adjuvant therapy and treatment is targeted at micrometastatic disease. The third situation is where chemotherapy is being used to shrink a tumour in an attempt to improve quality of life without any possibility of a remission (e.g. large metastatic mast cell tumours) and is described as palliative therapy. In some instances chemotherapy may be used in an attempt to shrink a tumour prior to surgery (neoadjuvant treatment).

It is the responsibility of the veterinary surgeon to fully understand the potential side effects of the drugs they intend to administer and when taking on that responsibility ensure that they have the facilities to provide adequate 24-hour care. Side effects can be acute (vomiting/diarrhoea), cumulative (bone marrow suppression) or idiosyncratic (haemorrhagic cystitis with cyclophosphamide).

It is the goal of every veterinary oncologist to give the cancer patient the greatest quantity of life without compromising the quality of that life or the bond between the client and their beloved companion.

Statistics on median survival times for the most common veterinary cancers are known, e.g. lymphoma (see Chapter 22) and osteosarcoma (see Chapter 21). With some cancers that occur less frequently a lot of data is unavailable, and the expertise and experience of the clinical oncologist are required to assess the balance between risk and benefit of chemotherapy in the individual. It is important to remember that every patient is an individual and that many factors can influence overall survival times, not least being signalment, stage of disease, concurrent medical problems and the protocol selected.

Combinations of drugs provide maximum tumour cell kill whilst limiting individual drug toxicity. Utilization of drugs that have different mechanisms of action means that resistance within a heterogeneous population will develop more slowly. Tumours that are large enough to be detected (>10⁶ cells) are a heterogeneous population containing drug-resistant clones (Goldie et al 1982). This means that with single-agent protocols response will be short because of the rapid repopulation with resistant cells.

Drug selection is based on proven efficacy of the drug against the tumour in question and the ability to give it at consistent intervals; the treatment-free interval between cycles should be the shortest time possible for the recovery of the most sensitive normal tissue, usually the bone marrow. The storage compartment of the bone marrow is able to supply mature cells for ~10 days after the stem cell pool has been damaged. This means that what is seen in the peripheral blood is about a week behind what is going on in the marrow.

The nadir of leucopenia exhibited by the various drugs is an important consideration in chemotherapy protocols. All drugs should be given at their optimal dose and schedule. When several drugs of a class are available, the drug selected should not have overlapping toxicities with other selected drugs. In some instances, however, single agents are used as the overall survival times with combination protocols have not been shown to be superior to single agents but the toxicity is significantly greater, e.g. doxorubicin in the management of splenic haemangiosarcoma (see Chapter 23).

There is an inverse relationship between the total number of neoplastic cells and ‘curability’. Early diagnosis and early treatment give the patient the best possible prognosis. The same percentage of cells is killed per cycle of a given drug, irrespective of the number of cells. This is known as the fractional kill hypothesis and each cycle of treatment will kill a specific fraction of the remaining cells. The objective of each cycle is to reduce the absolute number of remaining cells due to the cumulative effect of successful fractional kills.

The pharmacokinetics of chemotherapeutic agents is important as this examines the distribution of drugs and their metabolites throughout the body and ultimately the bioavailability of drugs to kill cancer cells and therefore their therapeutic effect (Ehrlichman 1992). Intravenous administration assumes 100% bioavailability but administration via other routes (oral, intramuscular, subcutaneous) may only be partial. It is important to remember that the bioavailability of many chemotherapeutic drugs used in veterinary oncology that are not given i.v. will not have had their bioavailability validated.

A number of factors influence the distribution of drugs within the body and include blood flow to different organs, diffusion of drug from blood vessels, protein binding and lipid solubility. Doxorubicin shows extensive tissue binding and therefore has slow release of the drug from these sites. A drug such as carmustine (BCNU) that is lipid soluble, and therefore penetrates the blood–brain barrier, should also have a slow elimination phase; however, it is inactivated quickly, meaning that there is only a very short exposure of body tissues to the drug.

The cell cycle (Figure 6.1) is important when putting together a chemotherapy protocol and drugs can be broadly classified into those that affect a particular point in the cell cycle, known as cell-cycle specific, e.g. the vinca alkaloids, and those that can act on the cell at any time during the cell cycle, non-cell cycle specific, e.g. alkylating agents.