treatment
of the cancer patient
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From theory to practice
caninE anD fElinE
Oncology treatment Of the cancer patient
Factors that affect treatment Planning cancer treatment is a complex task due to the many and diverse clinical presentations of tumours, the condition of the patient, owner considerations and the available treatment options.
If possible, all neoplastic cells should be removed from the patient (= cure) after the diagnosis has been made. This means acting immediately, rather than “wait and see”. If this is not possible, palliative treatment is perfectly acceptable. Malignant tumours do not resolve spontaneously. A delay in treatment in a patient with a suspected or confirmed malignant tumour, at least in theory, increases the likelihood of the tumour spreading locally or developing metastases, thereby reducing the probability of a cure.
1.0 0.9 0.8 Proportion of survivors
Broadly speaking, the main advantages and disadvantages of treatment are: ■■ Advantages: malignant tumours are one of the few chronic diseases that are potentially reversible, in contrast to heart disease (graph 1), renal insufficiency, osteoarthritis or most endocrine disorders. Furthermore, treatment can provide a good quality of life for the patient, contrary to popular belief. ■■ Disadvantages: the words “cancer” and “chemotherapy” cause apprehension and anxiety and are associated with death or toxicity, in particular in view of the adverse reactions that chemotherapy may cause in human patients. Most owners know of one or more human cancer patients who have been treated, but rarely know a cat or dog that has been treated.
Graph 1. Comparison of the survival time of patients with lymphoma and dilated cardiomyopathy.
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0
175
350
525
700
875
1050 1225 1400
1575 1750
Survival time (days) Substage A LSA. Substage B LSA. Dilated cardiomyopathy-DCM.
Survival (Kaplan-Meier) of three groups of dogs with: • Lymphoma (LSA) substage A (asymptomatic, green line). • Lymphoma (LSA) substage B (symptomatic, orange line). • Dilated cardiomyopathy-DCM (blue line). The two groups of dogs with lymphoma were treated with a COP-type chemotherapeutic protocol, and dogs with DCM were treated with conventional therapy without pimobendan. Survival was longer, even in the dogs with substage B lymphoma, compared to dogs with dilated cardiomyopathy.
Treatments can be classified as curative or palliative. Surgery and radiotherapy are potentially curative treatments, while chemotherapy is considered palliative, even though a variable percentage of patients will be cured.
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■■
■■
Curative treatments: most patients with local tumours (without metastases) and some patients with regional tumours can be cured with appropriate treatment (aggressive surgery, radiotherapy or a combination of both). Examples of such tumours include fibrosarcomas in dogs and cats, haemangiopericytomas in dogs and squamous cell carcinomas of the head and neck in cats. Palliative treatments: if a patient has a disseminated tumour (lymphoma) or metastases (osteosarcoma, haemangiosarcoma), the probability of cure is extremely low (< 10 %). However, palliative treatment will lead to remission in most patients (12 and 18 months in dogs with lymphoma or osteosarcoma treated with chemotherapy, or amputation plus chemotherapy, respectively). Certain tumours, such as sexually transmissible tumours, usually respond to chemotherapy (vincristine). Besides prolonging remission, treatment aims to provide the patient with quality of life and low toxicity at a reduced cost without hospitalisation.
Modified Karnofsky performance scale for cats and dogs. Score
Level of activity
0
Normal: fully active. Activity is similar to that prior to disease.
1
Restricted: Less active than before the disease but with an acceptable capacity to cope on its own.
2
Compromised: Severely restricted activity. Only moves to eat, defecate and urinate in designated areas.
3
Disabled: Completely incapacitated. The patient is force-fed, is unable to retain urine and faeces until reaching designated areas.
4
Death.
In the past 2 to 3 years, metronomic chemotherapy has allowed us to alleviate cancer in patients in an advanced stage of the disease, maintaining an excellent quality of life.
words, in poor general condition, is not a good candidate for treatment with aggressive chemotherapy or to receive the anaesthetics required for radiotherapy.
To decide which treatment is the most suitable, three key factors need to be considered:
Owner-related factors
Patient-related factors Regardless of the theoretical therapeutic indications for a tumour, it is essential to take into account the condition and characteristics of the patient (health problems, ease of venopuncture, character of the animal, etc.). The most important patient-related factors to take into account are its activity level and general health. Scales exist to assess the grade of activity, as will be shown below. For example, a cat or a dog with a significantly reduced activity and severe systemic signs, in other
The owner-patient bond is often the determining factor when choosing a treatment. It should be taken into account that owners are concerned and that the concepts of cancer and chemotherapy have very negative connotations. To avoid an outright rejection of the available alternatives, it may be useful to break bad news gradually to the owners and to give them time to digest it and to make a decision. Pet owners should be treated as members of the medical team, and tasks should be assigned to them to carry out at home: measuring the progression of the tumour size, checking the temperature, assessing the pet’s activity levels, etc. Usually, these duties will involve them in the treatment and improve cooperation with the clinician.
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From theory to practice
caninE anD fElinE
Oncology
The veterinarian should always be available to dispel the owner’s doubts and to offer help at difficult moments. On the other hand, all options should be discussed with the owners, including immediate euthanasia in case of failure of the proposed treatment. Expectations should be defined, as well as the concept of “tolerable” toxicity, i.e. the level of toxicity that can be tolerated by the pet in exchange for an improved quality of life and prognosis. The economic factor is also important, although initially all options should be discussed, together with their prognosis, independent of cost.
Criteria for determining the neoplastic response to treatment
Complete remission (CR): complete disappearance of all tumours.
Tumour-related factors It is necessary to evaluate the location, the malignancy and the stage of the tumour before deciding on the most appropriate treatment, as the criteria will be different. For example, invasive tumours with low metastatic potential require local treatment; for systemic tumours or those with a high metastatic potential, systemic treatment is recommended. In certain tumours (e.g. soft tissue haemangiosarcomas, high grade sarcomas), systemic treatment may be administered if local treatment fails. It is essential to take into account the possible adverse effects when planning the therapy. The patient should feel better with the treatment than with the disease. It is often difficult to choose between palliative and curative treatment; palliative treatment may become curative and vice versa. The best attitude is therefore to treat the initial tumour as aggressively as possible, and then treat depending on response.
Partial remission (PR): > 50 % decrease of the long axis of the tumour.
Stable disease (SD): < 25 % variation of the long axis of the tumour.
Progressive disease (PD): > 25 % increase of the long axis of the tumour.
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Cancer treatments available for dogs and cats Over the past decades, several therapeutic methods have been used in dogs and cats with cancer. However, in recent years, surgery has been the main treatment method in animals. Today, unresectable or metastatic tumours can be treated with one or more modalities described in this chapter, with varying degrees of success.
Surgery The goal is simple: complete removal of the neoplastic cells from the patient. This is obviously easier said than done. Surgery is particularly indicated in localised, accessible, non-invasive masses with a low metastatic potential. It can also be a complementary treatment in certain metastatic or locally highly invasive tumours.
Radiotherapy Mainly indicated for local tumours where surgery needs to be avoided. The main drawback is that special installations and equipment are required. In Europe, there are few centres where veterinary radiotherapy can be performed and the procedure is relatively expensive.
It is applied under general anaesthesia, using a central Broviac-type or peripheral venous catheter, or a mask with gaseous anaesthesia. The duration of each anaesthesia is 3 to 5 minutes.
Chemotherapy In this modality, local or systemic drugs are used with few secondary effects. As mentioned earlier, the term is not popular among pet owners. Chemotherapy has several clinical applications: ■ Sole treatment: some single drugs are able to control or even cure certain tumours without other treatments. This type of chemotherapy is indicated for lymphomas, leukaemias, transmissible venereal tumours and metastatic tumours, for example. ■ As a postoperative adjuvant treatment: in addition to surgery where the complete surgical removal of all neoplastic cells is unlikely, due to a high probability of metastases or to the invasive capacity of the tumour (haemangiosarcoma, osteosarcoma, grade 3 mast cell tumour, etc.). ■ As a neoadjuvant (before and after surgery): this permits surgical treatment of certain tumours that have first been controlled or reduced in size (thyroid carcinoma, poorly differentiated sarcomas, soft tissue haemangiosarcomas, etc.).
Types of surgery depending on the objective Potentially curative surgery: with this technique, it is possible to completely eliminate the cancer by removing all neoplastic cells. It is imperative to know the type of tumour and whether there are any metastases before opting for this technique. If the tumour has spread, no cure can be expected by removing the primary mass; or, if it is highly invasive, it is essential to know beforehand that aggressive surgery is required. For this, advanced imaging techniques are used, such as computerised tomography (CT) and magnetic resonance imaging (MRI). Palliative surgery: removal of the main part of the primary tumour, although traces will remain. Only applicable if the first technique is not feasible; it can be combined with another treatment such as
radiotherapy or postoperative chemotherapy (i.e. adjuvant radiotherapy or chemotherapy). The term palliative surgery is employed if used to improve the quality of life of the patient. Examples: Ulcerating mammary carcinoma with pulmonary metastases: resection of the ulcerated tumour allows an acceptable quality of life for several months until the pulmonary metastases curtail the respiratory capacity of the patient. Apocrine gland adenocarcinomas of the anal sac with sublumbar metastatic lymphadenopathy: the quality of life and the prognosis will improve by removing the primary tumour and the affected lymph nodes. If combined with chemotherapy, survival times of 1 to 3 years can be obtained.
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Oncology immunotherapy This is based on the development of monoclonal antibodies to destroy or identify tumour cells. There is currently no commercial product available, but it has great potential.
Gene therapy and molecular target inhibitors This consists of the introduction of genes into cells to treat or prevent cancer or the selective blockage of the abnormal metabolic steps that neoplastic cells adopt compared to somatic cells. Examples include toceranib and masitinib, which are used to block the c-kit receptor in mast cell tumours and in gastrointestinal stromal tumours.
Practical chemotherapy Tumour kinetics
To better understand the effects of chemotherapy, both in normal and neoplastic tissues, it is necessary to have a basic understanding of cell biology and kinetics of tumour cells, which is similar to that of somatic cells, with the same cycle phases. Mammalian cells have two replication phases, mitosis (M) and a resting phase. The latter can be divided into four phases (graphs 2 and 3): ■ Gap phase 1 (G1): synthesis of RNA and enzymes needed for the production of DNA. ■ Synthesis phase (S): synthesis of DNA. ■ Gap phase 2 (G2): formation of the spindle apparatus. ■ Gap phase 0 (G0): this is the true resting phase, induced by intercellular contact, cellular differentiation and anti-mitotic factors that keep the cells inactive. During this phase, cells can enter the final cellular replication phase or start a new cycle induced by mitogens, growth factors and nutrients, among others.
Somatic cells exhibit contact inhibition, a phenomenon that stops growth. Neoplastic cells, however, continue to divide in spite of contact with neighbouring cells. Neoplastic cells can disappear from the tumour by the following mechanisms: ■ Differentiation (taking on specific characteristics). Very rare in tumours. ■ Apoptosis (programmed cell death). ■ Metastasis (spreading).
Definitions • Mitotic index (MI): numbers of cells in mitosis. Term used in histopathology. • Growth fraction (GF): percentage or proportion of dividing tumour cells. • Doubling time (DT): time needed for the tumour to double its original size.
Graph 2. Cycle phases during which cytostatic drugs are effective. Cells in G0 (resting phase) are usually resistant to chemotherapy, but can be “recruited” into the cycle and become sensitive.
GO
G1
M
R
S
G2
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treatment of the cancer patient
Another point to be taken into account with cell kinetics is that chemotherapy is more effective in relatively small tumours than in large ones, even if the sensitivity to the drug is the same. This is because small
masses have a higher mitotic index, a higher growth fraction and therefore a faster doubling time than larger masses (graphs 4 and 5).
Graph 3. Illustration of the action of each drug on the cell cycle and the duration of each phase.
biotics Anti metabolites Anti S (2-6 h)
G2 (2-32 h) M (0.5-2 h)
Vinca alkaloids Mitotic inhibitors Taxoids
Alkylating agents
G1 (2-∞ h) G0
SURGERy–TREATMENT Logarithm of the number of tumour cells
Growth phase plateau with low Gf and Mi and high DT
Low Gf and Mi; prolonged DT
Graph 5. Tumour growth and clinical detection.
DEATH
GF: Growth fraction; MI: Mitotic index; DT: Doubling time.
Logarithm of the number of tumour cells
1014 1012
108 106
GF: Growth fraction; MI: Mitotic index; DT: Doubling time.
Logarithmic growth phase with high Gf and Mi and low DT
Time
1010
Graph 4. Behaviour of tumour populations.
Neoplastic mass of 1 kg TUMOUR PALPABLE fOR THE fiRST TiME Radiographic or ultrasound diagnosis possible (neoplastic mass of 150 g)
Neoplastic mass of 1 g
104 102
High Gf and Mi, low DT
0 Time
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caninE anD fElinE
Oncology Principles of chemotherapy To understand the mechanism of action in each situation, it is necessary to understand the principles of chemotherapy. In general terms, chemotherapeutic agents kill cells, in particular in rapidly dividing tissues. Chemotherapeutic agents have different applications according to the tumour: ■ Metastatic tumours: chemotherapy is indicated for combating unresectable metastases. ■ Unresectable tumours: chemotherapy is used to treat tumours that cannot be removed and that are resistant to radiotherapy. ■ Systemic tumours (e.g. lymphomas): chemotherapy is the treatment of choice. ■ Systemic chemotherapy: ■ Neoadjuvants: treatment prior to surgery to facilitate the operation and continued postoperatively. ■ Postoperative adjuvants: after surgery, in highly metastatic tumours (osteosarcoma). As a rule, chemotherapy should not be used to replace surgery or radiotherapy. Nor should it be administered to animals with severe multi-organ dysfunction, in view of the high risk of systemic toxicity. If its administration is nevertheless required, it is best done in moderation and at lower doses.
Chemotherapy should not be used to replace surgery or radiotherapy, nor in animals with multi-organ dysfunction.
Routes of administration of chemotherapy can be systemic (intravenous, oral), local or regional. To maximise the effects of chemotherapy, the action of three or more drugs should be combined (fig. 1). These drugs should be chosen according to the following principles: they should all be active against
the tumour to be treated, they should each have a different mode of action and they should not have cumulative toxicity. Protocols are commonly indicated with the initials of the drugs that are included, e.g. VAC: vincristine, adriamycine (doxorubicin) and cyclophosphamide. figure 1. Different drugs with a combined action on the same neoplastic cells.
As a rule, combinations of chemotherapeutic agents produce longer remissions and survival times than single-component therapies as multi-agent chemotherapy delays (and sometimes even prevents) the development of resistance. There are always exceptions: sometimes, single agents are the treatment of choice, e.g. carboplatin or doxorubicin in canine osteosarcoma, chlorambucil in lymphocytic leukaemia in dogs or vincristine in canine transmissible venereal tumours. Although controversial, the dosage of chemotherapeutic agents is still calculated on the basis of the body surface area (BSA), with some exceptions. This method appears to provide a relatively constant metabolic parameter, which permits the comparison of doses between species.
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Formula to calculate the body surface area
Conversion tables also exist (see table 1). For certain drugs such as doxorubicin, the dose calculated on the basis of the body surface area can produce toxicity in small dogs (under 10 kg) and cats. In these cases, it is more appropriate to administer a dose based on weight.
Action mechanism The effects of chemotherapeutic agents on a neoplastic cell population follow the principles of firstorder kinetics, i.e. the number of cells killed by a drug or a combination of drugs is directly proportional to the dose used. Such drugs always remove a constant proportion of cells rather than a constant number. This is why the efficacy of a drug or drug combination depends on the initial number of neoplastic cells. For example, if a combination of chemotherapeutic agents destroys 99 % of cells in a tumour containing 100,000,000 cells, around 1,000,000 viable neoplastic cells will remain. The action mechanism of chemotherapeutic agents is very variable. Those that kill tumour cells during division will not eliminate cells in phase G0. Those that act on the different phases of the cycle are called cell-cycle phase nonspecific drugs. In contrast, those that selectively kill tumour cells in a given phase are called cell-cycle phase specific drugs. Finally, drugs that eliminate cells regardless of their cycle stage are called cell-cycle nonspecific drugs and are extremely myelosuppressive (nitrosoureas) and are rarely used in veterinary medicine.
Weight (g) 2/3 x K
= m2 BSA 104 K= 10.1 for dogs and K= 10 for cats
Table 1. Conversion to body surface area (BSA) in dogs. Body weight (kg)
Body surface area (m2)
Body weight (kg)
Body surface area (m2)
0.5
0.06
26
0.88
1
0.1
27
0.9
2
0.15
28
0.92
3
0.2
29
0.94
4
0.25
30
0.96
5
0.29
31
0.99
6
0.33
32
1.01
7
0.36
33
1.03
8
0.4
34
1.05
9
0.43
35
1.07
10
0.46
36
1.09
11
0.49
37
1.11
12
0.52
38
1.13
13
0.55
39
1.15
14
0.58
40
1.17
15
0.6
41
1.19
16
0.63
42
1.21
17
0.66
43
1.23
18
0.69
44
1.25
19
0.71
45
1.26
20
0.74
46
1.28
21
0.76
47
1.3
22
0.78
48
1.32
23
0.81
49
1.34
24
0.83
50
1.36
From: Manual of Small Animal Internal Medicine, by Richard W. Nelson and C. Guillermo Couto.
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FROM THEORY TO PRACTICE
CANINE AND FELINE
Oncology Common drugs Anticancer drugs are usually classified into six categories. Many are available as generics.
Alkylating agents
Figure 2. Alkylating agents produce cross-linking of DNA.
These drugs produce cross-linking of the DNA thereby inhibiting its duplication (fig. 2). Their action is very similar to that of radiotherapy, which is why they are also called radiomimetics. They are not phase-specific and are more efficient if used intermittently at high doses. The toxicity of these drugs is due to the fact that they cause myelosuppression and gastrointestinal disturbances. Examples: cyclophosphamide, chlorambucil, melphalan, carboplatin and CCNU (lomustine).
Plant alkaloids
Figure 3. Plant alkaloids act by disrupting the spindle apparatus.
These are derived from the periwinkle (Catharantus roseus) and mayapple (Podophyllum peltatum). They act by disrupting the spindle apparatus of mitosis, which is why they are specific to the M phase of the cell cycle (fig. 3). The podophyllum derivatives cause cross-linking of DNA. The danger of these alkaloids is perivascular necrosis if the drug is extravasated. Etoposides should not be administered intravenously as its vehicle (Tween 80) produces anaphylaxis. Examples: vincristine, vinblastine, vinorelbine, etoposide and VP-16.
Antimetabolites Analogues of purines and pyrimidines, which they replace. They are specific to the S-phase of the cell cycle. Their activity is higher if administered repeatedly at low doses or by slow intravenous infusion. Their main toxic effect is myelosuppression and gastrointestinal disorders. Examples: cytosine arabinoside, methotrexate, 5-fluorouracil (this should never be used in cats) and azathioprine.
Figure 4. Antimetabolites substitute purines and pyrimidines.
AGCGGAGTTTCCAGT
Antitumour antibiotics They are not specific to a phase of the cell cycle as their action mechanism is different. They mainly damage the DNA with their free radicals. Their toxic effects are myelosuppression and gastrointestinal disorders.
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