Angela E. Frimberger, VMD, DACVIM (Oncology)
Cancer Care in Small Animal Practice
As wellness care, prevention of infectious disease, and avoidance of trauma become more effective in veterinary medicine; the Small Animal Practitioner will encounter more chronic and degenerative diseases. Likewise, the place that small companion animals hold in the family and emotional life of their owners and caretakers is now more important than ever before. Veterinary clients are increasingly well-informed and demand the highest available level of care for their pets. It is not only in the best medical interest of their patients, but also in the best business interest of their practice, for the small practitioner to respond to this demand enthusiastically. Good medicine is good business!
There is Never "Nothing You Can Do"
Cancer is not only one of the most common causes of illness and death–as well as sources of client concern - in both dogs and cats, but also one of the most professionally satisfying to treat. Our overriding philosophy is that every pet with cancer and their family can be helped in some way.
In veterinary oncology, quality of life for the patient is always the top priority. Some cancers can be cured by treatments compatible with good quality of life. In other cases, anticancer treatment may significantly extend good quality survival time even if the patient is not permanently cured. However for other patients, palliation may be a more appropriate goal; and because it delays the need for euthanasia, effective palliation can significantly enhance survival time as well as quality of life in veterinary medicine. Even in those cases where hospice care or euthanasia is the best option, performing this with compassion and skill can be one of the most valuable services a veterinarian can provide to help both patient and client.
Where Does Chemotherapy Fit In?
Chemotherapy is the principal modality used to treat systemic cancers such as haematologic malignancies, as well as metastatic solid tumours (carcinomas and sarcomas). Because of the focus on quality of life over quantity, the drug dosages and schedules used in veterinary chemotherapy are more conservative and less likely to result in side effects than those in human cancer patients. When discussing chemotherapy, communication and sharing of information between the veterinarian and the owner is essential, and should be gentle but honest. Options should never be limited by the veterinarian's impression of the owner's finances or preferences. Rather, a veterinarian should be well-informed and offer all the medically feasible options, and be able to discuss their potential benefit, side effects, and cost in order to allow a pet owner to make an informed decision.
Treat the Patient, Not the Pathology Report
Although it is tempting to think of chemotherapy protocols as a "recipe" for treating particular types of cancer, in fact they are a guide. Just because a treatment has shown the best efficacy for a particular type of cancer does not necessarily mean it is the best treatment for the individual patient. Just as every patient - and their metabolism and excretion of drugs - is individual, every cancer is also an individual. Complete evaluation of the cancer and the patient is therefore important both in prognosis and making an initial treatment plan, and continuing to tailor the plan in response to the patient's condition. It may also be necessary to consider other medical factors that may pose an increased toxicity risk (more below) and nonmedical factors, as well as owner factors such as finance, scheduling constraints or owner pregnancy, in deciding what course is best for a particular patient.
As a general rule of thumb, chemotherapy drugs are most active against cells that are actively cycling or in specific phases of the cell cycle. Tumours grow most rapidly when they are small. As they grow larger, the growth rate decreases. Poor perfusion also means chemotherapy drugs may not be delivered to cancer cells at cytotoxic levels, and hypoxia may decrease the tumour cell response to treatment. In addition, cellular heterogeneity increases as tumours grow, leading to a higher level of spontaneous drug resistance. So in general, chemotherapy will be most active against small tumours, following either early detection or a "debulking" procedure such as surgery or radiation therapy (more below).
Combination chemotherapy can avoid some drug resistance problems by affecting different metabolic pathways in cells that are resistant to other drugs. While combination chemotherapy could potentially be more toxic to normal cells, judicious scheduling of agents so that their toxicities do not overlap can be exploited to improve tumour kill without compounding toxicity.
While combination chemotherapy may circumvent individual drug resistance, it does not completely avoid the problem of cross-resistance to multiple unrelated chemotherapy drugs. The transmembrane pump protein (P-glycoprotein) is present at increased levels in some tumour cells, and both the level and prevalence increases with exposure to chemotherapy. This phenomenon of multiple drug resistance (mdr) occurs between natural product drugs such as anthracyclines (e.g., doxorubicin), and Vinca alkaloids (e.g., vincristine). In practical terms this means that a lymphoma that is resistant to the combination of vincristine, cyclophosphamide and prednisone (COP) may also be resistant to doxorubicin even if it has never been used, so drugs that are not mdr substrates should be used in preference (e.g., alkylating agents).
Adjuvant chemotherapy is used following resection of a primary tumour, where the patient is at significant risk of recurrence or metastasis but before recurrence or metastasis is clinically detectable, the classic example being canine osteosarcoma. The advantage is that when a primary tumour is resected, micrometastases have a high growth fraction and a low number of resistant cells, so the chemotherapy can have greatest efficacy. The disadvantage of adjuvant chemotherapy is that those patients cured by surgery are exposed to needless risks of toxicity. For tumours such as canine osteosarcoma and haemangiosarcoma, and feline mammary tumours, this percentage is small; but in other situations the decision whether to use adjuvant chemotherapy may be less clear.
Less commonly used, neoadjuvant chemotherapy is given before localized treatment modalities such as surgery or radiation therapy, with the objective of reducing the size of the primary tumour and reducing the scope and side effects of other definitive treatment.
Most chemotherapy drugs have a narrow therapeutic margin, so doses must be chosen and calculated with utmost care to provide minimum toxicity risk and maximum efficacy. Although imperfect, current dosage recommendations are often based on body surface area (BSA, m2). Overall, using the BSA formula means that smaller dogs receive a higher dosage than larger dogs (in proportion to body weight), supposedly compensating for more rapid drug distribution, metabolism and excretion. If this is true, then drug exposure, and efficacy and toxicity, should be relatively uniform across a species. If fact, this is not so, and for veterinary use, dosage based on BSA for many drugs is imperfect; and small dogs and cats should be dosed at a lower rate than larger dogs.
The problems with the BSA formula have been evaluated in studies. In the formula, the constant (K) is supposed to be a shape constant for a given species. K was derived from studies with very small sample sizes, and the highly variable shape of dogs probably means that the constant is NOT constant for different breeds of dogs.
Despite these limitations, until further guidelines are available, the veterinarian should use a BSA conversion table as the best practical solution, and become familiar with the individual drugs that require lower dosage for small pets. BSA can be determined using a conversion table, in textbooks and on our website at www.vetoncologyconsults.com/.
Dose intensity is defined as the amount of drug administered per unit time (mg/m2/wk) and can be increased by increasing the drug dosage or by shortening the intertreatment interval. Optimal dose intensity improves the outcome for chemotherapy, and dose intensity should be the highest tolerated by the patient with minimal toxicity.
The other benefit of maximizing dose intensity is to reduce the risk of drug resistance developing. It is important not to administer drugs at sub-therapeutic dosages. On the other hand, if there is tumour growth, it is not good practice to continue the same treatment protocol at the same dosages.
Effects of the Body on Chemotherapy Drugs
There are four major factors that affect how chemotherapeutics are handled in the body and therefore its toxicity or efficacy. These need to be considered in chemotherapy dosing for each individual patient, particularly in geriatric oncology patients.
Oral chemotherapeutics may have reduced absorption in a pet with malabsorption, for example GI lymphoma, leading to decreased efficacy of the drug.
Drugs affected by protein binding such as vinca alkaloids or mitoxantrone may be affected when an animal is hypoproteinaemic; a larger proportion of the drug may remain pharmacologically active, or may be more rapidly cleared from the body. The effect of other protein-bound drugs should also be considered.
The concentration of drug in blood over time is a function of total clearance by all eliminating organs. For example, decreases in glomerular filtration rate may affect drugs such as carboplatin; and bile transport disruption could reduce clearance of vincristine or doxorubicin.
Hepatic dysfunction may affect reductase metabolism of doxorubicin, thereby increasing toxicity. Cyclophosphamide and DTIC require hepatic activation, so reduced metabolism may reduce toxicity but also efficacy.
Chemotherapy in veterinary private practice can provide patients with extended survival time and excellent quality of life, and can be very rewarding. To achieve this, one needs to consider all individual patient- and tumour-specific variables in choosing chemotherapy schedules and doses.