Chemotherapy

M.J. Brearley

Although not used frequently in cats, chemotherapy can be an important primary or adjunctive therapy in the treatment of feline cancers. However, whilst there are anecdotal comments and single case reports advocating the use of anti-cancer drugs against many cancers in cats, there are only a few tumors for which efficacy has been described with any evidence base. These are the lymphoid malignancies, mammary cancer, vaccine-associated feline sarcoma and, by intralesional administration, squamous cell carcinoma of the mouth and face. It is worth reflecting that even in human oncology there are only a few tumors that are regularly cured by chemotherapy (for example, childhood leukemia and testicular cancer) and indeed the number of patients with other cancers that truly benefit from cytotoxic drugs overall is modest at best. The greatest progress in the treatment of cancer in humans has been by early diagnosis, effective surgical techniques and radiotherapy; it is almost a certainty that this will be true in veterinary oncology also.

Hippocrates is purported to have said, ‘First do no harm’ and to that end the speculative use of any treatment that can have serious side effects on the chance that it might do some good is not to be encouraged. Just as a radical chest wall resection to treat a cancer that has already metastasized would never be considered, the use of a drug that kills cells, and possibly also the patient, with little to no chance of controlling the disease should not be entertained. The use of a treatment that has potentially devastating side effects has to be based on evidence of efficacy and then with an understanding of all the potential ramifications.

Having given this stark introduction, chemotherapy can help control certain cancers and thereby benefit those individuals with an improved quality of life. This chapter therefore aims to give an insight into some of the drugs that are used, their potential side effects and the management of such problems, and the situations where cytotoxic drugs have been shown to have efficacy in cats. For further information the reader is referred to specialist oncology textbooks.1–4

Cancer chemotherapy

Cancer chemotherapy is the use of drugs that by some means control the growth of cancer cells either by killing them (cytotoxic) or by preventing their proliferation (cytostatic). To date there are few anti-cancer drugs that are truly specific against cancer cells and therefore their activity against normal cells also gives rise to potential toxicity. Toxicity to normal tissues is not unique to anti-cancer drugs; very few chemicals are totally free of side effects. However, unlike anti-bacterial agents, for example, that utilize the very different biology of bacterial versus eukaryotic cells, anti-cancer drugs are aimed at a cell population that is basically host cells doing something wrong. By a variety of mechanisms the therapeutic gain is the result of either more damage and/or less recovery from damage, in the cancer population compared with the normal host tissues. The therapeutic index, which is the ratio of benefit to toxicity, for most of the current anti-cancer drugs is narrow and indeed the fatal dose is rarely more than double that used therapeutically, thereby highlighting the need to use these medications with care.

How anti-cancer drugs work

Most of the ‘conventional’ anti-cancer drugs are cytotoxic and work by killing dividing cells (both normal and cancerous) either via damage to DNA synthesis or to a specific mechanism of cell division. The newer so-called targeted therapies, such as the tyrosine kinase inhibitors, act at specific cell surface receptors that promote cell proliferation, hence their cytostatic effect.

Few tumor types are truly insensitive to cytotoxic drugs. However, the cancers arising from cell types whose function is to detoxify or excrete toxic chemicals are relatively resistant; this includes hepatic, renal, and colon cancers. The majority of other cell types are innately sensitive to cytotoxic drugs, but may develop resistance to them either by acquiring mutations as they multiply (because cancer cells are genetically unstable) or by switching on genes in response to repeated exposure to cytotoxic drugs (i.e., an adaptive response). These acquired or activated genes tend to confer resistance to a range of drugs and not just to the chemotherapeutic agent to which they have been exposed. Such multi-drug resistance is the most frequent reason for relapse of a tumor that had apparently achieved complete remission.

Another property of tissues that influences efficacy of cytotoxic drugs is the growth rate (Box 16-1). The rate of clinical tumor growth and the mitotic index given by histology may provide surrogate information about the tissue growth rate. In theory, tumors with a high growth fraction and short cell cycle time are the most sensitive to cytotoxic agents. Lymphoblastic lymphoma is an example of a sensitive cell type of this nature, as the cells often exhibit a high mitotic rate, and hence this form of tumor in cats frequently responds to chemotherapy.

Box 16-1 Growth rate of cells

Growth rate is a function of:

• The number of cells in the population that are actively cycling (dividing), the so-called ‘growth fraction’

• The cell cycle time (rate of division)

• The number of cells being lost by cell death

A high growth rate is also seen with small or microscopic tumors, which have a high growth fraction and fast cell cycle time. Conversely, large bulky tumors tend to have a low growth fraction, slow cell cycle and increased cell loss. Chemotherapy is therefore more likely to be effective against early microscopic metastases or minimal residual disease following surgery, which is why the adjuvant use of chemotherapy should be actively considered for certain tumor types.

When chemotherapy is indicated

Cytotoxic drugs are used in several scenarios (Box 16-2). In practice, the probability of curing most cancer in dogs or cats with cytotoxic drugs is low because the actual range of tumors that respond to chemotherapy is quite limited, a fact especially true in cats.

Box 16-2 Cytotoxic drugs are used for the following reasons

Primary therapy with curative intent or for long remission

Part of multi-modality treatment as either:

• adjuvant therapy following surgery that has reduced the tumor burden to minimal residual disease or

• neoadjuvant therapy prior to another potentially curative modality

Palliative to achieve short-term control for improved quality of life

Drug dosing issues

There are several principles that should be followed when selecting drugs for chemotherapy (Box 16-3).

Box 16-3 Principles of drug selection for chemotherapy

Use drugs that have shown efficacy against the tumor in question

Use drugs at the highest acceptable dose intensity (a function of dose and dose interval)

Use drugs in combination that have different modes of action, resistance and toxicity when possible

The vast majority of anti-cancer agents used in dogs and cats are human drugs; it is only recently that drugs have been developed specifically for veterinary use. Some drug doses have been derived from toxicology data from the pharmaceutical development of human drugs, but this data is more readily available for dogs than cats as the latter are rarely used in the development of human drugs. In addition, dose escalation as part of phase I and II studies has been performed for some of the cytotoxic drugs used in veterinary oncology. However, most frequently the dose in clinical practice has been derived from clinical experience and the protocols using a single agent or a combination of drugs have often been developed in a rather empirical manner.

As already stated, the therapeutic index of anti-cancer drugs is narrow, which is an important consideration when veterinary surgeons have an ethical obligation to minimize the side effects any treatment may generate. In the main, most drugs are metabolized in a manner proportional to the metabolic rate of the animal. A major function of the basal metabolic rate (BMR) is to maintain the body temperature of the mammal. As heat loss from an object is proportional to its surface area rather than its volume, the BMR is related to the surface area rather than the volume (or weight) of the individual. Larger individuals have a lower surface area to volume ratio, hence a lower BMR and a lower rate of drug elimination. Dosing on a weight basis tends to over-dose larger individuals and under-dose small patients. Using a dose per surface area in theory smoothes this difference, but unfortunately for patients less than 10 kg this may not hold true. There is also species variation, so it is important that the dose for cats should not be simply extrapolated from that for small dogs.

The surface area is derived from the weight by equation in Box 16-4 (see also Table 16.1).The dose interval depends on which drug is being used, the dose given and the recovery time from adverse effects. For most cytotoxic drugs given as a ‘high dose’ bolus the average time to complete recovery is day 21 following the neutropenic nadir at day 5 to 7, and therefore a dose interval of three weeks is appropriate. However, some drugs (e.g., lomustine and, to a lesser extent, carboplatin)^5,6 have a second weaker nadir around day 20 and may warrant a four week cycle, so it is important to be aware of these individual drug variations when designing a therapeutic plan for individual patients. Drugs may also be given at a lower dose more frequently to give a chronic exposure.

Box 16-4 Equation for determining body surface area in cats

Body surface area (m²) = k × weight (kg)^2/3/100

k = 10.0 (for cats)

Table 16-1