In considering the application of chemotherapy to animals with cancer the following factors are of importance: 1) treatment setup; 2) type of patient; 3) type of tumour; and 4) the owner's view. Each of these factors will have a decisive influence on whether chemotherapy will be used or not.
i. Treatment set-up
With treatment set-up we refer here to the fact as to whether cytostatic drugs are given solely or in combination with other treatment modalities. In the latter instance it is called adjuvant chemotherapy and its potential value depends upon the efficacy of the combined forms of treatment. In veterinary medicine adjuvant chemotherapy is most often used in combination with surgery of tumours that are expected to have developed micrometastases at the time of treatment of the primary lesion, e.g., osteosarcoma in the dog. In general, the period of treatment is limited.
The set-up of treatment also includes its aim and potential. Chemotherapy may aim at a total kill of all tumour cells, i.e., curative chemotherapy, or at a reduction of the tumour mass and the related symptoms, i.e., palliative chemotherapy.
Curative chemotherapy is seldom attempted in veterinary oncology in view of the high treatment intensity often needed and the related toxicity. However, in some lymphomas in the dog and cat, and in about all of the condylomas in the dog, a cure may be achieved, but rarely so in other solid tumours.
On the other hand, chemotherapy can often achieve a palliation of symptoms of a cancer for up to several years. These symptoms include physical distress due to the tumour mass or it's infiltrative or metastatic growth, or due to paraneoplastic effects (e.g., hypercalcemia in lymphomas or hypoglycemia in insulinomas). However, one must realize that, even if effective, it may take some time before chemotherapy leads to a reduction in tumour-related morbidity.
ii. Type of patient
Various patient characteristics and interrelations with the therapy must be considered. These include the use of the dog, e.g., breeding, guarding or racing, and the life expectancy with and without the tumour disease. Life expectancy relates to age (although not a contra-indication in itself), clinical performance, function of critical organs and clinical stage. The presence of another, unrelated disease, may have influence. The clinical performance for pet animals tries to describe the ability of the animal to exert its normal activities and to keep it's normal metabolic state.
The function of critical organs may have been compromised by the tumour to an unacceptably low level, in particular if the chemotherapy in itself is expected to have some compromising effect. Many types of haematological tumours may damage bone marrow function, which, on the other hand, is very sensitive to the cytotoxicity of many types of chemotherapy agents. In addition, kidney and liver function may be important in excreting the chemotherapy agents and thereby determine their plasma and tissue concentrations and half-life, and risk for toxicity. Cyclophosphamide needs metabolic activation in the liver in order to have a cytostatic effect. Some platin compounds may damage the kidney; doxorubicin may be toxic to both the kidney and the heart. A critical analysis of organ function by physical and laboratory examination is mandatory before the start of chemotherapy.
The clinical stage (TNM: Tumour, Node, Metastasis) not only gives information regarding tumour mass (often inversely related to chemotherapy efficacy) but also regarding extension to regional nodes and distant sites. This may help to define the need for treatment (based on tumour aggressiveness) but may also point to the presence of limiting factors (severe organ dysfunction, perhaps irreversible). Reassessment of clinical performance and organ function must be performed at regular times during therapy.
III. Type of tumour
In addition to the clinical stage of the patient at the time it is presented for treatment, the type of tumour is of utmost importance for our decision whether or not to apply chemotherapy. The tumour type (and malignancy grade) may help to assess the biological behaviour. This includes the mode of growth, expansive versus infiltrative, and the capacity to metastasize.
Tumours that often grow in an infiltrative way are, amongst others, mastocytomas and many sarcomas. For some solid tumours the likelihood of (micro)metastatic spread at the time of first manifestation is almost absolute, even if signs of macrometastases are absent. This can be said, for instance, for dogs with osteosarcoma of the appendicular skeleton and cats with mammary carcinoma. Also many haematological tumours are systemic diseases at the time of first manifestation.
The assessment of the biological behaviour, thus, indicates the potential efficacy of surgical treatment to provide local tumour control, but may also predict systemic spread. Both factors may define the need for an additional therapy. Furthermore, there is a correlation between tumour type and sensitivity to specific forms of chemotherapy. Despite considerable progress in the last decades, knowledge on this correlation is incomplete for several types of animal tumours. For more details the reader is referred to oncology textbooks. Some examples are given in Table 1 which is based on literature data and personal experience, and may change as new drugs are proven to be effective. The sensitivity of a specific tumour type predicts the proportion of tumours that are sensitive to specific drugs used alone or in combination.
Table 1. Sensitivity of different tumour types to chemotherapy
A. Tumours which are often sensitive to cytotoxic drugs, where remissions are often obtained and life is prolonged:
Malignant Lymphoma (Dog/Cat)
Transmissible Venereal Tumour (Dog)
B. Tumours which are sometimes sensitive to cytotoxic drugs, where remissions occur and life may be prolonged:
Mammary carcinoma (Cat)
Thyroid carcinoma (Dog)
Ovarian carcinoma (Dog)
Mycosis fungoides (Dog)
C. Tumours where although response to chemotherapy occurs it is uncertain whether life is prolonged:
Mammary carcinoma (Dog)
Squamous cell carcinoma (Dog/Cat)
D. Tumours in which a response to chemotherapy is seldom seen and life is not prolonged:
Malignant histiocytoma (Dog)
IV. The owner's view
A good communication between the oncologist and the owner is at the basis of any balanced therapeutic approach. Clear information regarding the prospects and pitfalls of the chemotherapy should be provided, in order to enable the owner to establish justified expectations. Furthermore it must become clear what the owner's possibilities are to have the chemotherapy been carried out. These possibilities include available finances and time, as well as emotional strength. It is to be preferred that the owner becomes aware of the strength of his/her motivation before the start of treatment, in particular with more extensive therapeutic protocols.
Apart from veterinary aspects of chemotherapy potential hazards of cytostatic drugs to the clinician, technician or owner may also play an important role in the decision whether chemotherapy should be given to an animal or not.
The first report on the risks of cytostatic drugs was published in 1979. Mutagenic substances had been found in the urine of nurses who worked on an oncology ward and administered cytostatic drugs. A few years later other studies reported on liver damage and an increased percentage of miscarriages in such nurses. These miscarriages were evidently correlated with the handling of cytostatics in the first trimester of the pregnancy. In other publications skin lesions were reported after direct contact with cytostatic drugs or aerosols with cytostatics. In the mean time the first epidemiological studies were published, in which an increased risk of leukaemia was found in patients treated with chemotherapy for another tumour.
In addition, chromosomal aberrations were demonstrated in lymphocytes of nurses working on an oncology ward. Nurses who protected themselves against direct contact with cytostatic drugs did not have any chromosomal aberrations, in contrast to those nurses who were reckless and did not work with hand gloves, masks and a flow chamber. Also traces of cyclophosphamide were detected in the urine not only of patients but also of oncology ward nurses. This finding is noteworthy since the drug is metabolised in the liver leaving only very small amounts of the parent drug to be excreted in the urine.
Structural flaws can be found in some of these investigations. Still, one can conclude that the results of the combined laboratory studies, provocation tests, clinical observations, and experiences in occupational groups that handle these cytostatic drugs point all in the same direction. Handling cytostatic drugs is potentially dangerous, unless special safety measurements are being taken.
Directives for handling cytostatic drugs
a. Use latex hand gloves (latex is to be preferred to PVC) both at the time of preparation and administration. Better to use a double pair of hand gloves. Alcohol make these gloves permeable to substances, therefore be careful with alcohol disinfection of the animal's skin.
b. Use a mask.
c. Use special protective clothing.
a. Use a vertical laminar flow chamber for the preparation of the cytostatic drugs.
b. Do not eat, drink, or smoke in the same room were the cytostatic drugs are being prepared or administered.
3. Preparation of drugs
a. When opening an ampoule, use a sterile gauze at the neck of the ampoule.
b. Be careful with those cytostatic drugs which have to be dissolved. There is a danger of over-pressure in the ampoule and subsequent formation of aerosol when taking out the needle. Inject the solvent carefully and take away the over-pressure with the same syringe which contained the solvent.
c. Take away the air from the syringe by holding a sterile gauze at the needle and puss the plunger until all the air has left.
4. Cytostatic waste
a. Needles, syringes, ampoules have to be placed in special waste boxes.
b. Also masks, hand gloves and disposable protective clothing have to be deposit in these special waste boxes.
c. Urine, faeces and vomit of the patient can contain cytostatic drugs and must be considered as potentially dangerous.
a. Pregnant women or women planning to have babies, should not be in an area where cytostatic drugs are being prepared or administered.
6. Instructions to owners
a. Owners should wear latex hand gloves when administering cytostatic tablets to their pets
b. Tablets should be given intact and are not allowed to be broken.
c. After administration of chemotherapy the saliva of their pet will contain high levels of the drug. Therefore, the owner should not let their pet lick them during a few days.
d. Urine, faeces and vomit of the patient can contain cytostatic drugs and should be removed carefully with latex hand gloves on.
e. Preferably the pet should let out in areas where no children are playing.
f. The animal will be potentially dangerous during a period of 7-10 days after administration of the cytostatic drug.