TEXTBOOK OF
`SM ALL ANIMAL
`MEDICINE
`
`Edited by
`John K. Dunn MA, MVetSc, BVM&S, DSAM,
`DipECVIM, MRCVS
`Department of Clinical Veterinary M’edidne
`University of Cambridge, UK
`
`BRITISH LIBRARY
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`- 8 SEP 1999
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`used in the management of human cancers but
`veterinary experience of this technique is limited.
`The main problem with this combination is that
`irradiated soft tissues have poor tolerance of sur-
`gical manipulation and complications with wound
`healing may lead to dehiscence and necrosis.
`Radiation may also be applied to unresectable
`tumours at the time of surgery. Surgical exposure
`of the turnout site and removal of sensitive tissues
`from the treatment field allows the application
`of high doses of radiation to turnouts which
`are otherwise difficult to treat by radiation.
`Intraoperative radiation requires close proximity
`of surgical and radiation facilities and is not com-
`monly practised in the veterinary field although
`the technique has been used in the treatment of a
`number of tumours including canine bladder
`carcinomas (Walker and Breider, 1987; Withrow
`et al., 1989).
`
`~ P RINCIPLES OF ANTICANCER
`
`CHEMOTHERAPY
`
`The use of cytotoxic or anticancer drugs in the
`treatment of cancer is a relatively new branch of
`veterinary medicine. In contrast to surgery and
`radiation which are only effective against local
`neoplastic disease, chemotherapy has the poten-
`tial to act against systemic disease which is a major
`problem in oncology. Many cytotoxic drugs are
`now available for the treatment of human cancers
`and some of the major advances in human cancer
`therapy, for example in the treatment of child-
`hood leukaemias and testicular cancers, have been
`achieved through the use of such drugs. In ani-
`mals, chemotherapy has become established as
`the treatment of choice for lymphoproliferative
`and myeloproliferative diseases and significant
`increases in life expectancy can now be achieved
`in many of these conditions. The use of cytotoxic
`drugs in the treatment of other animal cancers is
`constantly being explored and as more drugs
`become available for veterinary use so the indica-
`tions for chemotherapy in animals are likely to
`expand.
`Cytotoxic drugs are highly potent agents and
`extreme care is required in all aspects of their use.
`Not only do they pose a danger to the patient but
`staff and owners should be aware of the potential
`hazards of exposure to these agents. Guidelines
`for safe handling of cytotoxic drugs are given later
`in this chapter. The therapeutic margin of most
`cytotoxic agents is extremely narrow and toxicity
`is the main dose-limiting factor. In humans, inten-
`
`PRINCIPLES OF ANTICANCER CHEMOTHERAPY ;~ 1005
`
`sive medical care is often necessary to support the
`patient through periods of severe toxicity result-
`ing from aggressive chemotherapy. Such intensive
`care is not routinely available or feasible in
`veterinary medicine and aggressive therapy which
`would result in serious toxicity to the patient also
`raises ethical questions. In veterinary practice
`treatment regimes and dosages are therefore a
`compromise between efficacy and toxicity.
`Careful consideration must always be given to
`the pharmacology and toxicity of the drug, the
`spectrum of its activity and the condition of the
`patient.
`
`Mechanisms of action of cytotoxic
`drugs
`
`Most cytotoxic drugs act on the processes of cell
`growth and division (Fig. 50.20); it therefore fol-
`lows that the growth kinetics of a turnout are a
`major factor governing response to chemother-
`apy. Tumours with a high growth fraction are
`more likely to respond favourably to chemother-
`apy than those with a low growth fraction. The
`proportion of resting (Go) cells is also important
`as these cells are resistant to the actions of
`cytotoxic drugs and therefore govern the ultimate
`response to therapy. Normal tissue toxicity fol-
`lows a similar pattern: organs containing a high
`
`methotrexate ~. / methotrexate
`METABOLITES
`
`mercaptopurine "~
`thioguanme
`
`’~ fluorouraoil
`cytosine
`arabinoside
`
`PURINES
`
`PYRIMIDINES
`
`DNA
`
`¯ ~ DNA REPLICATION
`
`Alkylating agents
`
`Antitumour antibiotics
`
`Platinum compoundy
`
`Vinca alkaloids - - -~ MITOSIS
`
`Figure 50.20 Summary of the mechanisms and sites of
`action of cytotoxic drugs.
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`1006 ~ PRINCIPLES OF CANCER THERAPY
`
`proportion of dividing cells, e.g. bone marrow
`and the gastrointestinal epithelium, are most
`susceptible to drug-induced toxicity. The resting
`stem cel! populations in these tissues are, how-
`ever, relatively resistant to the actions of cytotoxic
`drugs and most cytotoxic drug toxicity is
`reversible.
`Cytotoxic drugs are commonly divided into a
`number of classes each with characteristic sites or
`modes of action, antitumour activity and toxicity
`(see also Table 50.12 and Fig. 50.20).
`
`Table 50.12 Anticancer drugs by group
`
`Alkylating agents
`Nitrogen mustard derivatives
`
`Ethenimine derivatives
`Alkyl sulphonates
`Triazine derivatives
`Nitrosureas
`
`Antimetabolites
`Antifolates
`Pyrimidine analogues
`
`Purine analogues
`
`Antitumour antibiotics
`
`Vinca alkaloids
`
`Cortlcosteroids
`
`Miscellaneous agents
`
`Cyclophosphamide
`Chlorambucil
`Melphalan
`Thiotepa
`Busulphan
`Dacarbazine
`Carmustine
`Lomustine
`
`Methotrexate
`Cytosine arabinoside
`Fluorouracil
`Mercaptopurine
`Thioguanine
`
`Actinomycin D
`Bleomycin
`Daunorubicin
`Doxorubicin
`Epirubicin
`Mitoxantrone
`Mithramycin
`Mitomycin O
`Streptozotocin
`
`Vincristine
`Vinblastine
`
`Prednisolone
`Prednisone
`
`L-Asparaginase/
`cristantaspase
`Cisplatin
`Hydroxyurea
`
`Alkylating agents
`
`Alkylating agents are the most widely used
`cytotoxic agents in veterinary medicine. These
`drugs act by interfering with DNA replication
`and RNA transcription. They substitute alkyl
`radicals (R-CH2-CH_~) for hydrogen atoms in the
`DNA molecule. Alkylation of nucleotide bases
`(e.g. the N7 guanine of DNA) causes breaks,
`cross-linkages and abnormal base pairing in
`DNA. Alkylating agents also react with sul-
`phydryl, phosphate and amino groups causing
`inhibition of enzymes involved in protein and
`nucleic acid synthesis. These actions of the alky-
`lating agents are not cell cycle specific.
`Myelosuppression is the major side effect of these
`drugs, they may affect the gastrointestinal tract
`and can cause anorexia, vomiting and diarrhoea.
`Alkylating agents may also affect gametogenesis
`and cause alopecia in some breeds of dog.
`
`Antimetabolites
`
`Antimetabolites are a group of drugs which inter-
`fere with the normal metabolism of the cell. They
`are generally structural analogues of metabolites
`required for purine and pyrimidine synthesis and
`thus interfere with DNA and RNA synthesis by
`enzyme inhibition or by causing synthesis of non-
`functional molecules. Antimetabolites are cell
`cycle specific, acting during the S phase of the cell
`cycle. These agents all cause myelosuppression
`and may also affect the gastrointestinal tract caus-
`ing anorexia, vomiting and diarrhoea. Renal and
`neurological toxicity are features of individual
`drugs (see individual agents).
`
`Antitumour antibiotics
`Antitumour antibiotics are derived from soil
`fungi, e.g. Streptomyces. These agents act by
`forming stable complexes with DNA thus inhibit-
`ing DNA synthesis and transcription. These
`actions are not cell cycle specific. Antitumour
`antibiotics have a particularly wide spectrum of
`antitumour activity. With the exception of
`bleomycin, antitumour antibiotics are myelosup-
`pressive but they also cause a diverse range of
`selective toxicities (see individual agents).
`
`Vinca a/ka/oids
`The vinca alkaloids are plant alkaloids extracted
`from the periwinkle (Vinca rosea Linn). They
`bind to microtubular proteins (tubulin) and
`inhibit formation of the mitotic spindle, causing a
`metaphase arrest. These agents are thus cell cycle
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`specific, acting during the M phase. Vinca alka-
`loids may have other cytotoxic effects on the ceil
`which are less well documented, for example they
`may cause enzyme inhibition. Tubulin micro-
`tubules are also important in neurotransmission
`therefore neurological toxicity can occur.
`
`Hormones
`
`Hormonal manipulation has an important role in
`the management of breast, prostatic and endome-
`trial carcinomas in humans. Although hormones
`clearly play a role in the development and growth
`of sirnilar turnouts in animals, the therapeutic
`value of hormonal manipulation has yet to be
`clearly demonstrated. Oestrogens and androgen
`antagonists may be of value in the management of
`certain hyperplastic or benign neoplastic condi-
`tions of the prostate and perianal hepatoid glands
`in the dog.
`The cortieosteroids prednisone and pred-
`nisolone are widely used in oncology. They have a
`cytotoxic action on haematological malignancies,
`particularly lymphomas. Their immunosuppres-
`sive activity is valuable in the management of cer-
`tain turnout-related complications and finally,
`they have a role in the palliation of advanced
`disease.
`
`Miscellaneous agents
`
`There are a number of other agents with anti-
`tumour activity which do not fit into the previous
`groups. These include L-asparaginase (Cristan-
`taspase) and platinum coordination compounds.
`Doses of cytotoxic drugs are usually calculated
`as a function of body surface area (in M2) rather
`than body weight because the blood supply to the
`organs responsible for detoxification and excre-
`tion (liver and kidneys) is more closely related to
`surface area than body weight. The calculation of
`body surface area from body weight and con-
`version tables for cats and dogs are provided
`in Appendix I. Details of all cytotoxic drugs
`included in the following text and tables are pro-
`vided in an easy reference format in Appendix II.
`The dose rates, indications and side effects for
`these agents are only intended as an approximate
`guide to the use of these agents and more detailed
`information should be sought prior to their use.
`In the individual patient, the severity of the dis-
`ease, haematological or metabolic complications
`and the presence of concurrent health problems
`must be fully addressed since all may influence the
`prognosis and the ability of the patient to tolerate
`cytotoxic drug therapy. Care must be taken in
`
`PRINCIPLES OF ANTICANCER CHEMOTHERAPY ~! 1_007
`
`patients with compromised renal or hepatic func-
`tion as impaired metabolism and excretion of the
`drug may result in increased toxicity.
`
`The rationale of cytotoxic drug
`administration
`
`The theoretical basis for cytotoxic drug regimes
`used in clinical practice has been established
`through years of laboratory and clinical research
`concerning the interaction of cytotoxic drugs and
`cancer cells in vitro and in vivo. Such work has led
`to the realization that the successful clinical appli-
`cation of cytotoxic drugs demands a different
`approach to that governing the administration of
`antibiotics and other pharmacological agents
`commonly used in practice.
`
`The cell kill hypothesis
`
`One of the most important and basic principles of
`ant:icancer chemotherapy is described by the ’Cell
`Kill Hypothesis’ (Skipper et a!., 1964). This states
`that cytotoxic drugs kill tumour cells by first-
`order kinetics: that is to say that a given dose of a
`cytotoxic drug kills a fixed percentage of the total
`tumour population as opposed to a set number of
`tumour cells. For example, if a given dose of a
`drug A kills 90% of tumour cells then it will
`reduce a tumour cell population of 100 million to
`10 million, but if there are only 100 cells in a
`tumour the same dose of drug A will only reduce
`the number of tumour cells from 100 to 10. This
`theory therefore infers that, even a highly effec-
`tive drug acting on a highly sensitive tumour cell
`population is unlikely to eradicate the tumour cell
`population in a single dose. In most clinical situa-
`tions where tumours are known to be chemo-
`sensitive, a single treatment will achieve a log kill
`of 2 to 4.
`The Cell Kiil Hypothesis is essentially a theo-
`retical model, it assumes a constant rate of growth
`for all tumour cells, that all tumour cells are
`equally chemosensitive and that the drug is
`equally distributed to al! tumour cells. In the clin-
`ical setting these assumptions are not entirely
`accurate for reasons discussed earlier in this chap-
`ter. Furthermore, the toxicity of the drug to the
`patient is a major factor governing the dose of
`drug which can be administered. Nevertheless the
`Cell Kill Hypothesis does form the basis of two
`important principles of chemotherapy:
`
`1. Maximum doses of anticancer drugs should
`always be used where possible.
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`1008 i; PRINCIPLES OF CANCER THERAPY
`
`2. Chemotherapy should be instituted when the
`tumour burden is at its lowest, i.e. when the
`tumour is first detected or, in the treatment of
`micrometastases, following surgical removal of
`the primary turnout.
`
`Chemotherapy is unlikely to be effective if used as
`a last resort for the treatment of extensive and
`advanced disease.
`In clinical practice a single dose of a single
`chemotherapeutic agent is clearly insufficient
`to eradicate a tumour. The most effective
`chemotherapeutic protocols employ a combina-
`tion of cytotoxic agents delivered at timed inter-
`vals.
`
`Single agent versus combination therapy
`
`In most circumstances a combination of cytotoxic
`agents has proved to be more effective in the man-
`agement of cancers than the use of a single agent.
`As a result of turnout cell heterogeneity many
`turnouts contain cells which are inherently resis-
`tant to the actions of certain agents. By bombard-
`ing the tumour with a combination of agents
`which employ different mechanisms of action, the
`overall response can be enhanced. In addition,
`although all cytotoxic drugs have some damaging
`effects on normal tissues, different agents affect
`different normal tissues to varying degrees.
`Hence, if it is possible to combine drugs with dif-
`ferent actions and toxicities, an additive tumorici-
`dal effect can be achieved without an increase in
`toxicity. Most combination drug protocols have
`been designed according to these criteria, for
`example the COAP protocol, widely used in the
`treatment of multicentric lymphoma, employs:
`
`Cyclophosphamide:
`Vincristine:
`Cytarabine:
`Prednisolone:
`
`alkylating agent
`vinca alkaloid
`antimetabolite
`corticosteroid
`
`Dosage and timing of treatments
`
`The Cell Kill Hypothesis infers that it is desirable
`to administer the maximum possible dose of a
`drug to the patient. In practice, however, the dose
`of drug which can be administered is usually lim-
`ited by normal tissue toxicity. In most circum-
`stances the critical norma! tissue is the bone
`marrow and,to a lesser extent the gastrointestinal
`epithelium. Fortunately, these normal tissues have
`a tremendous capacity for recovery from cyto-
`toxic drug damage through processes of cellular
`repair and repopulation from recruitment of rest-
`ing stem cells. In comparison, turnout cell popula-
`
`tions have a reduced capacity for these reparative
`processes. Therefore, it is more beneficial to
`administer a cytotoxic drug at repeated intervals,
`allowing the normal tissues to recover between
`treatments than to use continuous therapy where
`the normal tissues are constantly exposed to the
`drug and unable to repair or repopulate (Fig.
`50.21). The interval between treatments has to be
`carefully timed to allow for recovery of the
`normal tissues without expansion of the residual
`tumour population. If the time interval is too
`short, cumulative toxicity will occur resulting in
`leucopenia and thrombocytopenia, vomiting and
`diarrhoea. If the time interval is too long the
`tumour will repopulate and the benefit of the pre-
`ceding treatment will have been lost.
`Thesplitting of cytotoxic drug treatment into
`short intensive intervals is termed ’pulse’ dosing
`and pulsed combination chemotherapy is now the
`most commonly used technique in the drug treat-
`ment of cancer. Certain chemosensitive turnouts,
`for example lymphomas, often show a remarkable
`response following one or two courses of such
`therapy. Clinically this may be seen as a complete
`regression of the turnout and remission of any
`associated signs. It is important to appreciate that
`a clinical remission is not synonymous with cure.
`A complete clinical remission merely reflects a
`reduction in the turnout cell population from
`to 10" cells and unless treatment is continued there
`
`Cytotoxix drug treatment pulses
`
`treatment treatment treatment
`1 2 3
`
`Normal
`tissue
`
`Time
`
`Figure 50.21 Theoretical basis for administration of
`cytotoxic drugs. If drug treatments can be sequenced to
`allow full recovery of normal tissues between treatments
`the reduced capacity for repair/recovery in the tumour
`results in increasing tumour cell kill.
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`will be a rapid expansion of the residual turnout
`mass resulting in a ’relapse’ of the disease. Even
`the most chemosensitive of tumours usually
`require 6-12 months of aggressive chemotherapy
`to effect a cure.
`
`Indications for chemotherapy in
`veterinary medicine
`
`The main indication for chemotherapy in veteri-
`nary cancer medicine is in the treatment of
`systemic or disseminated malignant disease. In
`practice there are broadly two categories of dis-
`ease where chemotherapy should be considered:
`
`I. In the treatment of lymphoproliferative and
`myeloproliferative diseases which are generally
`systemic in nature;
`2. As an adjunct to surgical and/or radiation
`treatment of the primary malignant tumours
`with a high risk of distant metastatic disease.
`
`L ymphoproliferative and myeloproliferative
`disease
`Definitions
`The term ’lymphoproliferative disease’ is used to
`describe all neoplastic conditions arising from
`lymphoid cells and includes all types of lym-
`phoma (malignant lymphoma, lymphosarcoma),
`myeloma (multiple myeloma, plasma cell
`myeloma) and lymphoid leukaemias.
`The term ’myeloproliferative disease’ describes
`all non-lymphoid neoplastic conditions arising
`from the haemopoietic stem cell and includes all
`non-lymphoid leukaemias (e.g. acute myeloid
`leukaemia, chronic granulocytic or myelogenous
`leukaemia, polycythaemia vera) and primary
`myelofibrosis.
`Chemotherapy is the treatment of choice for
`these conditions because of their systemic or
`widespread nature and because the tumours are
`usually sensitive to a wide range of cytotoxic
`drugs both as a result of a high growth fraction
`and inherent cell sensitivity.
`Lymphoma (synonyms: malignant iymphoma,
`lymphosarcoma)
`The disease
`Lymphoma is the most common haemopoietic
`malignancy encountered in small animal practice,
`accounting for approximately 30% of all feline
`malignancies and 8-10% of all canine malig-
`nancies (Rosenthal, 1982; Priester and MacKay,
`
`PRINCIPLES OF ANTICANCER CHEMOTHERAPY ’~ 1009
`
`1980). The disease is characterized by a malignant
`proliferation of lymphoid cells and may arise in
`any organ containing lymphoid tissues and many
`non-lymphoid tissues, e.g. lymph nodes, thymus,
`alimentary system and skin. Thus different
`anatomic forms of the disease may be recognized
`(Table 50.13). Irrespective .of the site of origin, the
`disease ultimately disseminates to involve other
`lymphoid and non-lymphoid tissues, particularly
`the spleen, liver, lungs and bone marrow. A clini-
`cal staging system can be used to describe the
`extent of the disease as shown in Table 50.14.
`Lymphoma may also be classified according to
`histological parameters, the cell type (e.g. lym-
`phocytic or lymphoblastic) and cel! distribution
`(e.g. nodular or diffuse) and according to the
`immunological type (e.g. T cell, B cell or null cell)
`(Moulton and Harvey, 1990).
`Multicentric lymphoma is the most common
`form of the disease in the dog. Affected patients
`usually present with gross enlargement of one or
`more peripheral or supe,’ficial lymph nodes (Fig.
`50.22). In our referral practice, most patients are
`presented with a generalized lymphadeno-
`pathy with or without hepatic and/or splenic
`involvement (i.e. Stage III or Stage IV disease).
`Approximately 30-50% of dogs presenting with
`
`Table 50.13 Anatomic forms of lymphoma
`
`Muliticentric
`Thymic
`Alimentary
`Cutaneous
`Solitary
`(leukaemia)
`
`Table 50.14 Cfinical staging of canine multicentric
`tymphoma
`
`Stage
`
`Extent
`
`I
`
`II
`
`III
`IV
`
`Involvement limited to a single lymph node or
`lymphoid tissue in a single organ
`Involvement of lymph nodes in a regional area
`+/- tonsils
`Generalized lymph node involvement
`Hepatic and/or splenic involvement (+/- stage III)
`Manifestations in the blood and/or involvement
`of bone marrow and/or other organ systems
`
`From Owen (1980).
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`.IUJI.U ~ t~HII~IUIYLI:::b Ul- UAI~IUI:::K IHI::HAEY
`
`Figure 50.22 Canine multicentric lymphoma. This
`Dobermann was presented with generalized lympha-
`denopathy. The gross enlargement of submandibular
`lymph nodes is typical of that commonly seen in canine
`multicentric lymphoma. See colour plate.
`
`multicentric lymphoma have metabolic or haema-
`tological complications, including dehydration,
`hypercalcaemia, anaemia, thrombocytopenia or
`white blood cell abnormalities. Approximately
`10% of animals are presented in Stage V with
`bone marrow involvement (Dobson and Gorman,
`1993).
`Lymphoma is a common problem in the cat and
`the association with the feline retrovirus feline
`leukaemia virus (FeLV) is well documented
`(Hardy, 1981; Jarrett, 1994). Not all cats present-
`ing with lymphoma are FeLV positive although
`serological and epidemiological evidence suggests
`that FeLV infection and retroviral transformation
`is an important causative agent in the vast major-
`ity of cases. The multicentric form of lymphoma
`is most common in middle-aged cats and approx-
`imately 50% of these cases will be FeLV positive.
`Thymic lymphoma is most common in young
`cats, aged 1-2 years, and 90% of such cases are
`FeLV positive. In elderly cats, the alimentary
`form of the disease is more common and a smaller
`
`Table 50.15 Diagnostic investigation of multicentric lymphoma
`
`Procedure
`
`Comment
`
`Lymph node aspirate or biopsy
`
`Haematological evaluation
`
`Biochemical ’screen’
`
`Essential
`for diagnosis and classification of disease
`
`Essential
`full haematological evaluation includes:
`RBC, WBC and platelet counts
`RBC parameters
`differential WBC count
`
`Essential
`screen should include:
`urea, creatinine,
`alkaline phosphatase, alanine
`aminotransferase (ALT), aspartate
`aminotransferase (AST), & gamma
`glutamyl transferase (GGT),
`glucose and
`electrolytes (Na, K, Ca)
`
`Radiography
`thorax and abdomen
`
`Important
`if anima! has respiratory signs or if there is
`evidence of organomegaly
`
`Ultrasonography
`liver and spleen
`
`Useful
`if animal has hepato/splenomegaly
`
`Bone marrow aspirate or biopsy
`
`Indicated
`in the case of haematological abnormalities
`
`FeLWFIV status
`
`Essential
`in cats
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`PRINCIPLES OF ANTICANCER CHEMOTHERAPY ~ 1011
`
`proportion (approximately 35%) of these cases
`are FeLV positive (Jarrett, 1994). The FeLV status
`of an affected cat does not in itself affect treatment
`of that case although clearly there are ethical con-
`siderations if the cat is likely to come into contact
`with other, non-affected animals and the progno-
`sis is worse for cats that are FeLV positive.
`
`The diagnosis of any form of lymphoma depends
`on the demonstration of malignant lymphoid ceils
`by cytological or histological examination of
`affected tissues. Although the clinica! presenta-
`tion and history may be strongly suggestive of a
`diagnosis of lymphoma, particularly in the multi-
`centric form of the disease, histological or cyto-
`logical confirmation of the disease is essential.
`Further investigations are necessary to establish
`the extent of the disease and determine whether
`there are any turnout-related complications. The
`minimum requirements for the full investigation
`of a suspected case of lymphoma are summarized
`
`in Table 50.15. Although these investigations
`entail some time and expense, the future manage-
`ment of the case depends on the disease being cor-
`rectly diagnosed and staged from the outset. Any
`tumour-related complications should be identi-
`fied and treated appropriately at this time.
`
`Therapy of lymph0ma
`Without treatment lymphoma is usually rapidly
`fatal and average survival times of 6-8 weeks are
`the norm. However, in both cats and dogs, lym-
`phoma generally responds well to cytotoxic drug
`therapy (Rosenthal and MacEwan, 1990). A vari-
`ety of chemotherapeutic protocols have been used
`in the treatment of canine lymphoma, many of
`which can also be used in the cat (Table 50.16;
`MacEwan et al., 1981; Madewell, 1985; Carter et
`al., 1987; Cotter and Goldstein, 1987; Postorino et
`al., 1989). In general, combination chemotherapy
`is more successful than single agent therapy but
`the results of treatment do not differ substantially
`with the different chemotherapeutic regimes
`
`:s
`
`n
`
`.a
`
`g
`"e
`Y
`
`Table 50.16 Chemotherapeutic protocols used in the treatment of canine
`lymphoma
`
`C.O.P. (high dose)
`Cyclophosphamide: 250-300 mg m-2 p.o. every 21 days
`Vincristine: 0.75 mg m-2 i.v. every 7 days for 4 weeks, then every 21 days
`Prednisolone: 1 mg kg-1 daily p.o. for 4 weeks then on alternate days
`
`C.O.P.A.
`As above but with:
`Doxorubicin: 30 mg m4 i.v. in place of cyclophosphamide every 9th week
`Cyclic combination therapy
`Vincristine: 0,75 mg m-2 iv. days 1 and 14
`Asparaginase: 400 IU kg-1 i.m. day 1
`Cyclophosphamide: 200-250 mg m-~ p.o. day 7
`Methotrexate: 0.6-0.8 mg kg4 i,v. day 21
`Repeat cycle every 4 weeks except asparaginase (given for rescue only)
`Chlorambucil may be used in place of cyclophosphamide for maintenance
`
`C.O.A.P.
`Cyclophosphamide: 50 mg m4 p.o. every 48 h or on first 4 days of each week
`Vincristine: 0.5 mg m-2 i.v. every 7 days
`Prednisolone: 40 mg m-2 p.o. daily for 7 days then 20 mg m-2 every 48 h
`Cytarabine: 100 mg m4 i.v. daily on days 1-4
`Maintenance: after minimum of 8 weeks, reduce above to alternate week treat-
`ment
`Chlorambucil or melphalan may be used in place of cyctophosphamide
`Doxorubicin or asparaginase may be used for rescue.
`
`C:O.P. (low dose)
`As for C,O.A.P. omitting cytarabine on days 1-4
`Doxorubicin - single agent
`Doxorubicin 30 mg m-2 i.v. every 3 weeks
`
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`

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`1012CII PRINCIPLES OF CANCER THERAPY
`
`Table 50.17 Clinical response to chemotherapeutic protocols used in the treatment of canine
`lymphoma
`
`,Remission time rather than overail survival time.
`bOverall response rate, i.e. complete and partial response rate.
`
`(Table 50.17). Whichever chemotherapy protocol
`is used approximately 70-80% of dogs with mul-
`ticentric lymphoma wil! achieve a partial or com-
`plete clinical remission with average periods of
`remission in the order of 6-9 months. Overall sur-
`vival times range from several weeks (in non-
`responding cases) to several years. Other forms of
`canine lymphoma may vary in their response to
`chemotherapy. Primary cutaneous lymphoma,
`for example, is a highly aggressive tumour and
`although the initial response to therapy may be
`favourable, this is usually short-lived.
`In cats most forms of lymphoma respond to
`therapy; the multicentric and mediastinal forms
`are the most treatable with response rat~s in the
`order of 90% and remission times of 5-6 months
`(Cotter, 1983). In both cats and dogs, treatment of
`the alimentary form of lymphoma is often prob-
`lematic. By the time the diagnosis is achieved the
`disease has often infiltrated large areas of bowel.
`Regression of the turnout in respons~ to treat-
`ment does not necessaril~ result in restoration of
`normal bowel anatomy and function. Indeed, the
`rapid removal of lymphoma tissue from the
`intestines can lead to ulceration and perforation.
`The same problems may be encountered in the
`treatment of renal lymphoma in cats.
`In practice the selection of a.treatment protocol
`should be based upon the experience of the clini-
`cian, cost and the facilities available for monitor-
`ing and treating the patient. The C.O.P.i~o~, do,02
`protocol is widely used because it causes minimal
`patient toxicity, the drugs are simple to administer
`and are relatively inexpensive. Great care must be
`taken in the administration of Doxorubicin to cats
`
`and for this reason the C.O.P. or C.O.A.P. proto-
`cols are favoured in this species.
`Corticosteroids are included in many of the
`protocols for the treatment of lymphoma because
`of their cytotoxic effect on lymphoid cells. The
`sole use of corticosteroids will result in a signifi-
`cant regression of the disease in many instances
`but this response is usually short-lived.
`Corticosteroids are therefore a useful means of
`achieving short-term palliation of lymphoma and
`this approach may be indicated in cases where
`combined chemotherapy is not feasible or appro-
`priate. Pretreatment with corticosteroids is not
`advisable, however, in cases where combined
`chemotherapy is to be used. The administration of
`corticosteroids before the initial work-up of the
`case can complicate the diagnosis and interpreta-
`tion of laboratory results. Furthermore, it has
`been shown that cases which have received prior
`.treatment with corticosteroids have significantly
`lower initial response rates and lower survival
`times than previously untreated cases (Dobson
`and Gorman, 1994).
`
`The leukaemias
`The. term ’leukaemia’ is applied to neoplastic con-
`ditions involving the bone marrow which arise
`from transformation of haemopoietic stem cells
`and result in leukaemia of the granulocytic, mono-
`cytic, erythroid and megakaryocytic as well as of
`the lymphoid cell series (Evans and Gorman, 1987;
`Sawyers et al., !990). The terms ’acute’ and
`’chronic’ are often used to describe the type or
`degree of cellular maturation of the leukaemia.
`’Acute’ refers to leukaemias of immature and
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